H UUUUUUUUUU US009795140B2

( 12 ) United States Patent Martin et al .

( 10 ) Patent No . : US 9 , 795 , 140 B2 ( 45 ) Date of Patent : * Oct . 24 , 2017

( 54 ) MOLECULES HAVING PESTICIDAL UTILITY , AND INTERMEDIATES , COMPOSITIONS , AND PROCESSES , RELATED THERETO

( 2013 . 01 ) ; AOIN 43 / 707 ( 2013 . 01 ) ; AOIN 43 / 82 ( 2013 . 01 ) ; AOIN 43 / 90 ( 2013 . 01 ) ; C07C

233 / 63 ( 2013 . 01 ) ; C07C 233 / 65 ( 2013 . 01 ) ; C07C 237 / 22 ( 2013 . 01 ) ;

( Continued ) Field of Classification Search None See application file for complete search history .

( 71 ) Applicant : Dow AgroSciences LLC , Indianapolis , IN ( US )

( 58 )

( 72 ) ( 56 ) References Cited

U . S . PATENT DOCUMENTS 7 , 754 , 717 B2 * 7 / 2010 Dimauro . . . . . . . . . . . . . . CO7D 213 / 75

514 / 248 8 , 067 , 599 B2 * 11 / 2011 Honold . . . . . . . . . . . . C07D 471 / 04

546 / 113

( Continued )

Inventors : Timothy P . Martin , Noblesville , IN ( US ) ; Joseph D . Eckelbarger , Carmel , IN ( US ) ; Ronald Ross , Jr . , Zionsville , IN ( US ) ; Kyle DeKorver , Grandville , MI ( US ) ; Ronald J . Heemstra , Fishers , IN ( US ) ; Daniel I . Knueppel , Zionsville , IN ( US ) ; Peter Vednor , Carmel , IN ( US ) ; Ricky Hunter , Westfield , IN ( US ) ; David A . Demeter , Fishers , IN ( US ) ; Tony K . Trullinger , Westfield , IN ( US ) ; Erich Baum , Greenwood , IN ( US ) ; Zoltan Benko , Indianapolis , IN ( US ) ; Nakyen Choy , Carmel , IN ( US ) ; Gary Crouse , Noblesville , IN ( US ) ; John F . Daeuble , Sr . , Carmel , IN ( US ) ; Fangzheng Li , Carmel , IN ( US ) ; Jeff Nissen , Indianapolis , IN ( US ) ; Michelle Riener , Newtonville , MA ( US ) ; Tom Sparks , Greenfield , IN ( US ) ; Frank Wessels , Indianapolis , IN ( US ) ; Maurice Yap , Zionsville , IN ( US )

FOREIGN PATENT DOCUMENTS WO wo

2016168056 Al 2016168058 A1 2016168059 A1

10 / 2016 10 / 2016 10 / 2016 WO

OTHER PUBLICATIONS A . E . Sheshenev , et . al . : “ Generation and stereoselective transfor mations of 3 - phenylcyclopropene ” , Tetrahedron , vol . 65 , No . 48 , Sep . 30 , 2009 , pp . 10036 to 10046 , Elsevier Science Publishers , Amsterdam , NL

( 73 ) Assignee : Dow AgroSciences LLC , Indianapolis , IN ( US )

Primary Examiner — Brian J Davis ( 74 ) Attorney , Agent , or Firm — Carl D . Corvin

( * ) Notice : Subject to any disclaimer , the term of this patent is extended or adjusted under 35 U . S . C . 154 ( b ) by 0 days . This patent is subject to a terminal dis claimer .

( 57 ) ABSTRACT This disclosure relates to the field of molecules having pesticidal utility against pests in Phyla Arthropoda , Mol lusca , and Nematoda , processes to produce such molecules , intermediates used in such processes , pesticidal composi tions containing such molecules , and processes of using such pesticidal compositions against such pests . These pes ticidal compositions may be used , for example , as acari cides , insecticides , miticides , molluscicides , and nemati cides . This document discloses molecules having the following formula ( “ Formula One ” ) .

( 21 ) Appl . No . : 15 / 092 , 646 ( 22 ) Filed : Apr . 7 , 2016 ( 65 ) Prior Publication Data

US 2016 / 0302418 A1 Oct . 20 , 2016 Formula One

R 12 Related U . S . Application Data

( 60 ) Provisional application No . 62 / 148 , 818 , filed on Apr . 17 , 2015 , provisional application No . 62 / 148 , 824 ,

( Continued ) R ! !

R R8 Qi R13 R8 R 15 M -

Z

R 16

T ' Ro R9 R10 R 14 R14 2 ( 51 ) Int . Ci .

AOIN 53 / 00 ( 2006 . 01 ) AOIN 43 / 90 ( 2006 . 01 )

( Continued ) ( 52 ) U . S . CI .

CPC . . . . . . . . . . . . . AOIN 53 / 00 ( 2013 . 01 ) ; AOIN 37 / 22 ( 2013 . 01 ) ; AOIN 37 / 34 ( 2013 . 01 ) ; AOIN 41 / 10 ( 2013 . 01 ) ; AOIN 43 / 40 ( 2013 . 01 ) ;

A01N 43760 ( 2013 . 01 ) ; A01N 437653 20 Claims , No Drawings

US 9 , 795 , 140 B2 Page 2

Related U . S . Application Data filed on Apr . 17 , 2015 , provisional application No . 62 / 148 , 830 , filed on Apr . 17 , 2015 , provisional ap plication No . 62 / 148 , 837 , filed on Apr . 17 , 2015 , provisional application No . 62 / 148 , 809 , filed on Apr . 17 , 2015 , provisional application No . 62 / 148 , 814 , filed on Apr . 17 , 2015 .

( 51 ) Int . Ci . CO7D 207 / 273 AOIN 43 / 82 C07D 307 33 CO7D 277 / 36 CO7D 263 / 26 C07D 261 / 12 C07D 333 / 48 CO7D 307 / 52 CO7D 27730 CO7D 213 / 56 C07C 237 / 22 CO7D 333 / 60 CO7D 233 / 80 CO7D 487 / 04 AOIN 43 / 707 AOIN 43 / 653 AOIN 43 / 60 AOIN 43 / 40 AOIN 41 / 10 A01N 37 / 34 AOIN 37 / 22 CO7D 253 / 07 CO7D 241 / 20 C07C 317 / 14 C07C 233 / 65 C07C 233 / 63 CO7D 209749 C07C 381 / 10 C07D 205 / 04 C07C 237 / 42 C070 207 / 10 C070 207452 C07C 255 / 29 C07C 255 / 57 CO7D 285 / 06 C07D 295 / 32 C07D 305 / 08 C07C 255 / 46 CO7D 213 / 75 C07C 255 / 60 C07C 259 / 10 CO7D 213 / 81 CO7D 213 / 84 CO7D 309 / 14 CO7D 213 / 89 C07D 215 / 227 C07C 271 / 28 C07C 271 / 66 CO7D 231 / 12 CO7D 331 / 04 CO7D 231 / 56

( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 ) ( 2006 . 01 )

C07D 333 / 36 ( 2006 . 01 ) CO7D 233 / 36 ( 2006 . 01 ) C07C 311 / 08 ( 2006 . 01 ) C07C 311 / 46 ( 2006 . 01 ) C07D 235 / 30 ( 2006 . 01 ) C07C 317 / 28 ( 2006 . 01 ) C07C 317 / 40 ( 2006 . 01 ) C07C 317 / 50 ( 2006 . 01 ) C07C 323 / 41 ( 2006 . 01 ) C07C 323 / 42 ( 2006 . 01 ) C07C 323 / 59 ( 2006 . 01 ) C07D 249 / 08 ( 2006 . 01 ) CO7C 331 / 12 ( 2006 . 01 ) C07D 215 / 38 ( 2006 . 01 )

( 52 ) U . S . CI . CPC . . . . . . . . . . C07C 237742 ( 2013 . 01 ) ; C07C 255 / 29

( 2013 . 01 ) ; C07C 255 / 46 ( 2013 . 01 ) ; C07C 255 / 57 ( 2013 . 01 ) ; C07C 255 / 60 ( 2013 . 01 ) ;

C07C 259 / 10 ( 2013 . 01 ) ; C07C 271 / 28 ( 2013 . 01 ) ; C07C 271 / 66 ( 2013 . 01 ) ; C07C 311 / 08 ( 2013 . 01 ) ; C07C 311 / 46 ( 2013 . 01 ) ;

C07C 317 / 14 ( 2013 . 01 ) ; C07C 317 / 28 ( 2013 . 01 ) ; C07C 317 / 40 ( 2013 . 01 ) ; C07C 317 / 50 ( 2013 . 01 ) ; C07C 323 / 41 ( 2013 . 01 ) ;

C07C 323 / 42 ( 2013 . 01 ) ; C07C 323 / 59 ( 2013 . 01 ) ; C07C 331 / 12 ( 2013 . 01 ) ; C07C 381 / 10 ( 2013 . 01 ) ; C07D 205 / 04 ( 2013 . 01 ) ;

CO7D 207 / 10 ( 2013 . 01 ) ; C070 207 / 273 ( 2013 . 01 ) ; CO7D 207 / 452 ( 2013 . 01 ) ; C07D 209 / 49 ( 2013 . 01 ) ; CO7D 213 / 56 ( 2013 . 01 ) ;

C07D 213 / 75 ( 2013 . 01 ) ; C07D 213 / 81 ( 2013 . 01 ) ; C07D 213 / 84 ( 2013 . 01 ) ; C07D

213 / 89 ( 2013 . 01 ) ; C07D 215 / 227 ( 2013 . 01 ) ; CO7D 215 / 38 ( 2013 . 01 ) ; C07D 231 / 12

( 2013 . 01 ) ; C07D 231 / 56 ( 2013 . 01 ) ; C07D 233 / 36 ( 2013 . 01 ) ; C07D 233 / 80 ( 2013 . 01 ) ;

C07D 235 / 30 ( 2013 . 01 ) ; C07D 241 / 20 ( 2013 . 01 ) ; C07D 249 / 08 ( 2013 . 01 ) ; C07D 253 / 07 ( 2013 . 01 ) ; C07D 261 / 12 ( 2013 . 01 ) ;

C07D 263 / 26 ( 2013 . 01 ) ; C07D 277 / 30 ( 2013 . 01 ) ; C07D 277136 ( 2013 . 01 ) ; C07D 285 / 06 ( 2013 . 01 ) ; C07D 295 / 32 ( 2013 . 01 ) ;

C07D 305 / 08 ( 2013 . 01 ) ; C07D 307 / 33 ( 2013 . 01 ) ; C070 307 / 52 ( 2013 . 01 ) ; C07D 309 / 14 ( 2013 . 01 ) ; CO7D 331 / 04 ( 2013 . 01 ) ;

CO7D 333 / 36 ( 2013 . 01 ) ; CO7D 333 / 48 ( 2013 . 01 ) ; C07D 333 / 60 ( 2013 . 01 ) ; C07D

487 / 04 ( 2013 . 01 ) ; C07C 2601 / 02 ( 2017 . 05 ) ; C07C 2601 / 04 ( 2017 . 05 ) ; C07C 2601 / 08

( 2017 . 05 ) ; C07C 2601 / 14 ( 2017 . 05 ) ( 56 ) References Cited

U . S . PATENT DOCUMENTS 8 , 492 , 404 B2 *

2002 / 0068838 AL 2014 / 0171308 A1

7 / 2013 Martin . . . . . . . . . . . . . . . . CO7D 213 / 75 514 / 313

6 / 2002 Demassey et al . 6 / 2014 Lo et al .

* cited by examiner

US 9 , 795 , 140 B2

5

MOLECULES HAVING PESTICIDAL It is noted that gastropods ( slugs and snails ) are pests of UTILITY , AND INTERMEDIATES , less economic importance than other arthropods or nema COMPOSITIONS , AND PROCESSES , todes , but in certain places , they may reduce yields substan

RELATED THERETO tially , severely affecting the quality of harvested products , as well as , transmitting human , animal , and plant diseases .

CROSS - REFERENCES TO RELATED While only a few dozen species of gastropods are serious APPLICATIONS regional pests , a handful of species are important pests on a

worldwide scale . In particular , gastropods affect a wide This application claims the benefit of , and priority from , variety of agricultural and horticultural crops , such as ,

U . S . provisional application Ser . Nos . 62 / 148 . 830 ; 62 / 148 . 10 arable , pastoral , and fiber crops ; vegetables ; bush and tree 837 ; 62 / 148 , 809 ; 62 / 148 , 814 ; 62 / 148 , 818 ; and 62 / 148 , 824 ; fruits ; herbs ; and ornamentals ( Speiser ) . all of which were filed on Apr . 17 , 2015 . The entire contents Termites cause damage to all types of private and public

structures , as well as to agricultural and forestry resources . of all of the above - identified applications are hereby incor porated by reference into this Application . In 2005 , it was estimated that termites cause over US $ 50

15 billion in damage worldwide each year ( Korb ) . FIELD OF THIS DISCLOSURE Consequently , for many reasons , including those men

tioned above , there is an on - going need for the costly ( estimated to be about US $ 256 million per pesticide in This disclosure relates to the field of molecules having 2010 ) , time - consuming ( on average about 10 years per pesticidal utility against pests in Phyla Arthropoda , Mol - 20 20 pesticide ) , and difficult , development of new pesticides lusca , and Nematoda , processes to produce such molecules , ( CropLife America ) . intermediates used in such processes , pesticidal composi

tions containing such molecules , and processes of using CERTAIN REFERENCES CITED IN THIS such pesticidal compositions against such pests . These pes DISCLOSURE ticidal compositions may be used , for example , as acari - 25 cides , insecticides , miticides , molluscicides , and nemati CropLife America , The Cost of New Agrochemical Prod cides . uct Discovery , Development & Registration , and Research

& Development predictions for the Future , 2010 . BACKGROUND OF THIS DISCLOSURE Drewes , M . , Tietjen , K . , Sparks , T . C . , High - Throughput

30 Screening in Agrochemical Research , Modern Methods in “ Many of the most dangerous human diseases are trans - Crop Protection Research , Part I , Methods for the Design

mitted by insect vectors ” ( Rivero et al . ) . " Historically , and Optimization of New Active Ingredients , Edited by malaria , dengue , yellow fever , plague , filariasis , louse - borne Jeschke , P . , Kramer , W . , Schirmer , U . , and Matthias W . , p . typhus , trypanomiasis , leishmaniasis , and other vector borne 1 - 20 , 2012 . diseases were responsible for more human disease and death 35 Gubler , D . , Resurgent Vector - Borne Diseases as a Global in the 17th through the early 20th centuries than all other Health Problem , Emerging Infectious Diseases , Vol . 4 , No . causes combined ” ( Gubler ) . Vector - borne diseases are 3 , p . 442 - 450 , 1998 . responsible for about 17 % of the global parasitic and infec - Korb , J . , Termites , Current Biology , Vol . 17 , No . 23 , tious diseases . Malaria alone causes over 800 , 000 deaths a 2007 . year , 85 % of which occur in children under five years of age . 40 Matthews , G . , Integrated Vector Management : Control Each year there are about 50 to about 100 million cases of ling Vectors of Malaria and Other Insect Vector Borne dengue fever . A further 250 , 000 to 500 , 000 cases of dengue Diseases , Ch . 1 , p . 1 , 2011 . hemorrhagic fever occur each year ( Matthews ) . Vector con - Nicol , J . , Turner S . , Coyne , L . , den Nijs , L . , Hocksland , trol plays a critical role in the prevention and control of L . , Tahna - Maafi , Z . , Current Nematode Threats to World infectious diseases . However , insecticide resistance , includ - 45 Agriculture , Genomic and Molecular Genetics of Plant ing resistance to multiple insecticides , has arisen in all insect Nematode Interactions , p . 21 - 43 , 2011 . species that are major vectors of human diseases ( Rivero et Pimental , D . , Pest Control in World Agriculture , Agricul al . ) . Recently , more than 550 arthropod species have devel tural Sciences — Vol . II , 2009 . oped resistance to at least one pesticide ( Whalon et al . ) . Rivero , A . , Vezilier , J . , Weill , M . , Read , A . , Gandon , S . , Furthermore , the cases of insect resistance continue to 50 Insect Control of Vector - Borne Diseases : When is Insect exceed by far the number of cases of herbicide and fungicide Resistance a Problem ? Public Library of Science Pathogens , resistance ( Sparks et al . ) . Vol . 6 , No . 8 , p . 1 - 9 , 2010 .

Each year insects , plant pathogens , and weeds , destroy Sparks T . C . , Nauen R . , IRAC : Mode of action classifi more than 40 % of all food production . This loss occurs cation and insecticide resistance management , Pesticide despite the application of pesticides and the use of a wide 55 Biochemistry and Physiology ( 2014 ) available online 4 Dec . array of non - chemical controls , such as , crop rotations , and 2014 . biological controls . If just some of this food could be saved , Speiser , B . , Molluscicides , Encyclopedia of Pest Man it could be used to feed the more than three billion people in to feed the more than three billion people in agement , Ch . 219 , p . 506 - 508 , 2002 . the world who are malnourished ( Pimental ) . Whalon , M . , Mota - Sanchez , D . , Hollingworth , R . , Analy

Plant parasitic nematodes are among the most widespread 60 sis of Global Pesticide Resistance in Arthropods , Global pests , and are frequently one of the most insidious and Pesticide Resistance in Arthropods , Ch . 1 , p . 5 - 33 , 2008 . costly . It has been estimated that losses attributable to nematodes are from about 9 % in developed countries to DEFINITIONS USED IN THIS DISCLOSURE about 15 % in undeveloped countries . However , in the United States of America a survey of 35 States on various 65 The examples given in these definitions are generally crops indicated nematode - derived losses of up to 25 % non - exhaustive and must not be construed as limiting this ( Nicol et al . ) . disclosure . It is understood that a substituent should comply

US 9 , 795 , 140 B2

with chemical bonding rules and steric compatibility con - hydroxamic acid , benzomate , benzophosphate , benzothiadi straints in relation to the particular molecule to which it is azole , benzovindiflupyr , benzoximate , benzoylprop , benz attached . These definitions are only to be used for the thiazuron , benzuocaotong , benzyl benzoate , benzyladenine , purposes of this disclosure . berberine , beta - cyfluthrin , beta - cypermethrin , bethoxazin ,

The phrase " active ingredient ” means a material having 5 BHC , bialaphos , bicyclopyrone , bifenazate , bifenox , bifen activity useful in controlling pests , and / or that is useful in thrin , bifujunzhi , bilanafos , binapacryl , bingqingxiao , bio helping other materials have better activity in controlling allethrin , bioethanomethrin , biopermethrin , bioresmethrin , pests , examples of such materials include , but are not limited biphenyl , bisazir , bismerthiazol , bismerthiazol - copper , bis to , acaricides , algicides , antifeedants , avicides , bactericides , phenylmercury methylenedi ( x - naphthalene - y - sulphonate ) , bird repellents , chemosterilants , fungicides , herbicide safen - 10 bispyribac , bistrifluron , bisultap , bitertanol , bithionol , bix ers , herbicides , insect attractants , insect repellents , insecti afen , blasticidin - S , borax , Bordeaux mixture , boric acid , cides , mammal repellents , mating disrupters , molluscicides , boscalid , BPPS , brassinolide , brassinolide - ethyl , brevi nematicides , plant activators , plant growth regulators , comin , brodifacoum , brofenprox , brofenvalerate , brofla rodenticides , synergists , and virucides ( see alanwood . net ) . nilide , brofluthrinate , bromacil , bromadiolone , bromchlo Specific examples of such materials include , but are not 15 phos , bromethalin , bromethrin , bromfenvinfos , limited to , the materials listed in active ingredient group bromoacetamide , bromobonil , bromobutide , bromociclen , alpha . bromocyclen , bromo - DDT , bromofenoxim , bromofos , bro

The phrase " active ingredient group alpha ” ( hereafter m omethane , bromophos , bromophos - ethyl , bromopropylate , “ AIGA ” ) means collectively the following materials : bromothalonil , bromoxynil , brompyrazon , bromuconazole ,

( 1 ) ( 3 - ethoxypropyl ) mercury bromide , 1 , 2 - dibromoeth - 20 bronopol , BRP , BTH , bucarpolate , bufencarb , buminafos , ane , 1 , 2 - dichloroethane , 1 , 2 - dichloropropane , 1 , 3 - dichloro bupirimate , buprofezin , Burgundy mixture , busulfan , busul propene , 1 - MCP , 1 - methylcyclopropene , 1 - naphthol , 2 - OC phan , butacarb , butachlor , butafenacil , butam , butamifos , tylthio ) ethanol , 2 , 3 , 3 - TPA , 2 , 3 , 5 - tri - iodobenzoic acid , 2 , 3 , butane - fipronil , butathiofos , butenachlor , butene - fipronil , 6 - TBA , 2 , 4 , 5 - T , 2 , 4 , 5 - TB , 2 , 4 , 5 - TP , 2 , 4 - D , 2 , 4 - DB , 2 , 4 - butethrin , buthidazole , buthiobate , buthiuron , butifos , buto DEB , 2 . 4 - DEP , 2 , 4 - DES , 2 , 4 - DP , 2 , 4 - MCPA , 2 , 4 - MCPB , 25 carboxim , butonate , butopyronoxyl , butoxycarboxim , butra 2iP , 2 - methoxyethylmercury chloride , 2 - phenylphenol , 3 , 4 lin , butrizol , butroxydim , buturon , butylamine , butylate , DA , 3 , 4 - DB , 3 , 4 - DP , 3 , 6 - dichloropicolinic acid , 4 - amin - butylchlorophos , butylene - fipronil , cacodylic acid , cadusa opyridine , 4 - CPA , 4 - CPB , 4 - CPP , 4 - hydroxyphenethyl alco - fos , cafenstrole , calciferol , calcium arsenate , calcium chlo hol , 8 - hydroxyquinoline sulfate , rate , calcium cyanamide , calcium cyanide , calcium polysul 8 - phenylmercurioxyquinoline , abamectin , abamectin - amin - 30 fide , calvinphos , cambendichlor , camphechlor , camphor , omethyl , abscisic acid , ACC , acephate , acequinocyl , acet - captafol , captan , carbam , carbamorph , carbanolate , carbaril , amiprid , acethion , acetochlor , acetofenate , acetophos , aceto - carbaryl , carbasulam , carbathion , carbendazim , carbenda prole , acibenzolar , acifluorfen , aclonifen , ACN , acrep , zol , carbetamide , carbofenotion , carbofuran , carbon disul acrinathrin , acrolein , acrylonitrile , acypetacs , afidopyropen , fide , carbon tetrachloride , carbonyl sulfide , carbopheno afoxolaner , alachlor , alanap , alanycarb , albendazole , aldi - 35 thion , carbophos , carbosulfan , carboxazole , carboxide , carb , aldicarb sulfone , aldimorph , aldoxycarb , aldrin , carboxin , carfentrazone , carpropamid , cartap , carvacrol , car allethrin , allicin , allidochlor , allosamidin , alloxydim , allyl vone , CAVP , CDAA , CDEA , CDEC , cellocidin , CEPC , alcohol , allyxycarb , alorac , alpha - cypermethrin , alpha - en - ceralure , cerenox , cevadilla , Cheshunt mixture , chinalphos , dosulfan , alphamethrin , altretamine , aluminium phosphide , chinalphos - methyl , chinomethionat , chinomethionate , chi aluminum phosphide , ametoctradin , ametridione , ametryn , 40 ralaxyl , chitosan , chlobenthiazone , chlomethoxyfen , chlo ametryne , amibuzin , amicarbazone , amicarthiazol , amidi ralose , chloramben , chloramine phosphorus , chlorampheni thion , amidoflumet , amidosulfuron , aminocarb , aminocyc - col , chloraniformethan , chloranil , chloranocryl , lopyrachlor , aminopyralid , aminotriazole , amiprofos chlorantraniliprole , chlorazifop , chlorazine , chlorbenside , methyl , amiprophos , amiprophos - methyl , amisulbrom , chlorbenzuron , chlorbicyclen , chlorbromuron , chlorbufam , amiton , amitraz , amitrole , ammonium sulfamate , amobam , 45 chlordane , chlordecone , chlordimeform , chlorempenthrin , amorphous silica gel , amorphous silicon dioxide , ampropy . chloretazate , chlorethephon , chlorethoxyfos , chloreturon , lfos , AMS , anabasine , ancymidol , anilazine , anilofos , ani - chlorfenac , chlorfenapyr , chlorfenazole , chlorfenethol , chlo suron , anthraquinone , antu , apholate , aramite , arprocarb , rfenidim , chlorfenprop , chlorfenson , chlorfensulphide , chlo arsenous oxide , asomate , aspirin , asulam , athidathion , atra - rfenvinphos , chlorfenvinphos - methyl , chlorfluazuron , chlo ton , atrazine , aureofungin , avermectin B1 , AVG , aviglycine , 50 rflurazole , chlorflurecol , chlorfluren , chlorflurenol , azaconazole , azadirachtin , azafenidin , azamethiphos , azidi - chloridazon , chlorimuron , chlorinate , chlor - IPC , chlorme thion , azimsulfuron , azinphosethyl , azinphos - ethyl , azin - phos , chlormequat , chlormesulone , chlormethoxynil , chlo phosmethyl , azinphos - methyl , aziprotryn , aziprotryne , rnidine , chlornitrofen , chloroacetic acid , chlorobenzilate , azithiram , azobenzene , azocyclotin , azothoate , azox - chlorodinitronaphthalenes , chlorofénizon , chloroform , chlo ystrobin , bachmedesh , barban , barbanate , barium hexafluo - 55 romebuform , chloromethiuron , chloroneb , chlorophacinone , rosilicate , barium polysulfide , barium silicofluoride , bar chlorophos , chloropicrin , chloropon , chloropropylate , chlo thrin , basic copper carbonate , basic copper chloride , basic rothalonil , chlorotoluron , chloroxifenidim , chloroxuron , copper sulfate , BCPC , beflubutamid , benalaxyl , benalaxyl chloroxynil , chlorphonium , chlorphoxim , chlorprazophos , M , benazolin , bencarbazone , benclothiaz , bendaqingbing - chlorprocarb , chlorpropham , chlorpyrifos , chlorpyrifos zhi , bendiocarb , bendioxide , benefin , benfluralin , benfurac - 60 methyl , chlorquinox , chlorsulfuron , chlorthal , chlorthiamid , arb , benfuresate , benmihuangcaoan , benodanil , benomyl , chlorthiophos , chlortoluron , chlozolinate , chltosan , chole benoxacor , benoxafos , benquinox , bensulfuron , bensulide , calciferol , choline chloride , chromafenozide , cicloheximide , bensultap , bentaluron , bentazon , bentazone , benthiavalicarb , cimectacarb , cimetacarb , cinerin I , cinerin II , cinerins , cini benthiazole , benthiocarb , bentranil , benzadox , benzalko - don - ethyl , cinmethylin , cinosulfuron , cintofen , ciobutide , nium chloride , benzamacril , benzamizole , benzamorf , ben - 65 cisanilide , cismethrin , clacyfos , clefoxydim , clenpirin , clen zene hexachloride , benzfendizone , benzimine , benzipram , pyrin , clethodim , climbazole , cliodinate , clodinafop , cloeth benzobicyclon , benzoepin , benzofenap , benzofluor , benzo ocarb , clofencet , clofenotane , clofentezine , clofenvinfos ,

41 .

nac .

US 9 , 795 , 140 B2 5

clofibric acid , clofop , clomazone , clomeprop , clonitralid , tetraborate , disosultap , disparlure , disugran , disul , disul cloprop , cloproxydim , clopyralid , cloquintocet , cloransu firam , disulfoton , ditalimfos , dithianon , dithicrofos , dithio lam , closantel , clothianidin , clotrimazole , cloxyfonac , ether , dithiometon , dithiopyr , diuron , dixanthogen , d - limo cloxylacon , clozylacon , CMA , CMMP , CMP , CMU , codle - nene , DMDS , DMPA , DNOC , dodemorph , dodicin , dodine , lure , colecalciferol , colophonate , copper 8 - quinolinolate , 5 dofenapyn , doguadine , dominicalure , doramectin , DPC , dra copper acetate , copper acetoarsenite , copper arsenate , cop - zoxolon , DSMA , d - trans - allethrin , d - trans - resmethrin , dufu per carbonate , basic , copper hydroxide , copper naphthenate , lin , dymron , EBEP , EBP , ebufos , ecdysterone , echlomezol , copper oleate , copper oxychloride , copper silicate , copper EDB , EDC , EDDP , edifenphos , eglinazine , emamectin , sulfate , copper sulfate , basic , copper zinc chromate , cou - EMPC , empenthrin , enadenine , endosulfan , endothal , machlor , coumafene , coumafos , coumafuryl , coumaphos , 10 endothall , endothion , endrin , enestroburin , enilconazole , coumatetralyl , coumethoxystrobin , coumithoate , coumox enoxastrobin , ephirsulfonate , EPN , epocholeone , ystrobin , CPMC , CPMF , CPPC , credazine , cresol , cresylic epofenonane , epoxiconazole , eprinomectin , epronaz , EPTC , acid , crimidine , crotamiton , crotoxyfos , crotoxyphos , crufo - erbon , ergocalciferol , erlujixiancaoan , esdépalléthrine , mate , cryolite , cue - lure , cufraneb , cumyleron , cumyluron , esfenvalerate , ESP , esprocarb , etacelasil , etaconazole , eta cuprobam , cuprous oxide , curcumenol , CVMP , cyanamide , 15 phos , etem , ethaboxam , ethachlor , ethalfluralin , ethametsul cyanatryn , cyanazine , cyanofenphos , cyanogen , cyanophos , furon , ethaprochlor , ethephon , ethidimuron , ethiofencarb , cyanthoate , cyantraniliprole , cyanuric acid , cyazofamid , ethiolate , ethion , ethiozin , ethiprole , ethirimol , ethoate cybutryne , cyclafuramid , cyclanilide , cyclaniliprole , methyl , ethobenzanid , ethofumesate , ethohexadiol , ethop cyclethrin , cycloate , cycloheximide , cycloprate , cyclopro rop , ethoprophos , ethoxyfen , ethoxyquin , ethoxysulfuron , thrin , cyclopyrimorate , cyclosulfamuron , cycloxydim , 20 ethychlozate , ethyl formate , ethyl pyrophosphate , ethylan , cycluron , cyenopyrafen , cyflufenamid , cyflumetofen , cyflu - ethyl - DDD , ethylene , ethylene dibromide , ethylene dichlo thrin , cyhalofop , cyhalothrin , cyhexatin , cymiazole , ride , ethylene oxide , ethylicin , ethylmercury 2 , 3 - dihydroxy cymoxanil , cyometrinil , cypendazole , cypermethrin , cyper propyl mercaptide , ethylmercury acetate , ethylmercury bro quat , cyphenothrin , cyprazine , cyprazole , cyproconazole , mide , ethylmercury chloride , ethylmercury phosphate , cyprodinil , cyprofuram , cypromid , cyprosulfamide , cyro - 25 etinofen , ETM , etnipromid , etobenzanid , etofenprox , etox mazine , cythioate , cytrex , daimuron , dalapon , daminozide , azole , etridiazole , etrimfos , étrimphos , eugenol , EXD , dayoutong , dazomet , DBCP , d - camphor , DCB , DCIP , famoxadone , famphur , fenac , fenamidone , fenaminosulf , DCPA , DCPTA , DCU , DDD , DDPP , DDT , DDVP , debac - fenaminstrobin , fenamiphos , fenapanil , fenarimol , fenasu arb , decafentin , decamethrin , decarbofuran , deet , dehy - lam , fenazaflor , fenazaquin , fenbuconazole , fenbutatin droacetic acid , deiquat , delachlor , delnav , deltamethrin , 30 oxide , fenchlorazole , fenchlorphos , fenclofos , fenclorim , demephion , demephion - O , demephion - S , demeton , deme - fenethacarb , fenfluthrin , fenfuram , fenhexamid , fenidin , ton - methyl , demeton - o , demeton - O - methyl , demeton - s , fenitropan , fenitrothion , fénizon , fenjuntong , fenobucarb , demeton - S - methyl , demeton - S - methyl sulphone , demeton fenolovo , fenoprop , fenothiocarb , fenoxacrim , fenoxanil , S - methylsulphon , DEP , depalléthrine , derris , desmedipham , fenoxaprop , fenoxaprop - P , fenoxasulfone , fenoxycarb , fen desmetryn , desmetryne , d - fanshiluquebingjuzhi , diafenthi - 35 piclonil , fenpirithrin , fenpropathrin , fenpropidin , fenpropi uron , dialifor , dialifos , diallate , diamidafos , dianat , diato - morph , fenpyrazamine , fenpyroximate , fenquinotrione , fen maceous earth , diatomite , diazinon , dibrom , dibutyl phtha ridazon , fenson , fensulfothion , fenteracol , fenthiaprop , late , dibutyl succinate , dicamba , dicapthon , dichlobenil , fenthion , fenthion - ethyl , fentiaprop , fentin , fentrazamide , dichlofenthion , dichlofluanid , dichlone , dichloralurea , fentrifanil , fenuron , fenuron - TCA , fenvalerate , ferbam , fer dichlorbenzuron , dichlorfenidim , dichlorflurecol , dichlo - 40 imzone , ferric phosphate , ferrous sulfate , fipronil , flamprop , rflurenol , dichlormate , dichlormid , dichloromethane , diclo - flamprop - M , flazasulfuron , flocoumafen , flometoquin , floni romezotiaz , dichlorophen , dichlorprop , dichlorprop - P , camid , florasulam , fluacrypyrim , fluazifop , fluazifop - P , flu dichlorvos , dichlozolin , dichlozoline , diclobutrazol , diclo - azinam , fluazolate , fluazuron , flubendiamide , flubenzimine , cymet , diclofop , diclomezine , dicloran , diclosulam , dicofol , flubrocythrinate , flucarbazone , flucetosulfuron , fluchloralin , dicophane , dicoumarol , dicresyl , dicrotophos , dicryl , 45 flucofuron , flucycloxuron , flucythrinate , fludioxonil , fluéné dicumarol , dicyclanil , dicyclonon , dieldrin , dienochlor , thyl , fluenetil , fluensulfone , flufenacet , flufenerim , flufeni diethamquat , diethatyl , diethion , diéthion , diethofencarb , can , flufenoxuron , flufenoxystrobin , flufenprox , flufenpyr , dietholate , diéthon , diethyl pyrocarbonate , diethyltolu - flufenzine , flufiprole , fluhexafon , flumethrin , flumetover , amide , difenacoum , difenoconazole , difenopenten , difenox - flumetralin , flumetsulam , flumezin , flumiclorac , flumiox uron , difenzoquat , difethialone , diflovidazin , diflubenzuron , 50 azin , flumipropyn , flumorph , fluometuron , fluopicolide , flu diflufenican , diflufenicanil , diflufenzopyr , diflumetorim , opyram , fluorbenside , fluoridamid , fluoroacetamide , fluoro dikegulac , dilor , dimatif , dimefluthrin , dimefox , dimefuron , acetic acid , fluorochloridone , fluorodifen , fluoroglycofen , dimehypo , dimepiperate , dimetachlone , dimetan , dimethac fluoroimide , fluoromide , fluoromidine , fluoronitrofen , fluo arb , dimethachlone , dimethachlor , dimethametryn , dimeth roxypyr , fluothiuron , fluotrimazole , fluoxastrobin , enamid , dimethenamid - P , dimethipin , dimethirimol , dime - 55 flupoxam , flupropacil , flupropadine , flupropanate , flupyra thoate , dimethomorph , dimethrin , dimethyl carbate , difurone , flupyrsulfuron , fluquinconazole , fluralaner , flura dimethyl disulfide , dimethyl phthalate , dimethylvinphos , zole , flurecol , flurenol , fluridone , flurochloridone , fluromi dimetilan , dimexano , dimidazon , dimoxystrobin , dimpylate , dine , fluroxypyr , flurprimidol , flursulamid , flurtamone , dimuron , dinex , dingjunezuo , diniconazole , diniconazole - flusilazole , flusulfamide , flutenzine , fluthiacet , fluthiamide , M , dinitramine , dinitrophenols , dinobuton , dinocap , 60 flutianil , flutolanil , flutriafol , fluvalinate , fluxapyroxad , flux dinocap - 4 , dinocap - 6 , dinocton , dinofenate , dinopenton , ofenim , folpel , folpet , fomesafen , fonofos , foramsulfuron , dinoprop , dinosam , dinoseb , dinosulfon , dinotefuran , forchlorfenuron , formaldehyde , formetanate , formothion , dinoterb , dinoterbon , diofenolan , dioxabenzofos , dioxacarb , formparanate , fosamine , fosetyl , fosmethilan , fospirate , fos dioxathion , dioxation , diphacin , diphacinone , diphenadione , thiazate , fosthietan , frontalin , fthalide , fuberidazole , fucao diphenamid , diphenamide , diphenyl sulfone , diphenylam - 65 jing , fucaomi , fujunmanzhi , fulumi , fumarin , funaihecaol ine , diphenylsulphide , diprogulic acid , dipropalin , dipropet - ing , fuphenthiourea , furalane , furalaxyl , furamethrin , ryn , dipterex , dipymetitrone , dipyrithione , diquat , disodium furametpyr , furan tebufenozide , furathiocarb , furcarbanil ,

US 9 , 795 , 140 B2

furconazole , furconazole - cis , furethrin , furfural , furilazole , methiopyrisulfuron , methiotepa , methiozolin , methiuron , furmecyclox , furophanate , furyloxyfen , gamma - BHC , methocrotophos , métholcarb , methometon , methomyl , gamma - cyhalothrin , gamma - HCH , genit , gibberellic acid , methoprene , methoprotryn , methoprotryne , methoquin - bu gibberellin A3 , gibberellins , gliftor , glitor , glucochloralose , tyl , methothrin , methoxychlor , methoxyfenozide , methoxy glufosinate , glufosinate - P , glyodin , glyoxime , glyphosate , 5 phenone , methyl apholate , methyl bromide , methyl eugenol , glyphosine , gossyplure , grandlure , griseofulvin , guanoctine , methyl iodide , methyl isothiocyanate , methyl parathion , guazatine , halacrinate , halauxifen , halfenprox , halofenozide , methylacetophos , methylchloroform , methyldithiocarbamic halosafen , halosulfuron , haloxydine , haloxyfop , haloxyfop - acid , methyldymron , methylene chloride , methyl - isofen P , haloxyfop - R , HCA , HCB , HCH , hemel , hempa , HEOD phos , methylmercaptophos , methylmercaptophos oxide , heptachlor , heptafluthrin , heptenophos , heptopargil , her - 10 methylmercaptophos thiol , methylmercury benzoate , meth bimycin , herbimycin A , heterophos , hexachlor , hexachloran , ylmercury dicyandiamide , methylmercury pentachlorophe hexachloroacetone , hexachlorobenzene , hexachlorobutadi noxide , methylneodecanamide , methylnitrophos , methyltri ene , hexachlorophene , hexaconazole , hexaflumuron , azothion , metiozolin , metiram , metiram - zinc , hexafluoramin , hexaflurate , hexalure , hexamide , hexazi - metobenzuron , metobromuron , metofluthrin , metolachlor , none , hexylthiofos , hexythiazox , HHDN , holosulf , homo - 15 metolcarb , metometuron , metominostrobin , metosulam , brassinolide , huancaiwo , huanchongjing , huangcaoling , metoxadiazone , metoxuron , metrafenone , metriam , huanjunzuo , hydramethylnon , hydrargaphen , hydrated lime , metribuzin , metrifonate , metriphonate , metsulfovax , metsul hydrogen cyanamide , hydrogen cyanide , hydroprene , furon , mevinphos , mexacarbate , miechuwei , mieshuan , mie hydroxyisoxazole , hymexazol , hyquincarb , IAA , IBA , IBP , wenjuzhi , milbemectin , milbemycin oxime , milneb , icaridin , imazalil , imazamethabenz , imazamox , imazapic , 20 mima2nan , mipafox , MIPC , mirex , MNAF , moguchun , imazapyr , imazaquin , imazethapyr , imazosulfuron , imiben - molinate , molosultap , momfluorothrin , monalide , moni conazole , imicyafos , imidacloprid , imidaclothiz , iminocta suron , monoamitraz , monochloroacetic acid , monocroto dine , imiprothrin , inabenfide , indanofan , indaziflam , indox - phos , monolinuron , monomehypo , monosulfiram , monosul acarb , inezin , infusorial earth , iodobonil , iodocarb , furon , monosultap , monuron , monuron - TCA , morfamquat , iodofenphos , iodomethane , iodosulfuron , iofensulfuron , 25 moroxydine , morphothion , morzid , moxidectin , MPMC , ioxynil , ipazine , IPC , ipconazole , ipfencarbazone , iproben - MSMA , MTMC , muscalure , myclobutanil , myclozolin , fos , iprodione , iprovalicarb , iprymidam , ipsdienol , ipsenol , myricyl alcohol , N - ( ethylmercury ) - p - toluenesulphonanilide , IPSP , IPX , isamidofos , isazofos , isobenzan , isocarbamid , NAA , NAAm , nabam , naftalofos , naled , naphthalene , naph isocarbamide , isocarbophos , isocil , isodrin , isofenphos , thaleneacetamide , naphthalic anhydride , naphthalophos , isofenphos - methyl , isofetamid , isolan , isomethiozin , isono - 30 naphthoxyacetic acids , naphthylacetic acids , naphthylin ruron , isopamphos , isopolinate , isoprocarb , isoprocil , iso - dane - 1 , 3 - diones , naphthyloxyacetic acids , naproanilide , propalin , isopropazol , isoprothiolane , isoproturon , isopyra - napropamide , napropamide - M , naptalam , natamycin , zam , isopyrimol , isothioate , isotianil , isouron , isovaledione , NBPOS , neburea , neburon , nendrin , neonicotine , nichlorfos , isoxaben , isoxachlortole , isoxadifen , isoxaflutole , isoxapy niclofen , niclosamide , nicobifen , nicosulfuron , nicotine , rifop , isoxathion , isuron , ivermectin , ixoxaben , izopamfos , 35 nicotine sulfate , nifluridide , nikkomycins , NIP , nipyra izopamphos , japonilure , japothrins , jasmolin 1 , jasmolin II , clofen , nipyralofen , nitenpyram , nithiazine , nitralin , nitrapy jasmonic acid , jiahuangchongzong , jiajizengxiaolin , jiaxi - rin , nitrilacarb , nitrofen , nitrofluorfen , nitrostyrene , angjunzhi , jiecaowan , jiecaoxi , jinganmycin A , jodfenphos , nitrothal - isopropyl , nobormide , nonanol , norbormide , norea , juvenile hormone I , juvenile hormone II , juvenile hormone norflurazon , nornicotine , noruron , novaluron , noviflumuron , III , kadethrin , kappa - bifenthrin , kappa - tefluthrin , karbuti - 40 NPA , nuarimol , nuranone , OCH , octachlorodipropyl ether , late , karetazan , kasugamycin , kejunlin , kelevan , ketospira - octhilinone , o - dichlorobenzene , ofurace , omethoate , O - phe dox , kieselguhr , kinetin , kinoprene , kiralaxyl , kresoxim - nylphenol , orbencarb , orfralure , orthobencarb , ortho - dichlo methyl , kuicaoxi , lactofen , lambda - cyhalothrin , latilure , robenzene , orthosulfamuron , oryctalure , orysastrobin , lead arsenate , lenacil , lepimectin , leptophos , lianbenjingzhi , oryzalin , osthol , osthole , ostramone , ovatron , ovex , oxabe lime sulfur , lindane , lineatin , linuron , lirimfos , litlure , 45 trinil , oxadiargyl , oxadiazon , oxadixyl , oxamate , oxamyl , looplure , lufenuron , lüxiancaolin , lvdingjunzhi , lvfumijvzhi , oxapyrazon , oxapyrazone , oxasulfuron , oxathiapiprolin , lvxiancaolin , lythidathion , M - 74 , M - 81 , MAA , magnesium oxaziclomefone , oxine - copper , oxine - Cu , oxolinic acid , phosphide , malathion , maldison , maleic hydrazide , malono - oxpoconazole , oxycarboxin , oxydemeton - methyl , ben , maltodextrin , MAMA , mancopper , mancozeb , mande - oxydeprofos , oxydisulfoton , oxyenadenine , oxyfluorfen , strobin , mandipropamid , maneb , matrine , mazidox , MCC , 50 oxymatrine , oxytetracycline , oxythioquinox , PAC , MCP , MCPA , MCPA - thioethyl , MCPB , MCPP , mebenil , paclobutrazol , paichongding , palléthrine , PAP , para - dichlo mecarbam , mecarbinzid , mecarphon , mecoprop , mecoprop - robenzene , parafluron , paraquat , parathion , parathion P , medimeform , medinoterb , medlure , mefenacet , methyl , parinol , Paris green , PCNB , PCP , PCP - Na , p - di mefenoxam , mefenpyr , mefluidide , megatomoic acid , melis chlorobenzene , PDJ , pebulate , pédinex , pefurazoate , syl alcohol , melitoxin , MEMC , menazon , MEP , mepanipy - 55 pelargonic acid , penconazole , pencycuron , pendimethalin , rim , meperfluthrin , mephenate , mephosfolan , mepiquat , penfenate , penflufen , penfluron , penoxalin , penoxsulam , mepronil , meptyldinocap , mercaptodimethur , mercapto - pentachlorophenol , pentachlorophenyl laurate , pentano phos , mercaptophos thiol , mercaptothion , mercuric chloride , chlor , penthiopyrad , pentmethrin , pentoxazone , perchlorde mercuric oxide , mercurous chloride , merphos , merphos cone , perfluidone , permethrin , pethoxamid , PHC , phe oxide , mesoprazine , mesosulfuron , mesotrione , mesulfen , 60 namacril , phenamacril - ethyl , phénaminosulf , phenazine mesulfenfos , mesulphen , metacresol , metaflumizone , meta - oxide , phénétacarbe , phenisopham , phenkapton , phenmed laxyl , metalaxyl - M , metaldehyde , metam , metamifop , met ipham , phenmedipham - ethyl , phenobenzuron , phenothiol , amitron , metaphos , metaxon , metazachlor , metazosulfuron , phenothrin , phenproxide , phenthoate , phenylmercuriurea , metazoxolon , metconazole , metepa , metflurazon , methaben - phenylmercury acetate , phenylmercury chloride , phenyl zthiazuron , methacrifos , methalpropalin , metham , methami - 65 mercury derivative of pyrocatechol , phenylmercury nitrate , dophos , methasulfocarb , methazole , methfuroxam , methi - phenylmercury salicylate , phorate , phosacetim , phosalone , benzuron , methidathion , methiobencarb , methiocarb , phosametine , phosazetim , phosazetin , phoscyclotin , phosdi

US 9 , 795 , 140 B2 10

phen , phosethyl , phosfolan , phosfolan - methyl , phosglycin , sedaxane , selamectin , semiamitraz , sesamex , sesamolin , phosmet , phosnichlor , phosphamide , phosphamidon , phos sesone , sethoxydim , sevin , shuangjiaancaolin , shuangji phine , phosphinothricin , phosphocarb , phosphorus , phostin , anancaolin , S - hydroprene , siduron , sifumijvzhi , siglure , phoxim , phoxim - methyl , phthalide , phthalophos , 5 silafluofen , silatrane , silica aerogel , silica gel , silthiofam , phthalthrin , picarbutrazox , picaridin , picloram , picolinafen , silthiopham , silthiophan , silvex , simazine , simeconazole , picoxystrobin , pimaricin , pindone , pinoxaden , piperalin , simeton , simetryn , simetryne , sintofen , S - kinoprene , slaked piperazine , piperonyl butoxide , piperonyl cyclonene , pip lime , SMA , S - methoprene , S - metolachlor , sodium arsenite , erophos , piproctanly , piproctanyl , piprotal , pirimetaphos , sodium azide , sodium chlorate , sodium cyanide , sodium pirimicarb , piriminil , pirimioxyphos , pirimiphos - ethyl , fluoride , sodium fluoroacetate , sodium hexafluorosilicate , pirimiphos - methyl , pival , pivaldione , plifenate , PMA , PMP , sodium naphthenate , sodium o - phenylphenoxide , sodium polybutenes , polycarbamate , polychlorcamphene , poly orthophenylphenoxide , sodium pentachlorophenate , sodium ethoxyquinoline , polyoxin D , polyoxins , polyoxorim , poly - pentachlorophenoxide , sodium polysulfide , sodium silico thialan , potassium arsenite , potassium azide , potassium 15 fluoride , sodium tetrathiocarbonate , sodium thiocyanate , cyanate , potassium ethylxanthate , potassium naphthenate , solan , sophamide , spinetoram , spinosad , spirodiclofen , potassium polysulfide , potassium thiocyanate , pp - DDT , spiromesifen , spirotetramat , spiroxamine , stirofos , strepto prallethrin , precocene I , precocene II , precocene III , preti mycin , strychnine , sulcatol , sulcofuron , sulcotrione , sulfal lachlor , primidophos , primisulfuron , probenazole , prochlo - 20 late , sulfentrazone , sulfiram , sulfluramid , sulfodiazole , sul raz , proclonol , procyazine , procymidone , prodiamine , pro fometuron , sulfosate , sulfosulfuron , sulfotep , sulfotepp , fenofos , profluazol , profluralin , profluthrin , profoxydim , sulfoxaflor , sulfoxide , sulfoxime , sulfur , sulfuric acid , sul profurite - aminium , proglinazine , prohexadione , prohydro furyl fluoride , sulglycapin , sulphosate , sulprofos , sultropen , jasmon , promacyl , promecarb , prometon , prometryn , prom - 25 swep , tau - fluvalinate , tavron , tazimcarb , TBTO , TBZ , TCA , etryne , promurit , pronamide , propachlor , propafos , propami - TCBA , TCMTB , TCNB , TDE , tebuconazole , tebufenozide , dine , propamocarb , propanil , propaphos , propaquizafop , tebufenpyrad , tebufloquin , tebupirimfos , tebutam , tebuthi propargite , proparthrin , propazine , propetamphos , propham , uron , tecloftalam , tecnazene , tecoram , tedion , teflubenzuron , propiconazole , propidine , propineb , propisochlor , propoxur , 30 tefluthrin , tefuryltrione , tembotrione , temefos , temephos , propoxycarbazone , propyl isome , propyrisulfuron , propyz - tepa , TEPP , tepraloxydim , teproloxydim , terallethrin , terba amide , proquinazid , prosuler , prosulfalin , prosulfocarb , pro cil , terbucarb , terbuchlor , terbufos , terbumeton , terbuthyla sulfuron , prothidathion , prothiocarb , prothioconazole , pro zine , terbutol , terbutryn , terbutryne , terraclor , terramicin , thiofos , prothoate , protrifenbute , proxan , prymidophos , 35 terramycin , tetcyclacis , tetrachloroethane , tetrachlorvin prynachlor , psoralen , psoralene , pydanon , pyflubumide , phos , tetraconazole , tetradifon , tetradisul , tetrafluron , pymetrozine , pyracarbolid , pyraclofos , pyraclonil , pyra tetramethrin , tetra methylfluthrin , tetramine , tetranactin , tet clostrobin , pyraflufen , pyrafluprole , pyramat , pyrameto raniliprole , tetrapion , tetrasul , thallium sulfate , thallous sul strobin , pyraoxystrobin , pyrasulfotole , pyraziflumid , pyra fate , thenylchlor , theta - cypermethrin , thiabendazole , thia zolate , pyrazolynate , pyrazon , pyrazophos , pyrazosulfuron , cloprid , thiadiazine , thiadifluor , thiamethoxam , thiameturon , pyrazothion , pyrazoxyfen , pyresmethrin , pyrethrin I , pyre thiapronil , thiazafluron , thiazfluron , thiazone , thiazopyr , thi thrin II , pyrethrins , pyribambenz - isopropyl , pyribambenz crofos , thicyofen , thidiazimin , thidiazuron , thiencarbazone , propyl , pyribencarb , pyribenzoxim , pyributicarb , pyriclor , thifensulfuron , thifluzamide , thimerosal , thimet , thioben pyridaben , pyridafol , pyridalyl , pyridaphenthion , pyrida - 45 carb , thiocarboxime , thiochlorfenphim , thiochlorphen phenthione , pyridate , pyridinitril , pyrifenox , pyrifluqui - phime , thiocyanatodinitrobenzenes , thiocyclam , thiodan , nazon , pyriftalid , pyrimétaphos , pyrimethanil , pyrimicarbe , thiodiazole - copper , thiodicarb , thiofanocarb , thiofanox , pyrimidifen , pyriminobac , pyriminostrobin , pyrimiphos - thiofluoximate , thiohempa , thiomersal , thiometon , thion éthyl , pyrimiphos - methyl , pyrimisulfan , pyrimitate , pyrin - 50 azin , thiophanate , thiophanate - ethyl , thiophanate - methyl , uron , pyriofenone , pyriprole , pyripropanol , pyriproxyfen , thiophos , thioquinox , thiosemicarbazide , thiosultap , thio pyrisoxazole , pyrithiobac , pyrolan , pyroquilon , pyroxasul - tepa , thioxamyl , thiram , thiuram , thuringiensin , tiabenda fone , pyroxsulam , pyroxychlor , pyroxyfur , qincaosuan , zole , tiadinil , tiafenacil , tiaojiean , TIBA , tifatol , tiocarbazil , qingkuling , quassia , quinacetol , quinalphos , quinalphos - 55 tioclorim , tioxazafen , tioxymid , tirpate , TMTD , tolclofos methyl , quinazamid , quinclorac , quinconazole , quinmerac , methyl , tolfenpyrad , tolprocarb , tolpyralate , tolyfluanid , quinoclamine , quinomethionate , quinonamid , quinothion , tolylfluanid , tolylmercury acetate , tomarin , topramezone , quinoxyfen , quintiofos , quintozene , quizalofop , quizalofop toxaphene , TPN , tralkoxydim , tralocythrin , tralomethrin , P , quwenzhi , quyingding , rabenzazole , rafoxanide , R - dini - 60 tralopyril , transfluthrin , transpermethrin , tretamine , triacon conazole , rebemide , reglone , renriduron , rescalure , res - tanol , triadimefon , triadimenol , triafamone , triallate , tri methrin , rhodethanil , rhodojaponin - III , ribavirin , allate , triamiphos , triapenthenol , triarathene , triarimol , tria rimsulfuron , rizazole , R - metalaxyl , rodéthanil , ronnel , rote sulfuron , triazamate , triazbutil , triaziflam , triazophos , none , ryania , sabadilla , saflufenacil , saijunmao , saisentong , 5 triazothion , triazoxide , tribasic copper chloride , tribasic cop salicylanilide , salifluofen , sanguinarine , santonin , S - bioal per sulfate , tribenuron , tribufos , tributyltin oxide , tricamba , lethrin , schradan , scilliroside , sebuthylazine , secbumeton , trichlamide , trichlopyr , trichlorfon , trichlormetaphos - 3 ,

US 9 , 795 , 140 B2 ( b ) ( 35 , 6S , 7R , 8R ) - 8 - benzyl - 3 - ( 3 - ( ( isobutyryloxy ) methoxy ) - 4 - methoxypicolinamido ) - 6 - methyl - 4 , 9 - dioxo 1 , 5 - dioxonan - 7 - yl isobutyrate ( hereafter “ Al - 2 ” )

H3C CH

CH ; H3C - 0 CHz

CH , O

trichloronat , trichloronate , trichlorotrinitrobenzenes , trichlo - rphon , triclopyr , triclopyricarb , tricresol , tricyclazole , tricy clohexyltin hydroxide , tridemorph , tridiphane , trietazine , trifenmorph , trifenofos , trifloxystrobin , trifloxysulfuron , tri fludimoxazin , triflumezopyrim , triflumizole , triflumuron , trifluralin , triflusulfuron , trifop , trifopsime , triforine , trihy droxytriazine , trimedlure , trimethacarb , trimeturon , trinex apac , triphenyltin , triprene , tripropindan , triptolide , tritac , trithialan , triticonazole , tritosulfuron , trunc - call , tuoyelin , 10 uniconazole , uniconazole - P , urbacide , uredepa , valerate , validamycin , validamycin A , valifenalate , valone , vamido thion , vangard , vaniliprole , vernolate , vinclozolin , vitamin D3 , warfarin , xiaochongliulin , xinjunan , xiwojunan , xiwo - 15 junzhi , XMC , xylachlor , xylenols , xylylcarb , xymiazole , yishijing , zarilamid , zeatin , zengxiaoan , zengxiaolin , zeta cypermethrin , zinc naphthenate , zinc phosphide , zinc thiaz ole , zinc thiozole , zinc trichlorophenate , zinc trichlorophe - 20 noxide , zineb , ziram , zolaprofos , zoocoumarin , zoxamide , zuoanjunzhi , zuocaoan , zuojunzhi , zuomihuanglong , a - chlorohydrin , a - ecdysone , a - multistriatin , a - naphthale neacetic acids , and B - ecdysone ;

( 2 ) the following molecules 2 ( a ) N - ( 3 - chloro - 1 - ( pyridin - 3 - yl ) - 1H - pyrazol - 4 - yl ) - N - ethyl -

3 - ( ( 3 , 3 , 3 - trifluoropropyl ) thio ) propanamide ( hereafter " AI - 1 " )

CH3 ,

HNITT

25 ( 3 ) a molecule known as Lotilaner that has the following structure

30 . CH ;

-

Cl 35

ZI .

V

E É ???

40 and ( 4 ) the following molecules in Table A

TABLE A Structure of M # - active ingredients

M # Structure

M1

RS CH WW R = CH , N Rj = H , Me

M2 X = F , CI R = H , F

1 F F

US 9 , 795 , 140 B2 13 14 TABLE A - continued

Structure of M # - active ingredients

M # Structure M3 Br

HC

M4

HzC ?

H3C

M5 CH3 Moto on NC N

M6 F F CI F

NN quyuyan F F

As used in this disclosure , each of the above is an active methrin , pyridalyl , pyrimidifen , spirodiclofen , tebufenozide , ingredient . For more information consult the “ Compendium 50 thiacloprid , thiamethoxam , thiodicarb , tolfenpyrad , and of Pesticide Common Names ” located at Alanwood . net and meta - cypermethrin ( hereafter “ AIGA - 3 ” ) . various editions , including the on - line edition , of “ The The term “ alkenyl ” means an acyclic , unsaturated ( at least Pesticide Manual ” located at bcpcdata . com . one carbon - carbon double bond ) , branched or unbranched ,

substituent consisting of carbon and hydrogen , for example , A particularly preferred selection of active ingredients are 55 vinyl , allyl , butenyl , pentenyl , and hexenyl . 1 , 3 dichloropropene , chlorpyrifos , hexaflumuron , methoxy The term “ alkenyloxy ” means an alkenyl further consist fenozide , noviflumuron , spinetoram , spinosad , and sulfox X i ng of a carbon - oxygen single bond , for example , allyloxy , aflor ( hereafter “ AIGA - 2 " ) . butenyloxy , pentenyloxy , hexenyloxy .

Additionally , another particularly preferred selection of The term " alkoxy ” means an alkyl further consisting of a active ingredients are acequinocyl , acetamiprid , acetoprole , 60 carbon - oxygen single bond , for example , methoxy , ethoxy , avermectin , azinphos - methyl , bifenazate , bifenthrin , car - propoxy , isopropoxy , butoxy , isobutoxy , and tertbutoxy . baryl , carbofuran , chlorfenapyr , chlorfluazuron , chromafe - The term “ alkyl ” means an acyclic , saturated , branched or nozide , clothianidin , cyfluthrin , cypermethrin , deltamethrin , unbranched , substituent consisting of carbon and hydrogen , diafenthiuron , emamectin benzoate , endosulfan , esfenvaler - for example , methyl , ethyl , propyl , isopropyl , butyl , and ate , ethiprole , etoxazole , fipronil , flonicamid , fluacrypyrim , 65 tertbutyl . gamma - cyhalothrin , halofenozide , indoxacarb , lambda - cy . The term “ alkynyl ” means an acyclic , unsaturated ( at least halothrin , lufenuron , malathion , methomyl , novaluron , per one carbon - carbon triple bond ) , branched or unbranched ,

and

US 9 , 795 , 140 B2 15 16

substituent consisting of carbon and hydrogen , for example , ( 2 ) fully saturated heterocyclyl substituents include , but ethynyl , propargyl , butynyl , and pentynyl . are not limited to , piperazinyl , piperidinyl , morpholinyl ,

The term “ alkynyloxy ” means an alkynyl further consist pyrrolidinyl , tetrahydrofuranyl , tetrahydropyranyl , tetrahy ing of a carbon - oxygen single bond , for example , pentyny drothiophenyl , tetrahydrothiophenyl - oxide , tetrahydrothio loxy , hexynyloxy , heptynyloxy , and octynyloxy . 5 phenyl - dioxide ;

The term “ aryl ” means a cyclic , aromatic substituent ( 3 ) partially or fully unsaturated heterocyclyl substituents consisting of hydrogen and carbon , for example , phenyl , include , but are not limited to , 4 , 5 - dihydro - isoxazolyl , 4 , 5 naphthyl , and biphenyl . dihydro - oxazolyl , 4 , 5 - dihydro - 1H - pyrazolyl , 2 , 3 - dihydro The term “ biopesticide ” means a microbial biological pest [ 1 , 3 , 4 ] - oxadiazolyl , 2 , 5 - dioxoimidazolidinyl , 2 , 4 - dioxo - 1 , control agent that , in general , is applied in a similar manner 105 3 - diazaspiro [ 4 . 4 ] nonanylisoxazolidinonyl , oxazolidinonyl , to chemical pesticides . Commonly they are bacterial , but imidazolidinonyl , isoxazolidinonyl , pyrrolidinonyl , 1 , 2 , 3 , 4 there are also examples of fungal control agents , including tetrahydro - quinolinyl , and thioxothiazolidinonyl ; and Trichoderma spp . and Ampelomyces quisqualis . One well ( 4 ) Additional examples of heterocyclyls include the known biopesticide example is Bacillus species , a bacterial following : disease of Lepidoptera , Coleoptera , and Diptera . Biopesti - 15 cides include products based on entomopathogenic fungi ( e . g . Metarhizium anisopliae ) , entomopathogenic nema todes ( e . g . Steinernema feltiae ) , and entomopathogenic viruses ( e . g . Cydia pomonella granulovirus ) . Other - S = 0 examples of entomopathogenic organisms include , but are 20 not limited to , baculoviruses , protozoa , and Microsporidia . thietanyl

For the avoidance of doubt , biopesticides are active ingre thietanyl - oxide thietanyl - dioxide dients .

The term “ cycloalkenyl ” means a monocyclic or polycy clic , unsaturated ( at least one carbon - carbon double bond ) 25 The term “ locus ” means a habitat , breeding ground , plant , substituent consisting of carbon and hydrogen , for example , seed , soil , material , or environment , in which a pest is cyclobutenyl , cyclopentenyl , cyclohexenyl , norbornenyl , growing , may grow , or may traverse . For example , a locus bicyclo [ 2 . 2 . 2 ] octenyl , tetrahydronaphthyl , hexahydronaph may be : where crops , trees , fruits , cereals , fodder species , thyl , and octahydronaphthyl . vines , turf , and / or ornamental plants , are growing ; where

The term “ cycloalkenyloxy ” means a cycloalkenyl further 30 domesticated animals are residing ; the interior or exterior consisting of a carbon - oxygen single bond , for example , surfaces of buildings ( such as places where grains are cyclobutenyloxy , cyclopentenyloxy , norbornenyloxy , and stored ) ; the materials of construction used in buildings ( such bicyclo [ 2 . 2 . 2 ] octenyloxy . as impregnated wood ) ; and the soil around buildings .

The term “ cycloalkyl ” means a monocyclic or polycyclic , The phrase “ MOA Material ” means an active ingredient saturated substituent consisting of carbon and hydrogen , for 35 having a mode of action ( “ MOA ” ) as indicated in IRAC example , cyclopropyl , cyclobutyl , cyclopentyl , norbornyl , MoA Classification v . 7 . 3 , located at irac - online . org . , which bicyclo [ 2 . 2 . 2 ] octyl , and decahydronaphthyl . describes the following groups .

The term “ cycloalkoxy ” means a cycloalkyl further con - ( 1 ) Acetylcholinesterase ( AChE ) inhibitors , includes the sisting of a carbon - oxygen single bond , for example , cyclo - following active ingredients alanycarb , aldicarb , bendio propyloxy , cyclobutyloxy , cyclopentyloxy , norbornyloxy , 40 carb , benfuracarb , butocarboxim , butoxycarboxim , carbaryl , and bicyclo [ 2 . 2 . 2 ] octyloxy . carbofuran , carbosulfan , ethiofencarb , fenobucarb , formeta

The term “ halo ” means fluoro , chloro , bromo , and iodo . nate , furathiocarb , isoprocarb , methiocarb , methomyl , The term “ haloalkoxy ” means an alkoxy further consist - metolcarb , oxamyl , pirimicarb , propoxur , thiodicarb , thio

ing of , from one to the maximum possible number of fanox , triazamate , trimethacarb , XMC , xylylcarb , acephate , identical or different , halos , for example , fluoromethoxy , 45 azamethiphos , azinphos - ethyl , azinphos - methyl , cadusafos , trifluoromethoxy , 2 , 2 - difluoropropoxy , chloromethoxy , chlorethoxyfos , chlorfenvinphos , chlormephos , chlorpyri trichloromethoxy , 1 , 1 , 2 , 2 - tetrafluoroethoxy , and pentafluo - fos , chlorpyrifos - methyl , coumaphos , cyanophos , demeton roethoxy . S - methyl , diazinon , dichlorvos / DDVP , dicrotophos , dime

The term “ haloalkyl ” means an alkyl further consisting of , thoate , dimethylvinphos , disulfoton , EPN , ethion , from one to the maximum possible number of , identical or 50 ethoprophos , famphur , fenamiphos , fenitrothion , fenthion , different , halos , for example , fluoromethyl , trifluoromethyl , fosthiazate , heptenophos , imicyafos , isofenphos , isopropyl 2 , 2 - difluoropropyl , chloromethyl , trichloromethyl , and 1 , 1 , O - methoxyaminothio - phosphoryl ) salicylate , isoxathion , 2 , 2 - tetrafluoroethyl . malathion , mecarbam , methamidophos , methidathion ,

The term " heterocyclyl ” means a cyclic substituent that mevinphos , monocrotophos , naled , omethoate , oxydeme may be aromatic , fully saturated , or partially or fully unsatu - 55 ton - methyl , parathion , parathion - methyl , phenthoate , phor rated , where the cyclic structure contains at least one carbon ate , phosalone , phosmet , phosphamidon , phoxim , pirimi and at least one heteroatom , where said heteroatom is p hos - methyl , profenofos , propetamphos , prothiofos , nitrogen , sulfur , or oxygen . Examples are : pyraclofos , pyridaphenthion , quinalphos , sulfotep ,

( 1 ) aromatic heterocyclyl substituents include , but are not tebupirimfos , temephos , terbufos , tetrachlorvinphos , thio limited to , benzofuranyl , benzoisothiazolyl , benzoisox - 60 meton , triazophos , trichlorfon , vamidothion . azolyl , benzothienyl , benzothiazolyl , benzoxazolyl , cinnoli ( 2 ) GABA - gated chloride channel antagonists , includes nyl , furanyl , imidazolyl , indazolyl , indolyl , isoindolyl , iso the following active ingredients chlordane , endosulfan , quinolinyl , isothiazolyl , isoxazolyl , oxadiazolyl , oxazolinyl , ethiprole , and fipronil . oxazolyl , phthalazinyl , pyrazinyl , pyrazolinyl , pyrazolyl , ( 3 ) Sodium channel modulators , includes the following pyridazinyl , pyridyl , pyrimidinyl , pyrrolyl , quinazolinyl , 65 active ingredients acrinathrin , allethrin , d - cis - trans allethrin , quinolinyl , quinoxalinyl , tetrazolyl , thiazolinyl , thiazolyl , d - trans allethrin , bifenthrin , bioallethrin , bioallethrin S - cy thienyl , triazinyl , and triazolyl ; clopentenyl , bioresmethrin , cycloprothrin , cyfluthrin , beta

17 US 9 , 795 , 140 B2

18 cyfluthrin , cyhalothrin , lambda - cyhalothrin , gamma - cyhalo ( 20 ) Mitochondrial complex III electron transport inhibi thrin , cypermethrin , alpha - cypermethrin , beta - cypermethrin , tors , includes the following active ingredients hydrameth theta - cypermethrin , zeta - cypermethrin , cyphenothrin [ ( 1R ) - ylnon , acequinocyl , and fluacrypyrim . trans - isomers ] , deltamethrin , empenthrin [ ( EZ ) - ( 1R ) - iso ( 21 ) Mitochondrial complex I electron transport inhibi mers ) , esfenvalerate , etofenprox , fenpropathrin , fenvalerate , 5 tors , includes the following active ingredients fenazaquin , flucythrinate , flumethrin , tau - fluvalinate , halfenprox , imi - fenpyroximate , pyrimidifen , pyridaben , tebufenpyrad , prothrin , kadethrin , permethrin , phenothrin ( 1R ) - trans - iso - tolfenpyrad , and rotenone . mer ] , prallethrin , pyrethrins ( pyrethrum ) , resmethrin , sila - ( 22 ) Voltage - dependent sodium channel blockers , fluofen , tefluthrin , tetramethrin , tetramethrin [ ( 1R ) . includes the following active ingredients indoxacarb and isomers ) , tralomethrin , and transfluthrin , and methoxychlor . 10 metaflumizone .

( 4 ) Nicotinic acetylcholine receptor ( nACHR ) agonists , ( 23 ) Inhibitors of acetyl CoA carboxylase , includes the includes the following active ingredients following active ingredients spirodiclofen , spiromesifen ,

( 4A ) acetamiprid , clothianidin , dinotefuran , imidacloprid , and spirotetramat . nitenpyram , thiacloprid , thiamethoxam , ( 24 ) Mitochondrial complex IV electron transport inhibi

( 4B ) nicotine , 15 tors , includes the following active ingredients , aluminium ( 4C ) sulfoxaflor , phosphide , calcium phosphide , phosphine , zinc phosphide , ( 4D ) flupyradifurone , and cyanide . ( 4E ) triflumezopyrim and dicloromezotiaz . ( 25 ) Mitochondrial complex II electron transport inhibi ( 5 ) Nicotinic acetylcholine receptor ( nACHR ) allosteric tors , includes the following active ingredients cyenopyrafen

activators , includes the following active ingredients spin - 20 and cyflumetofen , and etoram and spinosad . ( 28 ) Ryanodine receptor modulators , includes the follow

( 6 ) Chloride channel activators , includes the following ing active ingredients chlorantraniliprole , cyantraniliprole , active ingredients abamectin , emamectin benzoate , lepimec - and flubendiamide . Groups 26 and 27 are unassigned in this tin , and milbemectin . version of the classification scheme .

( 7 ) Juvenile hormone mimics , includes the following 25 Additionally , there is a Group UN that contains active active ingredients hydroprene , kinoprene , methoprene , ingredients of unknown or uncertain mode of action . This fenoxycarb , and pyriproxyfen . group includes the following active ingredients ,

( 8 ) Miscellaneous nonspecific ( multi - site ) inhibitors , azadirachtin , benzoximate , bifenazate , bromopropylate , chi includes the following active ingredients methyl bromide , nomethionat , cryolite , dicofol , pyridalyl , and pyrifluqui chloropicrin , sulfuryl fluoride , borax , and tartar emetic . 30 nazon .

( 9 ) Modulators of Chordotonal Organs , includes the fol - The term “ pest ” means an organism that is detrimental to lowing active ingredients pymetrozine and flonicamid . humans , or human concerns ( such as , crops , food , livestock ,

( 10 ) Mite growth inhibitors , includes the following active etc . ) , where said organism is from Phyla Arthropoda , Mol ingredients clofentezine , hexythiazox , diflovidazin , and lusca , or Nematoda . Particular examples are ants , aphids , etoxazole . 35 bed bugs , beetles , bristletails , caterpillars , cockroaches ,

( 11 ) Microbial disruptors of insect midgut membranes , crickets , earwigs , fleas , flies , grasshoppers , grubs , hornets , includes the following active ingredients Bacillus thuringi killer bees , leafhoppers , lice , locusts , maggots , mites , moths , ensis subsp . Israelensis , Bacillus thuringiensis subsp . nematodes , planthoppers , psyllids , sawflies , scales , silver aizawai , Bacillus thuringiensis subsp . Kurstaki , Bacillus fish , slugs , snails , spiders , springtails , stink bugs , symphy thuringiensis subsp . tenebrionenis , Bt crop proteins 40 lans , termites , thrips , ticks , wasps , whiteflies , and wire ( Cry1Ab , Cry1Ac , Cry1Fa , Cry1A . 105 , Cry2Ab , Vip3A , worms . mCry3A , Cry3Ab , Cry3Bb , Cry34Ab1 / Cry35Abl ) , and Additional examples are pests in Bacillus sphaericus . ( 1 ) Subphyla Chelicerata , Myriapoda , and Hexapoda .

( 12 ) Inhibitors of mitochondrial ATP synthase , includes ( 2 ) Classes of Arachnida , Symphyla , and Insecta . the following active ingredients tetradifon , propargite , azo - 45 ( 3 ) Order Anoplura . A non - exhaustive list of particular cyclotin , cyhexatin , fenbutatin oxide , and diafenthiuron . genera includes , but is not limited to , Haematopinus spp . ,

( 13 ) Uncouplers of oxidative phosphorylation via disrup Hoplopleura spp . , Linognathus spp . , Pediculus spp . , Poly tion of the proton gradient , includes the following active plax spp . , Solenopotes spp . , and Neohaematopinis spp . A ingredients chlorfenapyr , DNOC , and sulfluramid . non - exhaustive list of particular species includes , but is not

( 14 ) Nicotinic acetylcholine receptor ( nACHR ) channel 50 limited to , Haematopinus asini , Haematopinus suis , Linog blockers , includes the following active ingredients bensul nathus setosus , Linognathus ovillus , Pediculus humanus tap , cartap hydrochloride , thiocyclam , and thiosultap - so - capitis , Pediculus humanus humanus , and Pthirus pubis . dium . ( 4 ) Order Coleoptera . A non - exhaustive list of particular

( 15 ) Inhibitors of chitin biosynthesis , type 0 , includes the genera includes , but is not limited to , Acanthoscelides spp . , following active ingredients bistrifluron , chlorfluazuron , 55 Agriotes spp . , Anthonomus spp . , Apion spp . , Apogonia spp . , diflubenzuron , flucycloxuron , flufenoxuron , hexaflumuron , Araecerus spp . , Aulacophora spp . , Bruchus spp . , Cerosterna lufenuron , novaluron , noviflumuron , teflubenzuron , and tri spp . , Cerotoma spp . , Ceutorhynchus spp . , Chaetocnema flumuron . spp . , Colaspis spp . , Ctenicera spp . , Curculio spp . , Cyclo

( 16 ) Inhibitors of chitin biosynthesis , type 1 , includes the cephala spp . , Diabrotica spp . , Dinoderus spp . , Gnathocerus following active ingredient buprofezin . 60 spp . , Hemicoelus spp . , Heterobostruchus spp . , Hypera spp . ,

( 17 ) Moulting disruptor , Dipteran , includes the following Ips spp . , Lyctus spp . , Megascelis spp . , Meligethes spp . , active ingredient cyromazine . Mezium spp . , Niptus spp . , Otiorhynchus spp . , Pantomorus

( 18 ) Ecdysone receptor agonists , includes the following spp . , Phyllophaga spp . , Phyllotreta spp . , Ptinus spp . , active ingredients chromafenozide , halofenozide , methoxy Rhizotrogus spp . , Rhynchites spp . , Rhynchophorus spp . , fenozide , and tebufenozide . 65 Scolytus spp . , Sphenophorus spp . , Sitophilus spp . , Tenebrio

( 19 ) Octopamine receptor agonists , includes the following spp . , and Tribolium spp . A non - exhaustive list of particular active ingredient amitraz . species includes , but is not limited to , Acanthoscelides

US 9 , 795 , 140 B2 19 20

obtectus , Agrilus planipennis , Ahasverus advena , Alphito - rodes spp . , Triatoma spp . , and Unaspis spp . A non - exhaus bius diaperinus , Anoplophora glabripennis , Anthonomus tive list of particular species includes , but is not limited to , grandis , Anthrenus verbasci , Anthrenus falvipes , Ataenius Acrosternum hilare , Acyrthosiphon pisum , Aleyrodes prole spretulus , Atomaria linearis , Attagenus unicolor , Bothyno - tella , Aleurodicus dispersus , Aleurothrixus floccosus , deres punctiventris , Bruchus pisorum , Callosobruchus 5 Amrasca biguttula biguttula , Aonidiella aurantii , Aphis gos maculatus Carpophilus hemipterus , Cassida vittata , sypii , Aphis glycines , Aphis pomi , Aulacorthum solani , Bac Cathartus quadricollis , Cerotoma trifurcata , Ceutorhynchus tericera cockerelli , Bagrada hilaris , Bemisia argentifolii , assimilis , Ceutorhynchus napi , Conoderus scalaris , Bemisia tabaci , Blissus leucopterus , Boisea trivittata , Conoderus stigmosus , Conotrachelus nenuphar , Cotinis Brachycorynella asparagi , Brevennia rehi , Brevicoryne nitida , Crioceris asparagi , Cryptolestes ferrugineus , Cryp - 10 brassicae , Cacopsylla pyri , Cacopsylla pyricola , Calocoris tolestes pusillus , Cryptolestes turcicus , Cylindrocopturus norvegicus , Ceroplastes rubens , Cimex hemipterus , Cimex adspersus , Deporaus marginatus , Dermestes lardarius , Der lectularius , Dagbertus fasciatus , Dichelops furcatus , Diu mestes maculatus , Epilachna varivestis , Euvrilletta peltata , raphis noxia , Diaphorina citri , Dysaphis plantaginea , Dys Faustinus cubae , Hylobius pales , Hylotrupes bajulus , dercus suturellus , Edessa meditabunda , Eriosoma lanige Hypera postica , Hypothenemus hampei , Lasioderma serri - 15 rum , Eurygaster maura , Euschistus conspersus , Euschistus come , Leptinotarsa decemlineata , Limonius canus , Liogenys heros , Euschistus servus , Halyomorpha halys , Helopeltis fuscus , Liogenys suturalis , Lissorhoptrus oryzophilus , antonii , Helopeltis theivora , Icerya purchasi , Idioscopus Lophocateres pusillus , Lyctus planicollis , Maecolaspis jol nitidulus , Laodelphax striatellus , Leptocorisa oratorius , iveti , Melanotus communis , Meligethes aeneus , Melolontha Leptocorisa varicomis , Lygus hesperus , Maconellicoccus melolontha , Necrobia rufipes , Oberea brevis , Oberea lin - 20 hirsutus , Macrosiphum euphorbiae , Macrosiphum grana earis , Oryctes rhinoceros , Oryzaephilus mercator , Oryzae - rium , Macrosiphum rosae , Macrosteles quadrilineatus , philus surinamensis , Oulema melanopus , Oulema oryzae , Mahanarva frimbiolata , Megacopta cribraria , Metopolo Phyllophaga cuyabana , Polycaon stoutti , Popillia japonica , phium dirhodum , Mictis longicomis , Myzus persicae , Prostephanus truncatus , Rhyzopertha dominica , Sitona lin - Nephotettix cincticeps , Neurocolpus longirostris , Nezara eatus , Sitophilus granarius , Sitophilus oryzae , Sitophilus 25 viridula , Nilaparvata lugens , Parlatoria pergandii , Parla zeamais , Stegobium paniceum , Tenebroides mauritanicus , toria ziziphi , Peregrinus maidis , Phylloxera vitifoliae , Tribolium castaneum , Tribolium confusum , Trogoderma Physokermes piceae , Phytocoris califomicus , Phytocoris granarium , Trogoderma variabile , Xestobium rufovillosum , relativus , Piezodorus guildinii , Poecilocapsus lineatus , and Zabrus tenebrioides . Psallus vaccinicola , Pseudacysta perseae , Pseudococcus

( 5 ) Order Dermaptera . A non - exhaustive list of particular 30 brevipes , Quadraspidiotus pemiciosus , Rhopalosiphum species includes , but is not limited to , Forficula auricularia . maidis , Rhopalosiphum padi , Saissetia oleae , Scaptocoris

( 6 ) Order Blattaria . A non - exhaustive list of particular castanea , Schizaphis graminum , Sitobion avenae , Sogatella species includes , but is not limited to , Blattella germanica , furcifera , Trialeurodes vaporariorum , Trialeurodes Blattella asahinai , Blatta orientalis , Blatta lateralis , Parco - abutiloneus , Unaspis yanonensis , and Zulia entrerriana . blatta pennsylvanica , Periplaneta americana , Periplaneta 35 ( 9 ) Order Hymenoptera . A non - exhaustive list of particu australasiae , Periplaneta brunnea , Periplaneta fuliginosa , lar genera includes , but is not limited to , Acromyrmex spp . , Pycnoscelus surinamensis , and Supella longipalpa . Atta spp . , Camponotus spp . , Diprion spp . , Dolichovespula

( 7 ) Order Diptera . A non - exhaustive list of particular spp . , Formica spp . , Monomorium spp . , Neodiprion spp . , genera includes , but is not limited to , Aedes spp . , Agromyza Paratrechina spp . , Pheidole spp . , Pogonomyrmex spp . , spp . , Anastrepha spp . , Anopheles spp . , Bactrocera spp . , 40 Polistes spp . , Solenopsis spp . , Technomyrmex , spp . , Ceratitis spp . , Chrysops spp . , Cochliomyia spp . , Contarinia Tetramorium spp . , Vespula spp . , Vespa spp . , and Xylocopa spp . , Culex spp . , Culicoides spp . , Dasineura spp . , Delia spp . A non - exhaustive list of particular species includes , but spp . , Drosophila spp . , Fannia spp . , Hylemya spp . , Liriomyza is not limited to , Athalia rosae , Atta texana , Caliroa cerasi , spp . , Musca spp . , Phorbia spp . , Pollenia spp . , Psychoda Cimbex americana , Iridomyrmex humilis , Linepithema spp . , Simulium spp . , Tabanus spp . , and Tipula spp . A non - 45 humile , Mellifera Scutellata , Monomorium minimum , exhaustive list of particular species includes , but is not Monomorium pharaonis , Neodiprion sertifer , Solenopsis limited to , Agromyza frontella , Anastrepha suspensa , Anas - invicta , Solenopsis geminata , Solenopsis molesta , Solenop trepha ludens , Anastrepha obliqua , Bactrocera cucurbitae , sis richtery , Solenopsis xyloni , Tapinoma sessile , and Was Bactrocera dorsalis , Bactrocera invadens , Bactrocera mannia auropunctata . zonata , Ceratitis capitata , Dasineura brassicae , Delia pla - 50 ( 10 ) Order Isoptera . A non - exhaustive list of particular tura , Fannia canicularis , Fannia scalaris , Gasterophilus genera includes , but is not limited to , Coptotermes spp . , intestinalis , Gracillia perseae , Haematobia irritans , Hypo - Comitermes spp . , Cryptotermes spp . , Heterotermes spp . , derma lineatum , Liriomyza brassicae , Melophagus ovinus , Kalotermes spp . , Incisitermes spp . , Macrotermes spp . , Mar Musca autumnalis , Musca domestica , Oestrus ovis , ginitermes spp . , Microcerotermes spp . , Procomitermes spp . , Oscinella frit , Pegomya betae , Piophila casei , Psila rosae , 55 Reticulitermes spp . , Schedorhinotermes spp . , and Zooter Rhagoletis cerasi , Rhagoletis pomonella , Rhagoletis men mopsis spp . A non - exhaustive list of particular species dax , Sitodiplosis mosellana , and Stomoxys calcitrans . includes , but is not limited to , Coptotermes acinaciformis ,

( 8 ) Order Hemiptera . A non - exhaustive list of particular Coptotermes curvignathus , Coptotermes frenchi , Copto genera includes , but is not limited to , Adelges spp . , Aulac - termes formosanus , Coptotermes gestroi , Cryptotermes bre aspis spp . , Aphrophora spp . , Aphis spp . , Bemisia spp . , 60 vis , Heterotermes aureus , Heterotermes tenuis , Incisitermes Ceroplastes spp . , Chionaspis spp . , Chrysomphalus spp . , minor , Incisitermes snyderi , Microtermes obesi , Nasuti Coccus spp . , Empoasca spp . , Euschistus spp . , Lepidosaphes termes comiger , Odontotermes formosanus , Odontotermes spp . , Lagynotomus spp . , Lygus spp . , Macrosiphum spp . , obesus , Reticulitermes banyulensis , Reticulitermes grassei , Nephotettix spp . , Nezara spp . , Nilaparvata spp . , Philaenus Reticulitermes flavipes , Reticulitermes hageni , Reticuli spp . , Phytocoris spp . , Piezodorus spp . , Planococcus spp . , 65 termes hesperus , Reticulitermes santonensis , Reticulitermes Pseudococcus spp . , Rhopalosiphum spp . , Saissetia spp . , speratus , Reticulitermes tibialis , and Reticulitermes virgini Therioaphis spp . , Toumeyella spp . , Toxoptera spp . , Trialeu CUS .

21 US 9 , 795 , 140 B2

22 ( 11 ) Order Lepidoptera . A non - exhaustive list of particu - ( 14 ) Order Psocoptera . A non - exhaustive list of particular

lar genera includes , but is not limited to , Adoxophyes spp . , species includes , but is not limited to , Liposcelis decolor , Agrotis spp . , Argyrotaenia spp . , Cacoecia spp . , Caloptilia Liposcelis entomophila , Lachesilla quercus , and Trogium spp . , Chilo spp . , Chrysodeixis spp . , Colias spp . , Crambus pulsatorium . spp . , Diaphania spp . , Diatraea spp . , Earias spp . , Ephestia 5 ( 15 ) Order Siphonaptera . A non - exhaustive list of particu spp . , Epimecis spp . , Feltia spp . , Gortyna spp . , Helicoverpa lar species includes , but is not limited to , Ceratophyllus spp . , Heliothis spp . , Indarbela spp . , Lithocolletis spp . , Loxa - gallinae , Ceratophyllus niger , Ctenocephalides canis , grotis spp . , Malacosoma spp . , Nemapogon spp . , Peridroma Ctenocephalides felis , and Pulex irritans . spp . , Phyllonorycter spp . , Pseudaletia spp . , Plutella spp . , ( 16 ) Order Thysanoptera . A non - exhaustive list of par Sesamia spp . , Spodoptera spp . , Synanthedon spp . , and 10 ticular genera includes , but is not limited to , Caliothrips Yponomeuta spp . A non - exhaustive list of particular species spp . , Frankliniella spp . , Scirtothrips spp . , and Thrips spp . A includes , but is not limited to , Achaea Janata , Adoxophyes non - exhaustive list of particular species includes , but is not orana , Agrotis ipsilon , Alabama argillacea , Amorbia limited to , Frankliniella bispinosa , Frankliniella fusca , cuneana , Amyelois transitella , Anacamptodes defectaria , Frankliniella occidentalis , Frankliniella schultzei , Anarsia lineatella , Anomis sabulifera , Anticarsia gemmata - 15 Frankliniella tritici , Frankliniella williamsi , Heliothrips lis , Archips argyrospila , Archips rosana , Argyrotaenia cit haemorrhoidalis , Rhipiphorothrips cruentatus , Scirtothrips rana , Autographa gamma , Bonagota cranaodes , Borbo cin citri , Scirtothrips dorsalis , Taeniothrips rhopalantennalis , nara , Bucculatrix thurberiella , Capua reticulana , Thrips hawaiiensis , Thrips nigropilosus , Thrips orientalis , Carposina niponensis , Chlumetia trans versa , Choris Thrips palmi , and Thrips tabaci . toneura rosaceana , Cnaphalocrocis medinalis , Conopomor - 20 ( 17 ) Order Thysanura . A non - exhaustive list of particular pha cramerella , Corcyra cephalonica , Cossus cossus , Cydia genera includes , but is not limited to , Lepisma spp . and caryana , Cydia funebrana , Cydia molesta , Cydia nigricana , Thermobia spp . Cydia pomonella , Darna diducta , Diaphania nitidalis , Dia - ( 18 ) Order Acarina . A non - exhaustive list of particular traea saccharalis , Diatraea grandiosella , Earias insulana , genera includes , but is not limited to , Acarus spp . , Aculops Earias vittella , Ecdytolopha aurantianum , Elasmopalpus 25 spp . , Argus spp . , Boophilus spp . , Demodex spp . , Dermacen lignosellus , Ephestia cautella , Ephestia elutella , Ephestia tor spp . , Epitrimerus spp . , Eriophyes spp . , Ixodes spp . , kuehniella , Epinotia aporema , Epiphyas postvittana , Eri - Oligonychus spp . , Panonychus spp . , Rhizoglyphus spp . , and onota thrax , Estigmene acrea , Eupoecilia ambiguella , Tetranychus spp . A non - exhaustive list of particular species Euxoa auxiliaris , Galleria mellonella , Grapholita molesta , includes , but is not limited to , Acarapis woodi , Acarus siro , Hedylepta indicata , Helicoverpa armigera , Helicoverpa 30 Aceria mangiferae , Aculops lycopersici , Aculus pelekassi , zea , Heliothis virescens , Hellula undalis , Keiferia lycoper - Aculus schlechtendali , Amblyomma americanum , Brevipal sicella , Leucinodes orbonalis , Leucoptera coffeella , Leucop - pus obovatus , Brevipalpus phoenicis , Dermacentor variabi tera malifoliella , Lobesia botrana , Loxagrotis albicosta , lis , Dermatophagoides pteronyssinus , Eotetranychus car Lymantria dispar , Lyonetia derkella , Mahasena corbetti , pini , Liponyssoides sanguineus , Notoedres cati , Mamestra brassicae , Manduca sexta , Maruca testulalis , 35 Oligonychus coffeae , Oligonychus ilicis , Ornithonyssus Metisa plana , Mythimna unipuncta , Neoleucinodes elegan bacoti , Panonychus citri , Panonychus ulmi , Phyllocoptruta talis Nymphula depunctalis , Operophtera brumata , oleivora , Polyphagotarsonemus latus , Rhipicephalus san Ostrinia nubilalis , Oxydia vesulia , Pandemis cerasana , guineus , Sarcoptes scabiei , Tegolophus perseaflorae , Tet Pandemis heparana , Papilio demodocus , Pectinophora gos - ranychus urticae , Tyrophagus longior , and Varroa destruc sypiella , Peridroma saucia , Perileucoptera coffeella , Phtho - 40 tor . rimaea operculella , Phyllocnistis citrella , Phyllonorycter ( 19 ) Order Araneae . A non - exhaustive list of particular blancardella , Pieris rapae , Plathypena scabra , Platynota genera includes , but is not limited to , Loxosceles spp . , idaeusalis , Plodia interpunctella , Plutella xylostella , Poly - Latrodectus spp . , and Atrax spp . A non - exhaustive list of chrosis viteana , Prays endocarpa , Prays oleae , Pseudaletia particular species includes , but is not limited to , Loxosceles unipuncta , Pseudoplusia indudens , Rachiplusia nu , Scir - 45 recluse , Latrodectus mactans , and Atrax robustus . pophaga incertulas , Sesamia inferens , Sesamia nonagri - ( 20 ) Class Symphyla . A non - exhaustive list of particular oides , Setora nitens , Sitotroga cerealella , Sparganothis species includes , but is not limited to , Scutigerella immacu pilleriana , Spodoptera exigua , Spodoptera frugiperda , late . Spodoptera eridania , Thecla basilides , Tinea pellionella , ( 21 ) Subclass Collembola . A non - exhaustive list of par Tineola bisselliella , Trichoplusia ni , Tuta absoluta , Zeuzera 50 ticular species includes , but is not limited to , Bourletiella coffeae , and Zeuzea pyrina . hortensis , Onychiurus armatus , Onychiurus fimetarius , and

( 12 ) Order Mallophaga . A non - exhaustive list of particu - Sminthurus viridis . lar genera includes , but is not limited to , Anaticola spp . , ( 22 ) Phylum Nematoda . A non - exhaustive list of particu Bovicola spp . , Chelopistes spp . , Goniodes spp . , Menacan - lar genera includes , but is not limited to , Aphelenchoides thus spp . , and Trichodectes spp . A non - exhaustive list of 55 spp . , Belonolaimus spp . , Criconemella spp . , Ditylenchus particular species includes , but is not limited to , Bovicola spp . , Globodera spp . , Heterodera spp . , Hirschmanniella bovis , Bovicola caprae , Bovicola ovis , Chelopistes melea spp . , Hoplolaimus spp . , Meloidogyne spp . , Pratylenchus gridis , Goniodes dissimilis , Goniodes gigas , Menacanthus spp . , and Radopholus spp . À non - exhaustive list of particular stramineus , Menopon gallinae , and Trichodectes canis . species includes , but is not limited to , Dirofilaria immitis ,

( 13 ) Order Orthoptera . A non - exhaustive list of particular 60 Globodera pallida , Heterodera glycines , Heterodera zeae , genera includes , but is not limited to , Melanoplus spp . and Meloidogyne incognita , Meloidogyne javanica , Onchocerca Pterophylla spp . A non - exhaustive list of particular species volvulus , Pratylenchus penetrans , Radopholus similis , and includes , but is not limited to , Acheta domesticus , Anabrus Rotylenchulus reniformis . simplex , Gryllotalpa africana , Gryllotalpa australis , Gryl - ( 23 ) Phylum Mollusca . A non - exhaustive list of particular lotalpa brachyptera , Gryllotalpa hexadactyla , Locusta 65 species includes , but is not limited to , Arion vulgaris , Cornu migratoria , Microcentrum retinerve , Schistocerca gregaria , aspersum , Deroceras reticulatum , Limax flavus , Milax and Scudderia furcata . gagates , and Pomacea canaliculata .

23 US 9 , 795 , 140 B2

24 A particularly preferred pest group to control is sap - wherein :

feeding pests . Sap - feeding pests , in general , have piercing ( A ) Rl is selected from the group consisting of H , F , CI , and / or sucking mouthparts and feed on the sap and inner Br , I , CN , NH , , NO2 , ( C , - C4 ) alkyl , ( Cz - C . ) cycloalkyl , plant tissues of plants . Examples of sap - feeding pests of ( C . - C ) alkenyl , ( CZ - C ) cycloalkenyl , ( C . - C . ) alkynyl , ( C , particular concern to agriculture include , but are not limited 5 C Jalkoxy , ( C , - C2 ) haloalkyl , ( Cz - C . ) halocycloalkyl , ( C , to , aphids , leafhoppers , moths , scales , thrips , psyllids , C2 ) haloalkenyl , ( C3 - C . ) halocycloalkenyl , ( C , - C2 ) ha mealybugs , stinkbugs , and whiteflies . Specific examples of loalkoxy . siC . - C . Jalkvi SCOX? . - Jalkyl scoC loalkoxy , S ( C - C ) alkyl , S ( O ) ( C2 - C4 ) alkyl , S ( O ) 2 ( CZ - C4 ) - C ) Orders that have sap - feeding pests of concern in agriculture alkyl , S ( C2 - C4 ) haloalkyl , S ( O ) ( C , - C4 ) haloalkyl , S ( O ) 2 ( C1 include but are not limited to , Anoplura and Hemiptera . P C4 ) haloalkyl , o ( C , - C4 ) alkyl - S ( O ) 2NH2 , and ( C1 - C4 ) Specific examples of Hemiptera that are of concern in 10 haloalkyl - S ( O ) 2NH2 ; agriculture include , but are not limited to , Aulacaspis spp . , Aphrophora spp . , Aphis spp . , Bemisia spp . , Coccus spp . , ( B ) R2 is selected from the group consisting of H , F , C1 , Euschistus spp . , Lygus spp . , Macrosiphum spp . , Nezara spp . , Br , I , CN , NH2 , NO2 , ( C , - C4 ) alkyl , ( C3 - Co ) cycloalkyl , and Rhopalosiphum spp . ( C2 - C4 ) alkenyl , ( C3 - C . ) cycloalkenyl , ( C2 - C4 ) alkynyl , ( C1

Another particularly preferred pest group to control is C _ ) alkoxy , ( C , - C2 ) haloalkyl , ( C3 - C . ) halocycloalkyl , ( C2 chewing pests . Chewing pests , in general . have mouthparts 15 C4 ) haloalkenyl , ( Cz - Cohalocycloalkenyl , ( C , - Caha that allow them to chew on the plant tissue including roots , loalkoxy , S ( C , - C4 ) alkyl , S ( O ) ( CZ - C4 ) alkyl , S ( O ) 2 ( C . - C . ) stems , leaves , buds , and reproductive tissues ( including , but alkyl , S ( C1 - C4 ) haloalkyl , S ( O ) ( CZ - C4 ) haloalkyl , S ( O ) 2 ( C not limited to flowers , fruit , and seeds ) . Examples of chew C4 ) haloalkyl , ( C - C4 ) alkyl - S ( O ) 2NH2 , and ( C - C4 ) ing pests of particular concern to agricultural include , but are haloalkyl - S ( O ) 2NH2 ; not limited to caterpillars . beetles , grasshoppers , and 20 ( C ) R is selected from the group consisting of H , F , CI , locusts . Specific examples of Orders that have chewing pests Br , I , CN , NH2 , NO ) , ( C , - CA ) alkyl , ( C2 - Cmcycloalkyl , of concern in agriculture include but are not limited to , ( C2 - C4 ) alkenyl , ( C3 - C . ) cycloalkenyl , ( C2 - C4 ) alkynyl , ( C1 Coleoptera and Lepidoptera . Specific examples of Coleop C4 ) alkoxy , ( C , - C4 ) haloalkyl , ( Cz - C ) halocycloalkyl , ( C2 tera that are of concern in agriculture include , but are not C _ ) haloalkenyl , ( Cz - C . ) halocycloalkenyl , ( C1 - C4 ) ha limited to . Anthonomus spp . . Cerotoma spp . , Chaetocnema 25 loalkoxy , S ( C1 - C4 ) alkyl , S ( O ) ( C , - CA ) alkyl , S ( O ) , ( C , - CA ) spp . , Colaspis spp . , Cyclocephala spp . , Diabrotica spp . , alkyl , S ( C1 - C4 ) haloalkyl , S ( O ) ( CZ - C4 ) haloalkyl , S ( O ) 2 ( C Hypera spp . , Phyllophaga spp . , Phyllotreta spp . , Spheno - C4 ) haloalkyl , naloalkyli ( C2 - C4 ) alkyl - S ( O ) 2NH2 , 14 - 4 ) alkyl - s ( ) 2NH2 and and 1964 ) ( CZ - C4 ) phorus spp . , Sitophilus spp . haloalkyl - S ( O ) , NH , ;

The phrase " pesticidally effective amount ” means the ( D ) R is selected from the group consisting of H , F , CI , amount of a pesticide needed to achieve an observable effect 30 Br , 1 , CN , NH2 , NO2 , ( C1 - C4 ) alkyl , ( C3 - C6 ) cycloalkyl , on a pest , for example , the effects of necrosis , death , ( C2 - C4 ) alkenyl , ( C3 - C . ) cycloalkenyl , ( C2 - C4 ) alkynyl , ( C1 retardation , prevention , removal , destruction , or otherwise C4 ) alkoxy , ( C1 - C4 ) haloalkyl , ( C3 - C6 ) halocycloalkyl , ( C2 diminishing the occurrence and / or activity of a pest in a Chaloalkenyl , 13 - C6 ) ha C4 ) haloalkenyl , ( C3 - C . ) halocycloalkenyl , ( C , - C2 ) ha locus . This effect may come about when pest populations are loalkoxy , S ( CZ - C4 ) alkyl , S ( O ) ( C1 - C4 ) alkyl , S ( O ) 2 ( CZ - C4 ) repulsed from a locus , pests are incapacitated in , or around . 35 alkyl , S ( C1 - C4 ) haloalkyl , S ( O ) ( C , - C2 ) haloalkyl , S ( O ) , ( C , a locus , and / or pests are exterminated in , or around , a locus . C2 ) haloalkyl , ( C , - C _ ) alkyl - S ( O ) 2NH2 , and ( C , - CA ) Of course , a combination of these effects can occur . Gen haloalkyl - S ( O ) 2NH2 ; erally , pest populations , activity , or both are desirably ( E ) R is selected from the group consisting of H , F , C1 , reduced more than fifty percent , preferably more than 90 Br , I , CN , NH2 , NO2 , ( C1 - C4 ) alkyl , ( C3 - C6 ) cycloalkyl , percent , and most preferably more than 99 percent . In 40 ( C2 - C4 ) alkenyl , ( C3 - C . ) cycloalkenyl , ( C - CA ) alkynyl , ( C , general , a pesticidally effective amount , for agricultural C4 ) alkoxy , ( C , - C4 ) haloalkyl , ( C3 - C . ) halocycloalkyl , ( C2 purposes , is from about 0 . 0001 grams per hectare to about C _ ) haloalkenyl , ( C3 - C6 ) halocycloalkenyl , ( C , - C4 ) ha 5000 grams per hectare , preferably from about 0 . 0001 grams loalkoxy , S ( C , - C4 ) alkyl , S ( O ) ( C , - C4 ) alkyl , S ( O ) 2 ( C , - CA ) per hectare to about 500 grams per hectare , and it is even alkyl , ( 1 - 4 ) naloalkyl , DO 14 ) naloalkyl , 21 " more preferably from about 0 . 0001 grams per hectare to 45 4haloalkyl , 191 - C4 ) alkyl - S ( O ) 2NH2 , and ( 1 - 2 ) about 50 grams per hectare . haloalkyl - S ( O ) 2NH2 ;

( F ) R is selected from the group consisting of H and DETAILED DESCRIPTION OF THIS ( C1 - C4 ) alkyl ;

DISCLOSURE ( G ) R7 is selected from the group consisting of H , F , C1 , 50 Br , and I ;

This document discloses molecules of Formula One ( H ) R8 is selected from the group consisting of F , C1 , Br , and I ;

( I ) Rº is selected from the group consisting of H and Formula One Formula One ( C , - C4 ) alkyl ;

55 ( I ) R16 is selected from the group consisting of H , ( C1 C ) alkyl , ( C2 - C2 ) alkenyl , ( C , - C4 ) haloalkyl , ( C , - C4 ) alkyl ( C2 - C4 ) alkoxy , CEO ) ( C1 - C4 ) alkyl , and ( C1 - C4 ) alkoxyC R7 R80 R15 FO ) ( C - C4 ) alkyl ;

( K ) Rll is selected from the group consisting of H , F , C1 , 60 Br , I , CN , NH2 , NO2 , ( C , - C4 ) alkyl , ( Cz - C . ) cycloalkyl ,

( C2 - C4 ) alkenyl , ( Cz - C . ) cycloalkenyl , ( C2 - C4 ) alkynyl , ( C , R10 R14 C _ ) alkoxy , ( C , - C4 ) haloalkyl , ( Cz - Chalocycloalkyl , ( C2

C4 ) haloalkenyl , ( C3 - C . ) halocycloalkenyl , ( C , - C4 ) ha Y R1 loalkoxy , S ( C , - C4 ) alkyl , S ( O ) ( C1 - C4 ) alkyl , S ( O ) 2 ( C1 - C4 ) 65 alkyl , S ( C , - C4 ) haloalkyl , S ( O ) ( CZ - C4 ) haloalkyl , S ( O ) 2 ( C )

C4 ) haloalkyl , ( C2 - C4 ) alkyl - S ( O ) 2NH2 , and ( CZ - C4 ) haloalkyl - S ( O ) 2NH2 ;

R 12

R13

Z

R4 R 16 - Z

R14

R3

US 9 , 795 , 140 B2 25 26

( L ) Ru is selected from the group consisting of H , F , C1 , One or more centers of chirality may be present in which Br , I , CN , NH , NO2 , ( C , - C ) alkyl , ( C3 - C . ) cycloalkyl , case molecules of Formula One may be present as pure ( C2 - C4 ) alkenyl , ( C3 - C . ) cycloalkenyl , ( C2 - C4 ) alkynyl , ( C1 enantiomers , mixtures of enantiomers , pure diastereomers or C4 ) alkoxy , ( C1 - C4 ) haloalkyl , ( C3 - C6 ) halocycloalkyl , ( C2 - mixtures of diastereomers . It will be appreciated by those C2 ) haloalkenyl , ( Cz - C ) halocycloalkenyl , ( C1 - C4 ) ha - 5 skilled in the art that one stereoisomer may be more active loalkoxy , S ( C , - C4 ) alkyl , S ( O ) ( C2 - C4 ) alkyl , S ( O ) 2 ( C7 - C4 ) than the other stereoisomers . Individual stereoisomers may alkyl , S ( C , - C4 ) haloalkyl , S ( O ) ( C , - C ) haloalkyl , S ( O ) 2 ( C1 be obtained by known selective synthetic procedures , by C4 ) haloalkyl , ( C , - C4 ) alkyl - S ( O ) 2NH2 , and ( C2 - C4 ) conventional synthetic procedures using resolved starting haloalkyl - S ( O ) 2NH2 ; materials , or by conventional resolution procedures . There ( M ) R13 is selected from the group consisting of H , F , C1 , 10 may be double bonds present in the molecule , in which case Br , I , CN , NH2 , NO2 , ( C - C ) alkyl , ( C3 - C . ) cycloalkyl , compounds of Formula One may exist as single geometric ( C2 - C _ ) alkenyl , ( C3 - C . ) cycloalkenyl , ( C2 - C4 ) alkynyl , ( C isomers ( cis or trans , E or Z ) or mixtures of geometric C4 ) alkoxy , ( C - C2 ) haloalkyl , ( C3 - C . ) halocycloalkyl , ( C2 isomers ( cis and trans , E and Z ) . Centers of tautomerisation C4 ) haloalkenyl , ( C3 - C . ) halocycloalkenyl , ( C , - C2 ) ha loalkoxy . S ( C . - C . Jalkyl . S ( O ) ( C . - C . Jalkyl . SOC . - C . ) 15 may be present . This disclosure covers all such isomers , alkyl , S ( C , - C4 ) haloalkyl , S ( O ) ( C , - C4 ) haloalkyl , S ( O ) 2 ( C , tautomers , and mixtures thereof , in all proportions . C2 ) haloalkyl , ( C , - C2 ) alkyl - S ( O ) , NH , and ( C . - C . ) In another embodiment the molecules of Formula One , haloalkyl - S ( O ) 2NH2 ; the carboxamido , and the phenyl , which are bonded to the

( N ) R14 is selected from the group consisting of H , F , CI , cyclopropane , are in the R , R configuration . This embodi Br , I , CN , NH , , NO , , ( C , - C . ) alkyl , ( C . - C . ) cycloalkyl , 20 ment may be used in combination with the other embodi ( C2 - C4 ) alkenyl , ( Cz - Co ) cycloalkenyl , ( C2 - C Jalkynyl , ( C , - ments of R1 , R2 , R3 , R4 , RS , R " , R7 , R8 , R9 , R10 , R1 , R12 , C4 ) alkoxy , ( C1 - C2 ) haloalkyl , ( C3 - C . ) halocycloalkyl , ( C2 - R13 , R14 , RS , RIO , Q ' , and Q ? . C4 ) haloalkenyl , ( Cz - C . ) halocycloalkenyl , ( C , - C4 ) ha - In another embodiment Rl is H or F . This embodiment loalkoxy , S ( C , - C2 ) alkyl , S ( O ) ( C , - C2 ) alkyl , S ( O ) 2 ( C , - C4 ) may be used in combination with the other embodiments of alkyl , S ( C , - C4 ) haloalkyl , S ( O ) ( C1 - C4 ) haloalkyl , S ( O ) 2 ( C ) - 25 R2 , R3 , R4 , RS , R " , R7 , RS , Rº , R19 , R11 , R12 , R13 , R14 , R15 , C4 ) haloalkyl , ( C , - C4 ) alkyl - S ( O ) 2NH2 , and ( C2 - C4 ) R16 , 01 , and 02 . haloalkyl - S ( O ) 2NH2 ; In another embodiment R2 is selected from the group ( O ) R15 is selected from the group consisting of ( Q ) , H , consisting of H , F , and Cl . This embodiment may be used in ( C , - C4 ) alkyl , ( C2 - C4 ) alkenyl , ( C - C4 ) haloalkyl , ( C , - CA ) combination with the other embodiments of R ' , R3 , R4 , RS , alkyl ( C , - C4 ) alkoxy , C = O ) ( C7 - C4 ) alkyl , and ( C1 - C4 ) 30 R6 R7 R8 . R2 . R10 R11 R12 R13 . R14 R15 R16 . 01 . and O2 . alkoxyCeO ) ( C , - C4 ) alkyl ; In another embodiment R3 is selected from the group ( P ) R is selected from the group consisting of ( Q ) , consisting of H , F , and Cl . This embodiment may be used in ( C , - C ) alkyl , ( C , - C2 ) alkyl - 0 — ( C , - C3 ) alkyl , ( C , - C2 ) alkyl combination with the other embodiments of R1 , R2 , R4 , RS , ( Cz - Cg ) cycloalkyl , ( C , - C , Jalkylphenyl , ( C2 - C3 ) alkenyl , ( C2 - C3 ) alkynyl , ( C , - C ) haloalkyl , ( C , - Cg ) alkyl - S ( C7 - C3 ) 35 R " , R7 , R8 , R9 , R19 , R11 , R12 , R13 , R14 , R15 , R16 , 01 , and Q2 . alkyl , ( C7 - C , Jalkyl - S ( O ) ( C - C ) alkyl , ( C , - C , Jalkyl In another embodiment R4 is F or Cl . This embodiment S ( O ) 2 - ( C ) - C ) alkyl , O - phenyl , O ( C2 - C3 ) alkenyl , may be used in combination with the other embodiments of 0 - ( C7 - C Jalkyl ( Cz - C ) cycloalkyl , 0 - C - C Jalkylphe - R ' , R " , R " , R " , Rº , R ' , R? , Rº , R ' ' , R " , R " , R ' s , R4 , RS , nyl , ( C , - C2 ) alkyl - 0 ( C , - C ) alkyl ( Cz - C2 ) cycloalkyl , ( C , - R " , Q ' , and Q . C Jalkyl - 0 — ( C . - C . ) haloalkyl , ( C , - C Jalkyl - C ( = O ) NH — 40 In another embodiment Rºis H or F . This embodiment ( C - C ) haloalkyl , ( C - Cs ) alkyl - NHC ( O ) - ( C , - C , Jalkyl , may be used in combination with the other embodiments of ( C , - C ) alkyl - s — ( C . - C . ) haloalkyl , ( C , - C , ) alkyl - S ( O ) — R ' , R2 , R3 , R4 , R " , R7 , R8 , R9 , R10 , R1 , R12 , R13 , R14 , R15 , ( C1 - C2 ) haloalkyl , ( C , - Cg ) alkyl - S ( O ) 2 - ( C1 - C2 ) haloalkyl , and ( C , - Cg ) alkyl - S ( O ) 2 - NH2 , In another embodiment Ris H . This embodiment may be wherein each alkyl , alkenyl , alkynyl , cycloalkyl , 45 used in combination with the other embodiments of R1 , R² ,

haloalkyl , and phenyl , may be optionally substituted R3 , R4 , RS , R ? , R8 , R9 , R19 , R11 , R12 , R13 , R14 , R15 , R16 , Q ' , with one or more substituents selected from the group and Q ? . consisting of F , C1 , Br , I , CN , OH , NH2 , NO2 , ( C , - C3 ) In another embodiment R7 is selected from the group alkyl , ( C , - C Jalkoxy , ( C . - C . ) haloalkyl , N ( ( C . - C . ) consisting of Br and Cl . This embodiment may be used in alkyl ) 2 , C ( O ) O ( C7 - C ) alkyl , benzothioenyl , 2 , 3 - di - 50 combination with the other embodiments of R ' , R² , R3 , R4 , hydro - 1H - imidazolonyl , furanyl , pyrazolyl , pyridinyl , RS , R " , R8 , R9 , R1 , R1 , R12 , R13 , R14 , R15 , R16 , Q1 , and Q ? . thiazolyl , and triazolyl ; In another embodiment RS is selected from the group

( Q ) Rls and R16 together can optionally form a 2 - to consisting of Br and Cl . This embodiment may be used in 5 - membered saturated or unsaturated , hydrocarbyl link , combination with the other embodiments of R ' , R2 , R3 , R4 , which may contain one or more heteroatoms selected from 55 RS , R " , R ? , R " , R19 , R1 , R12 , R13 , R14 , R15 , R16 , Q ' , and Q2 . the group consisting of nitrogen , sulfur , and oxygen , In another embodiment Rº is H . This embodiment may be wherein said hydrocarbyl link may be optionally substituted used in combination with the other embodiments of R1 , R2 , with one or more substituents selected from the group R ’ , R4 , RS , R " , R ? , R8 , R19 , R11 , R12 , R13 , R14 , R15 , R16 , Q ' , consisting of F , C1 , Br , I , CN , NH , , and NO , ; and QP .

( R ) Q1 and Q ? are each independently selected from the 60 In another embodiment R1° is H . This embodiment may group consisting of O and S ; and be used in combination with the other embodiments of R ' ,

N - oxides , agriculturally acceptable acid addition salts , R ? , R3 , R4 , RS , RÓ , R7 , R8 , Rº , R1 , R1 , R13 , R14 , R15 , R16 , salt derivatives , solvates , ester derivatives , crystal poly - Q ! , and Q2 . morphs , isotopes , resolved stereoisomers , and tautomers , of In another embodiment Rll is H . This embodiment may the molecules of Formula One . 65 be used in combination with the other embodiments of R1 ,

The molecules of Formula One may exist in different R2 , R3 , R4 , RS , R " , R ? , R8 , R9 , R10 , R12 , R13 , R14 , R15 , R16 , geometric or optical isomeric or different tautomeric forms . Q ' , and Q ? .

27 US 9 , 795 , 140 B2

28 In another embodiment R12 is H . This embodiment may embodiments of R1 , R2 , R3 , R4 , RS , R6 , R7 , RS , R , Q1 , R10 ,

be used in combination with the other embodiments of R1 , R11 , R12 , R13 , R14 , Q ? , and R15 . R ? , R3 , R4 , RS , RÓ , R7 , R8 , R9 , R19 , R1 , R13 , R14 , R15 , R16 , In another embodiment R15 and R16 together are a 4 - mem Q ' , and Q ? . bered saturated , hydrocarbyl link ,

In another embodiment R13 is selected from the group 5 wherein said hydrocarbyl link is substituted with one or consisting of H , CI , and ( C7 - C2 ) haloalkyl . This embodiment more F . This embodiment may be used in combination with may be used in combination with the other embodiments of the other embodiments of R1 , R2 , R3 , R4 , RS , R , R7 , R8 , Rº , R1 , R2 , R3 , R4 , RS , R " , R7 , RS , R " , R10 , R1 , R12 , R14 , R15 , O , R19 , R1 , R12 , R13 , R14 , and Q ? .

In another embodiment R15 and R16 together are R16 , Q ' , and Q ? . In another embodiment R13 is selected from the group 10 CH CH CF2CH2 — . This embodiment may be used in

combination with the other embodiments of R ' , R2 , R3 , RA , consisting of H , C1 , and CF2 . This embodiment may be used RS , R " , R7 , R8 , R ' , Q ' , R10 , R1 , R1 , R13 , R14 , and Q ? in combination with the other embodiments of R1 , R2 , R , In another embodiment Q ' is O . This embodiment may be R4 , RS , RÓ , R7 , R8 , Rº , R10 , R ! ! , R1 , R14 , R15 , R16 , Q ' , and used in combination with the other embodiments of R1 , R2 , 02 . 15 R3 , R4 , RS , R , R ? , R8 , R9 , R19 , R1 , R ! ? , R13 , R14 , R15 , R16 , In another embodiment R14 is H . This embodiment may and Q2 . be used in combination with the other embodiments of R ' In another embodiment Q2 is O . This embodiment may be R ? , R3 , R4 , RS , R " , R7 , RS , Rº , R10 , R1 , R1 ? , R13 , R15 , R16 , used in combination with the other embodiments of R1 , R2 , Q ! , and Q ? . R3 , R4 , RS , R " , R7 , RS , Rº , R10 , R1 , R12 , R13 , R14 , R15 , R16 ,

In another embodiment R15 is selected from the group 20 and Q1 . . consisting of H and ( C , - C4 ) alkyl . This embodiment may be In another embodiment : used in combination with the other embodiments of R1 , R² , ( A ) R is H ; R3 , R4 , RS , R " , R7 , R? , Rº , R10 , R11 , R12 , R13 , R14 , R16 , O ! , ( B ) RP is selected from the group consisting of H and Cl ; and Q2 . ( C ) R3 is selected from the group consisting of H and Cl ;

In another embodiment R15 is selected from the group 25 ( D ) R4 is Cl ; consisting of H and CH3 . This embodiment may be used in ( E ) R is H ; combination with the other embodiments of R1 , R2 , R3 , R4 , ( F ) R is H ; RS , R " , R ? , R8 , R9 , R19 , R1 , R12 , R1 , R13 , R16 , Q1 , and Q2 . ( G ) R ' is selected from the group consisting of Cl and Br ;

In another embodiment Riº is selected from the group ( H ) R® is selected from the group consisting of Cl and Br ; consisting of ( C1 - C2 ) alkyl , ( C1 - C2 ) alkyl - 0 — ( C - C Jalkyl , 30 ( 1 ) Rºis H ; ( C2 - Cg ) alkyl ( C3 - Cg ) cycloalkyl , ( C , - Cg ) alkylphenyl , ( C2 ( J ) R10 is H ; Cg Jalkenyl , ( C2 - C3 ) alkynyl , ( C , - C ) haloalkyl , ( C , - C ) ( K ) R1 is H ; alkyl - S — ( C ; - Cg ) alkyl , ( C , - C2 ) alkyl - S ( O ) - ( C1 - C2 ) alkyl , ( L ) R12 is H ; ( C1 - C2 ) alkyl - S ( O ) 2 - ( C1 - Cg ) alkyl , O - phenyl , O ( C2 - C ) ( M ) R13 is selected from the group consisting of H , CI , alkenyl , O ( C , - C3 ) alkyl ( Cz - C3 ) cycloalkyl , O ( C , - C3 ) 35 and CFz ; alkylphenyl , ( C1 - C2 ) alkyl - 0 — ( C - Cg ) alkyl ( C3 - C3 ) cy ( N ) R14 is H ; cloalkyl , ( C , - Cg ) alkyl - 0 — ( C1 - C2 ) haloalkyl , ( C , - Cg ) alkyl ( 0 ) R15 is selected from the group consisting of H and

C O ) NH — ( C1 - C2 ) haloalkyl , and ( C1 - C2 ) alkyl - NHC CHz ; ( O ) ( C . - C ) alkyl , ( P ) R16 is selected from the group consisting of CH2 ,

wherein each alkyl , alkenyl , alkynyl , cycloalkyl , 40 CH2CH2 C H2CH2CH2 C H2CH2CH2CH2 , haloalkyl , and phenyl , may be optionally substituted with CH2CH2CH2OCH2CH2 , CH3 , CH2CH3 , CH2CH2CH3 , one or more substituents selected from the group consisting CH2CH2CH2CH3 , CHÚCH , CH , CH , CH , of F , C1 , I , CN , ( C , - Cg ) alkyl , ( C2 - C3 ) alkoxy , ( C , - C ) ha CH2CH2CH2CH2CH2CH3 , | CH CH ( CH3 ) , loalkyl , N ( ( C1 - C2 ) alkyl ) 2 , and pyridinyl . This embodiment CH _ cyclopropyl , CH CH cyclopropyl , CH?cyclobutyl , may be used in combination with the other embodiments of 45 CH phenyl , CH CH2phenyl , CH2C = CH , CH2C = CH , R1 , R² , R3 , R4 , RS , RÓ , R7 , R8 , Rº , Q1 , R1 , R1 , R12 , R13 , CH CF3 , CH , CHF2 , CH CH CF3 , CH CF2CF3 , R14 , Q ? , and R15 . CH CH CH CF3 , CH CH CF2CF3 , CH , CF CF CF3 ,

In another embodiment R16 is selected from the group CH2CH2CH2CH F , CH CH SCH , CH CH S ( O ) CHz , consisting of CH , CH2CH2 CH2CH2CH2 , CH2CH2S ( O ) 2CH3 , C ( CH3 ) 2CH S ( O ) 2CH3 , Ophenyl , CH2CH2CH2CH2 , CH CH CH _ OCH CH2 , CH3 , CH2CH3 , 50 OCH CH = CH2 , OCH cyclopropyl , OCHyphenyl , CH , CH , CH , CH?CH , CH , CH , , CH?CH , CH - CH - CH , CH?CH , OCHÚcyclopropyl , CH2CH2CH , OCH , CF , CH?C CH2CH2CH2CH2CH2CH3 , CH3CH ( CH? ) , ( ~ O ) NHCH CF , and CH?CH NHCK2O ) CH , CH?cyclopropyl , CH CH cyclopropyl , CH cyclobutyl , wherein each CH2 CH2CH2 CH2CH2CH2 , CH2phenyl , CH CH phenyl , CH2C = CH , CH2C = CH , CH2CH2CH2CH2 , cyclopropyl , cyclobutyl , and phe CH , CF3 , CH CHF2 , CH , CH CF3 , CH , CF , CF3 , 55 nyl , may be optionally substituted with one or more CH , CH , CH , CF3 , CH , CH , CF CF3 , CH , CF CF CF3 , substituents selected from the group consisting of F , C1 , CH , CH , CH , CHF , CH CH . SCH , CH , CH , S ( O ) CH , CN , C ( CH3 ) 3 , CF3 , OCH3 , OCH CH3 , N ( CH3 ) 2 , and CH2CH2S ( O ) 2CH3 , C ( CH3 ) 2CH S ( O ) 2CH3 , Ophenyl , pyridinyl ; and OCH2CH = CH2 , OCH cyclopropyl , OCH phenyl , ( Q ) Ris and R16 together are a 4 - membered saturated , CH _ CH _ OCH cyclopropyl , CH CH CH OCH CF3 , CH2C 60 hydrocarbyl link , ( JOONHCH3CF , , and CH?CH NHCUZO ) CH , wherein said hydrocarbyl link is substituted with one or

wherein each CH2 CH2CH2 CH2CH2CH2 , more F . CH2CH2CH2CH2 , cyclopropyl , cyclobutyl , and phenyl , may ( R ) Q ' and Q ? are 0 . be optionally substituted with one or more substituents In another embodiment : selected from the group consisting of F , C1 , CN , C ( CH3 ) 3 , 65 ( A ) R ' , R2 , R3 , R4 , RS , R1 , R12 , R13 , and R14 are each CF3 , OCHZ , OCH CHz , N ( CH3 ) 2 , and pyridinyl . This independently selected from the group consisting of H , CI , embodiment may be used in combination with the other and ( C1 - C4 ) haloalkyl ;

CI :

US 9 , 795 , 140 B2 29 30

( B ) R and Rºare H ; ( G ) R15 is selected from the group consisting of ( I ) , H , and ( C ) R7 is Cl ; ( C . - C4 ) alkyl ; ( D ) R8 is Cl ; ( H ) R16 is selected from the group consisting of ( I ) , ( E ) Q ' and Q ? are 0 ; ( C , - C2 ) alkyl , ( C , - C3 ) alkyl - 04C - C , Jalkyl , ( C , - C Jalkyl ( F ) R10 is H ; 5 ( Cz - Cg ) cycloalkyl , ( C , - Cg ) alkylphenyl , ( C2 - C , ) alkenyl , ( G ) Ris is selected from the group consisting of ( I ) , H , and ( C2 - C2 ) alkynyl , ( C , - C2 ) haloalkyl , ( C , - C2 ) alkyl - S ( C1 - C2 )

alkyl , ( C1 - C2 ) alkyl - S ( O ) - ( C1 - C2 ) alkyl , ( C , - Cg ) alkyl - S ( O ) ( C1 - C4 ) alkyl ; 2 - ( C , - C3 ) alkyl , O — ( C2 - C3 ) alkenyl , 0 - C - C2 ) alkyl ( C3 ( H ) R16 is selected from the group consisting of ( I ) , Cs ) cycloalkyl , 0 - ( C , - Cg ) alkylphenyl , ( C1 - C2 ) alkyl - 0 ( C1 - Cg ) alkyl , ( C , - C8 ) alkyl - 0 — ( C1 - Cg ) alkyl , ( C - Cg ) alkyl ( C . - C . Jalkyl ( Cz - C ) cycloalkyl , ( C , - C , Jalkyl - 0 - C , - C2 ) ( C3 - C8 ) cycloalkyl , ( C1 - C2 ) alkylphenyl , ( C2 - Cg ) alkenyl , " haloalkyl , ( C , - Cg ) alkyl - C ( = O ) NH ( C ; - Cg ) haloalkyl , and ( C2 - C2 ) alkynyl , ( C , - C ) haloalkyl , ( C , - Cg ) alkyl - S ( C2 - C3 ) ( C , - C2 ) alkyl - NHC ( O ) ( C - C Jalkyl , alkyl , ( C1 - C8 ) alkyl - S ( O ) - ( C1 - C2 ) alkyl , ( C - Cg ) alkyl wherein each alkyl , alkenyl , alkynyl , cycloalkyl , S ( O ) 2 - ( C - C Jalkyl , Ophenyl , 0 ( C2 - C ) alkenyl , haloalkyl , and phenyl , may be optionally substituted with 0 — ( C1 - C2 ) alkyl ( C3 - C ) cycloalkyl , O – ( C1 - C2 ) alkylphe - is one or more substituents selected from the group consisting nyl , ( C , - Cg ) alkyl - 0 ( C , - Cg ) alkyl ( Cz - C3 ) cycloalkyl , ( C , - " of F , C1 , CN , ( C , - C ) alkoxy , and ( C1 - C2 ) haloalkyl ; and Cg ) alkyl - 0 — ( C2 - C3 ) haloalkyl , ( C , - C2 ) alkyl - C ( O ) NH — ( I ) R15 and R16 together can optionally form a 2 - to ( C - C2 ) haloalkyl , and ( C7 - C , ) alkyl - NHC ( O ) ( C , - C ) 5 - membered saturated , hydrocarbyl link , alkyl , wherein said hydrocarbyl link may be optionally substi wherein each alkyl , alkenyl , alkynyl , cycloalkyl , tuted with one or more substituent selected from the group

haloalkyl , and phenyl , may be optionally substituted with consisting of F , C1 , Br , and I . one or more substituents selected from the group consisting Preparation of Cyclopropyl Carboxylic Acids of F , C1 , CN , ( C1 - C2 ) alkyl , ( C - Cg ) alkoxy , ( C , - C8 ) ha - Stilbenes 1 - 1 , wherein R ' , R “ , Rº , R * , Rº , Rº , and Rºare loalkyl , and N ( ( C1 - C2 ) alkyl ) , ; and as previously disclosed , may be treated with a base such as

( I ) R15 and RIo together can optionally form a 2 - to sodium hydroxide in the presence of a carbene source such 5 - membered saturated , hydrocarbyl link , wherein said - as chloroform or bromoform and a phase transfer catalyst hydrocarbyl link may be optionally substituted with one or such as N - benzyl - N , N - diethylethanaminium chloride in a more substituent selected from the group consisting of F , C1 , polar protic solvent such as water at temperatures from Br , and I . about 0° C . to about 40° C . to provide diaryl cyclopropanes

In another embodiment : 1 - 2 , wherein R ' , R ? , R " , R4 , R " , R " , R ? , R® , and Rºare as ( A ) R ' , R2 , R3 , R4 , RS , R1 , R12 , R13 , and R 14 are each previously disclosed ( Scheme 1 , step a ) . Treatment of diaryl

independently selected from the group consisting of H , CI , cyclopropanes 1 - 2 with a transition metal such as ruthenium and ( C , - C2 ) haloalkyl ; ( III ) chloride in the presence of a stoichiometric oxidant

( B ) R and Rºare H ; such as sodium periodate in a solvent mixture preferably ( C ) R7 is Cl ; water , ethyl acetate , and acetonitrile at temperatures from ( D ) R is Cl ; about 0° C . to about 40° C . may provide cyclopropyl ( E ) Q1 and Q ? are 0 ; carboxylic acids 1 - 3 , wherein R1 , R² , R3 , R4 , R " , R " , R7 , RS , ( F ) R10 is H ; and Rº are as previously disclosed ( Scheme 1 , step b ) .

Scheme 1

R5 R6 ( C1 - C4 ) alkyl R4

RO RO R

R2 1 - 1

R7 R8s R7 R8 ' ( C1 - C4 ) alkyl RS

P6 RO / R $ ROOH Beton R2

1 - 2 1 - 3

32 - continued R6 0 R5

P

R9 R3 RA

1 . 5 - 2

RO RS

OH C

RI RO

1 . 5 - 3

RS RO A R :

o

US 9 , 795 , 140 B2 31

In yet other embodiments , 1 - 3 may be prepared from the aryl ketone 1 . 5 - 1 , wherein R ' , R2 , R3 , R4 , and Rs are as previously disclosed , and R is methyl . The acetophenone 1 . 5 - 1 may be reacted in a first step with a stabilized phosphonate carbanion , generated by treating a phospho nate , such as ethyl 2 - diethoxyphosphoryl ) - acetate with a strong base like sodium hydride or potassium tert - butoxide in a polar aprotic solvent , such as tetrahydrofuran at a temperature from about 0° C . to about 5° C . ( Scheme 1 . 5 , step a ) . This reaction , like many others involving the treat ment of aldehydes or ketones with stabilized phosphonate 10 carbanions to give olefins , will be readily recognized by one skilled in the art as the Horner - Wadsworth - Emmons olefi nation . In a second step , the a , ß - unsaturated ester 1 . 5 - 2 , wherein R ' , R2 , Rº , R4 , R " , and Rare as defined above , may be treated with a reducing agent , for example a metal hydride like diisobutylaluminum hydride , in an aromatic 15 hydrocarbon solvent like toluene at a temperature from about - 78° C . to about 22° C . to give the intermediate primary alcohol 1 . 5 - 3 ( Scheme 1 . 5 , step b ) , wherein R ? , R , R ? , R4 , RP , and R are as defined above and Rº is as previously disclosed . Protection of the primary alcohol 1 . 5 - 3 is required for the successful completion of subsequent 20 chemical transformations , and a wide variety of protecting group strategies could be utilized . For example , treating the alcohol 1 . 5 - 3 with 3 , 4 - dihydro - 2 - H - pyran in the presence of a catalytic amount of an organic acid , such as para - toluene sulfonic acid monohydrate , in an aprotic solvent like diethyl 25 ether from a temperature of about 0° C . to about ambient temperature affords the tetrahydro - 2 - H - pyran ( THP ) pro tected alcohol 1 . 5 - 4 ( Scheme 1 . 5 , step c ) , wherein R1 , R² , R ? , R4 , RS , R and Rºare as defined above . The THP protected styryl intermediate may be converted to the THP - 30 protected cyclopropane intermediate 1 . 5 - 5 , wherein R1 , R² , R ? , R4 , RS , Rand Rº are as defined above and R7 and R8 are as previously disclosed , by treatment with carbene source such as chloroform in the presence of a base , such as sodium or potassium hydroxide , and a catalyst such as tetrabuty lammonium hexafluorophosphate at a temperature from 35 about 25 to about 45° C . ( Scheme 1 . 5 , step d ) . Deprotection of the THP - protected cyclopropane intermediate 1 . 5 - 5 , wherein R1 , R2 , Rº , R4 , R " , R , R , RS , and Rºare as defined above , can be achieved by treatment with a catalytic amount of an organic acid , such as para - toluenesulfonic acid mono - 40 hydrate , in polar , protic solvent , such as methanol , at a temperature of about 22° C . to give the cyclopropyl metha nol intermediate 1 . 5 - 6 ( Scheme 1 . 5 , step e ) . Oxidation of the primary alcohol intermediate 1 . 5 - 6 , wherein R1 , R² , R " , R4 , R® , R " , R7 , RS , and Rºare as defined above , can be achieved 45 using a wide range of reagents and conditions known in the art ( Figadere , B . and Franck , X . , “ Carboxylic Acids : Syn thesis from Alcohols ” Science of Synthesis 2006 , ( 20a ) pp 173 - 204 ) , many of which offer differential functional group compatibility and selectivity . For example , treating the alco hol intermediate 1 . 5 - 6 with solutions of chromium trioxide 50 in solutions of dilute sulfuric acid and acetone , Jones reagent , affords the cyclopropyl carboxylic acid 1 - 3 , wherein R ' , R² , R3 , R4 , RS , RS , R " , R8 , and Rºare as defined above ( Scheme 1 . 5 , step f ) .

tha R

R2 1 . 5 - 4

R7 R8 30

R4

R2

1 . 5 - 5

R7 R8

14 OH f Re

P3 R

1 . 5 - 6

R R8 sps R6

P OH ROOD R3 55

Scheme 1 . 5 1 - 3

RS R6

Pe

3YR R3

60 Preparation of Stilbenes Stilbenes 1 - 1 may be prepared by several different meth

ods as outlined in Scheme 2 . Phenyl carbonyls 2 - 1 , wherein R1 , R2 , R ’ , R4 , RS , and R? are as previously disclosed , may

65 be treated with alkoxy benzyl phosphonates 2 - 2 in the presence of a base such as sodium methoxide in a polar aprotic solvent such as N , N - dimethylformamide at tempera

R2 1 . 5 - 1

US 9 , 795 , 140 B2 33 34

tures from about - 10° C . to about 30° C . and subsequently heated to 40° C . to about 80° C . to provide stilbenes 1 - 1 ( Scheme 2 , step a ) .

Scheme 2

R5 R6

halides 2 - 3 may be treated with vinylboronates 2 - 5 , wherein R and Rºare as previously disclosed , in the presence of a transition metal catalyst such as tetrakis ( triphenylphos phine palladium ( 0 ) and a base such as potassium carbonate

5 in a solvent mixture such as 1 , 2 - dimethoxyethane and water at temperatures from about 60° C . to about 100° C . to provide stilbenes 1 - 1 ( Scheme 2 , step c ) .

In yet another embodiment , stilbenes 1 - 1 may also be prepared by the Wittig olefination method ( Chalal , M . ; Vervandier - Fasseur , D . ; Meunier , P . ; Cattey , H . ; Hierso , 10 J . - C . Tetrahedron 2012 , 68 , 3899 - 3907 ) as outlined in Scheme 2 . 5 . Phenyl carbonyls 2 - 1 , wherein R1 , R² , R " , R4 , and Rs are as previously disclosed and R is H , may be treated with alkoxy benzyl triphenylphosphonium chlorides 2 . 5 - 2 in the presence of a base such as n - butyl lithium in a polar aprotic solvent such as tetrahydrofuran at temperatures from about - 78° C . to ambient temperature to provide stilbenes 1 - 1 ( Scheme 2 . 5 , step a ) .

O

R3 R /

R ?

2 - 1 15

O = ( C1 - C4 ) alkyl indrom 3 H2

20 Scheme 2 . 5

RS RO CH3 4

R4 2 - 2

25 +

Br I

R2

2 - 1 P3 . 30 30

2 - 3 2 - 3 ( C1 - C4 ) alkyl

Po ( C1 - C4 ) alkyl 35 35 b - l 1 - 1

C

2 - 4 40

Ps 2 . 5 - 2 2 . 5 - 2

R4 Br I RS PO ( C1 - C4 ) alkyl +

45 D3

R2 R3 2 - 3 R2

( C1 - C4 ) alkyl 50 50 1 - 1

o R9

2 - 5

Preparation of Cyclopropyl Amides Cyclopropyl amides 3 - 3 , wherein Q ' is O , and R1 , R² , R3 ,

55 R4 , RS , R , R7 , R8 , R9 , R10 , R1 , R12 , R13 , R14 , Q2 , R15 , and HzC CHz R16 are as previously disclosed , may be prepared by treat

ment with amines or amine salts 3 - 2 , wherein R19 , R11 , R12 , R13 , R14 , Q ? , and R15 , and R16 are as previously disclosed , and activated carboxylic acids 3 - 1 , wherein A is an activat

Aryl halides 2 - 3 , wherein R ' , R² , R3 , R4 , and Rs are as 60 ing group , and R1 , R2 , R ’ , R4 , RS , RÓ , R7 , RS , and Rº are as previously disclosed , may be treated with vinylbenzenes previously disclosed , with a base , such as triethylamine , 2 - 4 , wherein Rº and Rºare as previously disclosed , in the diisopropyl ) ethylamine , 4 - methylmorpholine , or 4 - dimeth presence of a transition metal catalyst such as palladium ( II ) ylaminopyridine in an anhydrous aprotic solvent such as acetate and a bisphosphine ligand such as 1 , 1 ' - bis ( diphenyl - dichloromethane , tetrahydrofuran , 1 , 2 - dichloroethane , dim phosphino ) ferrocene in a basic solvent such as triethylamine 65 ethylformamide , or any combination thereof , at tempera at temperatures from about 60° C . to about 100° C . to tures between about 0° C . and about 120° C . ( Scheme 3 , step provide stilbenes 1 - 1 ( Scheme 2 , step b ) . Alternatively , aryl a ) .

35

Scheme 3

R7 Roo

R4 po 4

R

R2

pe R13

R15

HN R16

3 - 2 DIZ R12

R13 R7 R8 RII RIS

As

R9 ] e

US 9 , 795 , 140 B2 36

Activated carboxylic acids 3 - 1 may be an acid halide , such as an acid chloride , an acid bromide , or an acid fluoride ; a carboxylic ester , such as a para - nitrophenyl ester , a pentafluorophenyl ester , an ethyl ( hydroxyiminio cyano - 5 acetate ester , a methyl ester , an ethyl ester , a benzyl ester , an R N - hydroxysuccinimidyl ester , a hydroxybenzotriazol - 1 - yl ester , or a hydroxypyridyltriazol - 1 - yl ester ; an O - acylisou rea ; an acid anhydride ; or a thioester . Acid chlorides may be 10 R3 prepared from the corresponding carboxylic acids by treat ment with a dehydrating chlorinating reagent , such as oxalyl chloride or thionyl chloride . Activated carboxylic esters 3 - 1 may be prepared from carboxylic acids in situ with a 15 uronium salt , such as 1 - [ bis ( dimethylamino ) methylene ) - 1H 1 , 2 , 3 - triazolo [ 4 , 5 - b ] pyridinium 3 - oxid hexafluorophosphate R ! ! ( HATU ) , O - ( benzotriazol - 1 - yl ) - N , N , N ' , N ' - tetramethyluro nium hexafluorophosphate ( HBTU ) , or ( 1 - cyano - 2 - ethoxy - 20 2 - oxoethylidenaminooxy ) dimethylamino - morpholino - car benium hexafluorophosphate ( COMU ) . Activated R10 R14 carboxylic esters 3 - 1 may also be prepared from carboxylic acids in situ with a phosphonium salt such as benzotriazol - 25 1 - yl - oxytripyrrolidinophosphonium hexafluorophosphate ( PyBop ) . Activated carboxylic esters 3 - 1 may also be pre pared from carboxylic acids in situ with a coupling reagent such as 1 - ( 3 - dimethylamino propyl ) - 3 - ethylcarbodiimide , or 30 dicyclohexylcarbodiimide in the presence of a triazole such R10 R14 as hydroxybenzotriazole . monohydrate ( HOBt ) or 1 - hy Y R droxy - 7 - azabenzotriazole ( HOAt ) . O - Acylisoureas may be prepared with a dehydrating carbodimide such as 1 - ( 3 - 35 dimethylamino propyl ) - 3 - ethylcarbodiimide or dicyclohex ylcarbodiimide . Activated carboxylic esters 3 - 1 may also be prepared from carboxylic acids in situ with a coupling Cyclopropyl amides 4 - 3 , wherein Q?is O , and R ' , R " , Rº ,

R4 , RS , RÓ , R7 , RS , Rº , Q1 , R10 , R1 , R12 , R13 , R14 , R15 , and reagent such as 2 - chloro - 1 , 3 - dimethylimidazolidinium 40 0 Rio are as previously disclosed , may be prepared by treat hexafluorophosphate ( CIP ) in the presence of a triazole such ment with amines or amine salts 4 - 2 , wherein Ris and R16 as 1 - hydroxy - 7 - azabenzotriazole ( HOA ) . Activated carbox - are as previously disclosed , and activated carboxylic acids ylic esters 3 - 1 may also be prepared from carboxylic acids 4 - 1 , wherein A is an activating group , and R1 , R² , R " , R4 , R ” , in situ with a coupling reagent such as 2 , 4 , 6 - tripropyl - 1 , 3 , 45 Rº , R ' , Rº , R , Q ' , R " , R " , R " , R ' ' , and R ' * are as 5 , 2 , 4 , 6 - trioxatriphosphinane 2 , 4 , 6 - trioxide ( T3P® ) in the previously disclosed , with a base , such as triethylamine ,

diisopropylethylamine , 4 - methylmorpholine , or 4 - dimethyl presence of a base such as pyridine . aminopyridine in an anhydrous aprotic solvent such as Cyclopropyl amides 3 - 3 , wherein R ' ° contains a sulfide dichloromethane , tetrahydrofuran . 1 . 2 - dichloroethane , dim

and RlS is as previously disclosed , may be oxidized to the 50 ethylformamide , or any combination thereof , at tempera corresponding sulfoxide or sulfone by treatment with about tures between about 0° C . and about 120° C . ( Scheme 4 , step one equivalent of meta - chloroperoxybenzoic acid in a polar a ) . Activated carboxylic acids 4 - 1 may be an acid halide , aprotic solvent such as dichloromethane ( sulfoxide ) or about such as an acid chloride , an acid bromide , or an acid two equivalents of meta - chloroperoxybenzoic acid ( sulfone ) 55 fluoride ; a carboxylic ester , such as a para - nitrophenyl ester , at temperatures between about 0° C . to about 40° C . Alter - a pentafluorophenyl ester , an ethyl ( hydroxyiminio ) cyano natively , cyclopropyl amides 3 - 3 , wherein R16 contains a acetate ester , a methyl ester , an ethyl ester , a benzyl ester , an

N - hydroxysuccinimidyl ester , a hydroxybenzotriazol - 1 - yl sulfide may be oxidized to the corresponding sulfoxide or ester , or a hydroxypyridyltriazol - 1 - yl ester ; an O - acylisou sulfone by treatment with one equivalent of sodium perbo - 60 rea ; an acid anhydride ; or a thioester . Acid chlorides may be rate in a protic solvent such as acetic acid ( sulfoxide ) or two prepared from the corresponding carboxylic acids by treat equivalents of sodium perborate ( sulfone ) . Preferably , the ment with a dehydrating chlorinating reagent , such as oxaly ] oxidation will be performed at temperatures between about chloride or thionyl chloride . Activated carboxylic esters 4 - 1

may be prepared from carboxylic acids in situ with a 40° C . to about 100° C . using about 1 . 5 equivalents of 65 about low equivalents Or 65 uronium salt , such as 1 - [ bis ( dimethylamino ) methylene ] - 1H sodium perborate to provide chromatographically separable 1 , 2 , 3 - triazolo [ 4 , 5 - b ] pyridinium 3 - oxid hexafluorophosphate mixtures of sulfoxide and sulfone cyclopropyl amides 3 - 3 . ( HATU ) , O - ( benzotriazol - 1 - yl ) - N , N , N ' , N - tetramethyluro

3 - 3

37 US 9 , 795 , 140 B2

38 nium hexafluorophosphate ( HBTU ) , or ( 1 - cyano - 2 - ethoxy ence of an acid whose pH is 0 - 5 such as hydrobromic acid , 2 - oxoethylidenaminooxy ) dimethylamino - morpholino - car N - bromosuccinimide , hydrochloric acid , N - chlorosuccinim benium hexafluorophosphate ( COMU ) . Activated ide , and pyridinium p - toluenesulfonate ( PPTS ) , in a ( C1 - C ) carboxylic esters 4 - 1 may also be prepared from carboxylic alkanol solvent , at a temperature from 0° C . to ambient and acids in situ with a phosphonium salt such as benzotriazol - 5 under ambient pressure provides the acetal 5 - 2 , wherein R ' , 1 - yl - oxytripyrrolidinophosphonium hexafluorophosphate R ? , R3 , R4 , RS , R " , and Rºare as previously disclosed and ( PyBop ) . Activated carboxylic esters 4 - 1 may also be pre Rº is a ( C , - C6 ) alkyl or Rº and Rº taken together can form a pared from carboxylic acids in situ with a coupling reagent cyclic acetal ( Scheme 5 , step a ) . The acetal 5 - 2 may be such as 1 - ( 3 - dimethylamino propyl ) - 3 - ethylcarbodiimide , or converted to the cyclopropyl acetal 5 - 3 , wherein R ' , R ? , RS , dicyclohexylcarbodiimide in the presence of a triazole such 10 R4 R5 R6 R7 R8 R2 and Ra are as previously disclosed , as hydroxybenzotriazole . monohydrate ( HOBt ) or 1 - hy by treatment with a carbene source such as a haloform , for droxy - 7 - azabenzotriazole ( HOA ) . O - Acylisoureas may be example , bromoform or chloroform , in the presence of an prepared with a dehydrating carbodimide such as 1 - ( 3 inorganic base , such as sodium or potassium hydroxide or dimethylamino propyl ) - 3 - ethylcarbodiimide or dicyclohex sodium or potassium carbonate , and a phase - transfer catalyst ylcarbodiimide . Activated carboxylic esters 4 - 1 may also be 15 such as benzyl triethylammonium chloride , ( - ) - N - dodecyl prepared from carboxylic acids in situ with a coupling reagent such as 2 - chloro - 1 , 3 - dimethylimidazolidinium N - methylephedrinium bromide , tetramethylammonium bro hexafluorophosphate ( CIP ) in the presence of a triazole such mide , tetrapropylammonium bromide , tetrabutylammonium as 1 - hydroxy - 7 - azabenzotriazole ( HOAT ) . Activated carbox tetrafluoroborate , tetramethylammonium chloride or tetra vlic esters 4 - 1 may also be prepared from carboxylic acids 20 butylammonium hexafluorophosphate at a temperature from in situ with a coupling reagent such as 2 , 4 , 6 - tripropyl - 1 , 3 , about ambient temperature up to below the boiling point of 5 , 2 , 4 , 6 - trioxatriphosphinane 2 , 4 , 6 - trioxide ( T3P® ) in the the haloform ( Scheme 5 , step b ) . Caution : Step B is an presence of a base such as pyridine . exothermic reaction and careful control of the exotherm

should be exercised when conducting this reaction . The 25 cyclopropyl acetal 5 - 3 may be transformed into the aldehyde

Scheme 4 5 - 4 , wherein R1 , R2 , R3 , R4 , RS , R " , R7 , R8 , and Rº are as previously disclosed , in a polar solvent selected from the group consisting of acetone , acetonitrile , methanol , ethanol , nitromethane , N , N - dimethylformamide , dimethyl sulfoxide , ethyl acetate , tetrahydrofuran and 1 , 4 - dioxane , in the pres ence of an aqueous mineral acid selected from the group consisting of nitric acid , hydrochloric acid , hydrobromic

R9 acid , and sulfuric acid ( Scheme 5 , step c ) at ambient R10 R14 Ö s temperature . The cyclopropyl acid 1 - 3 , wherein R ' , R2 , R " , R4 , RP , R? , R² , RS , and Rº are as previously disclosed , may be obtained by oxidation of the aldehyde 5 - 4 with oxidants such sodium permanganate or potassium permanganate , or under Pinnick oxidation conditions in a polar aprotic solvent

40 selected from the group consisting of acetone , acetonitrile , N , N - dimethylformamide , dimethyl sulfoxide , ethyl acetate , tetrahydrofuran and 1 , 4 - dioxane at a temperature from about 0° C . to about ambient temperature ( Scheme 5 , step d ) . Standard safety precautions should be exercised because an

45 exotherm may occur when conducting this reaction .

R 12

R ! 7 I . R R7 R8 R13

Rs N

RIO R14

R2 4 - 1

+

RIS HN

R16 A 4 - 2

R ! ! R13 Scheme 5 R8 R ol R15 RS RO O Ps 50

? R16 2 16 R4 Y R9 H a

R10 R10 R14 R 14 Ö Y R R3 SP3 pe

5 - 1 4 - 3 R5 RO OR

R4 Y ORS b In some embodiments , 1 - 3 may be prepared from the 60

A , B - unsaturated aldehyde 5 - 1 , wherein R ' , R2 , R3 , R4 , R ” , Rº , and Rºare as previously . It will be understood by one skilled in the art that compound 5 - 1 may be synthesized via Aldol condensation ( see Yoshikawa , M . ; Kamei , T . PCT Int . Appl . 2010123006 , 2010 ) of an appropriately substituted , 65 commercially available aldehyde and acetaldehyde . Treat ment of 5 - 1 with a ( C , - C . ) alkyl orthoformate , in the pres

5 - 2

US 9 , 795 , 140 B2 39 40

- continued - continued R ? R8 Ora R2 R ROO

R Rs Î R RO RV R6

R4 R4 ORA ORA OH SILVER ) ( R ) VIRO

RI R3 R2

5 - 3 ( R , R ) +

R7 R8 o BS RH

R4 3 / * * * 0111

R7 R8 o RZ po OH S )

RS Ro Y

< Hd P3 R

R2 ( S , S )

B

5 - 4 EXAMPLES

R ?

RS

R4 RO OH

R3 RI

These examples are for illustration purposes and are not 30 to be construed as limiting this disclosure to only the

embodiments disclosed in these examples . Starting materials , reagents , and solvents that were

obtained from commercial sources were used without fur ther purification . Anhydrous solvents were purchased as

R ? RO Sure / SealTM from Aldrich and were used as received . Melt ing points were obtained on a Thomas Hoover Unimelt capillary melting point apparatus or an OptiMelt Automated

R4 Melting Point System from Stanford Research Systems and are uncorrected . Examples using " room temperature ” or “ ambient temperature ” were conducted in climate controlled

40 laboratories with temperatures ranging from about 20° C . to about 24° C . Molecules are given their known names , named according to naming programs within ISIS Draw , Chem

1 - 3 Draw , or ACD Name Pro . If such programs are unable to name a molecule , such molecule is named using conven

45 tional naming rules . ' H NMR spectral data are in ppm ( d ) It will be understood by those skilled in the art that , in and were recorded at 300 , 400 , 500 , or 600 MHz ; 13C NMR

some embodiments , the cyclopropyl acid 1 - 3 . wherein RI spectral data are in ppm ( 0 ) and were recorded at 75 , 100 , or R ? , R3 , R4 , RS , RÓ , R ? , R8 , and Rº are as previously 150 MHz , and ' °F NMR spectral data are in ppm ( 8 ) and disclosed , may be resolved into its ( R , R ) and ( S , S ) were recorded at 376 MHz , unless otherwise stated . enantiomers via a method such as that in Kovalenko V . N . , 30 Example 1 Kulinkovich O . G . Tetrahedron : Asymmetry 2011 , 22 , 26 ( Scheme 6 , step a ) . Preparation of trans - 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro

phenyl ) cyclopropanecarboxylic acid ( C1 ) Scheme 6 55

R7 R8 Ciclo Ps R6

R4 [ ??? OH a ??

R Y DI

1 - 3

42

OH

US 9 , 795 , 140 B2 41

Ruthenium ( III ) chloride ( 0 . 080 g , 0 . 39 mmol ) was added Example 2 to a stirred mixture of trans - 1 , 3 - dichloro - 5 - ( - 2 , 2 - dichloro 3 - ( 4 - methoxyphenyl ) cyclopropyl ) benzene ( C22 ) ( 2 . 8 g , 7 . 7 Preparation of trans - 2 , 2 - dichloro - 3 - ( 4 - ( trifluorom mmol ) and sodium periodate ( 33 g , 160 mmol ) in water : ethyl ) phenyl ) cyclopropanecarboxylic acid ( C4 ) ethyl acetate : acetonitrile ( 8 : 1 : 1 , 155 mL ) at 23° C . The 5 resulting biphasic brown mixture was vigorously stirred at 23° C . for 5 hours . The reaction mixture was diluted with water ( 1000 mL ) and extracted with dichloromethane cl cl ( 4x200 mL ) . The combined organic layers were dried over magnesium sulfate , filtered , and concentrated . The residue was diluted with a sodium hydroxide solution ( 1 M , 100 mL ) and washed with diethyl ether ( 4x50 mL ) . The aqueous layer was adjusted to pH 2 , using concentrated hydrochloric acid , and extracted with dichloromethane ( 3x50 mL ) . The com - 15 . bined organic layers were dried over magnesium sulfate , filtered , and concentrated to afford the title product as a light brown powder ( 0 . 78 g , 34 % ) : mp 117 - 120° C . ; H NMR To a stirred mixture of trans - 1 - ( 2 , 2 - dichloro - 3 - ( 4 - ( trifluo ( 400 MHz , DMSO - d . ) 5 13 . 38 ( brs , 1H ) , 7 . 52 - 7 . 65 m , 3H ) , romethyl ) phenyl ) cyclopropyl ) - 4 - methoxybenzene ( C25 ) 3 . 57 ( d , J = 8 . 5 Hz , 1H ) , 3 . 50 ( d , J = 8 . 5 Hz , 1H ) ; IR ( thin film ) 20 ( 3 . 50 g . 9 . 60 mmol ) and sodium periodate ( 30 . 8 g . 144 3083 ( s ) , 3011 ( s ) , 1731 ( s ) , 1590 ( w ) , 1566 ( s ) , 1448 ( w ) , mmol ) in water : ethyl acetate : acetonitrile ( 8 : 1 : 1 , 200 mL ) 1431 ( m ) , 1416 ( m ) cm - . was added ruthenium ( III ) chloride ( 0 . 100 g , 0 . 400 mmol ) at

The following compounds were prepared in like manner 23° C . The resulting mixture was vigorously stirred at 23° C . to the procedure outlined in Example 1 : for about 5 hours . The reaction mixture was diluted with

dichloromethane and washed with water . The combined trans - 2 , 2 - Dichloro - 3 - ( 3 , 4 , 5 - trichlorophenyl ) cyclo organic layers were dried over sodium sulfate , filtered , and

propanecarboxylic acid ( C2 ) concentrated . Purification by flash column chromatography provided the title compound as an off - white solid ( 0 . 630 g , 38 % ) : mp 100 - 102° C . ; ' H NMR ( 400 MHz , DMSO - do ) 8 13 . 43 ( brs , 1H ) , 7 . 77 - 7 . 73 ( m , 2H ) , 7 . 67 - 7 . 64 ( m , 2H ) , 3 . 55 ( d , J = 8 . 8 Hz , 1H ) , 3 . 44 ( d , J = 8 . 8 Hz , 1H ) ; ESIMS m / z 347 ( [ M - H ] ) ) .

The following compounds were prepared in like manner 36 to the procedure outlined in Example 2 :

Ciclo

OH

trans - 2 , 2 - Dichloro - 3 - ( 3 - ( trifluoromethyl ) phenyl ) cyclopropane carboxylic acid ( C5 )

40

ciclo F Isolated as a yellow powder ( 1 . 5 g , 39 % ) : ' H NMR ( 400

MHz , CDC13 ) 8 7 . 31 ( d , J = 0 . 7 Hz , 2H ) , 3 . 40 ( d , J = 8 . 2 Hz , 1H ) , 2 . 86 ( d , J = 8 . 3 Hz , 1H ) ; 13C NMR ( 101 MHz , CDC12 ) 8 171 . 05 , 134 . 55 , 132 . 44 , 131 . 75 , 128 . 89 , 61 . 18 , 39 . 26 , 45 37 . 14 ; ESIMS m / z 333 ( M - H ] ; ) .

OH I

trans - 2 , 2 - Dichloro - 3 - ( 3 , 4 - dichlorophenyl ) cyclopro panecarboxylic acid ( C3 ) Isolated as an off - white solid ( 0 . 81 g , 33 % ) : mp 86 - 88°

°C . ; ' H NMR ( 400 MHz , DMSO - do ) & 13 . 37 ( brs , 1H ) , 7 . 83 ( s , 1H ) , 7 . 76 - 7 . 69 ( m , 2H ) , 7 . 65 - 7 . 59 ( m , 1H ) , 3 . 59 - 3 . 51 ( m , 2H ) ; ESIMS m / z 297 ( [ M - H ] ) .

CICI

55 55 ti trans - 2 , 2 - Dichloro - 3 - ( 3 - chloro - 4 - ( trifluoromethoxy ) phenyl ) cyclopropanecarboxylic acid ( C6 )

OH

ciclo 60

CD OH Isolated as a pale yellow solid ( 3 . 2 g , 51 % ) : ' H NMR ( 400 MHz , CDC1 ) 87 . 47 ( d , J = 8 . 3 Hz , 1H ) , 7 . 37 ( d , J = 1 . 6 Hz , 1H ) , 7 . 12 ( ddd , J = 8 . 3 , 2 . 1 , 0 . 6 Hz , 1H ) , 3 . 43 ( d , J = 8 . 3 Hz , 1H ) , 2 . 86 ( d , J = 8 . 3 Hz , 1H ) ; 13C NMR ( 101 MHz , CDC1z ) 65 8 171 . 52 , 132 . 91 , 132 . 76 , 132 . 29 , 130 . 66 , 130 . 62 , 128 . 02 , 61 . 48 , 39 . 65 , 37 . 13 ; ESIMS m / z 298 ( [ M - H ] " ) .

IT

US 9 , 795 , 140 B2 43 44

Isolated as an off - white solid ( 0 . 3 g , 19 % ) : mp 134 - 136° ( d , J = 1 . 5 Hz , 2H ) , 7 . 72 ( d , J = 1 . 5 Hz , 2H ) , 3 . 57 - 3 . 53 ( m , 1H ) , C . ; ' H NMR ( 400 MHz , DMSO - do ) 8 13 . 45 ( brs , 1H ) , 7 . 82 3 . 51 - 3 . 47 ( m , 1H ) ; ESIMS m / z 387 ( [ M - H ] ) . ( d , J = 1 . 6 Hz , 1H ) , 7 . 60 - 7 . 53 ( m , 2H ) , 3 . 53 - 3 . 47 ( m , 2H ) ; ESIMS m / z 347 ( [ M - H ] ; ) . trans - 2 , 2 - Dichloro - 3 - ( 3 - chloro - 5 - ( trifluoromethyl )

phenyl ) cyclopropanecarboxylic acid ( C10 ) trans - 2 , 2 - Dichloro - 3 - ( 2 , 4 , 5 - trichlorophenyl ) cyclo

propanecarboxylic acid ( C7 ) 10 cl . Clo

F Ciclo

OH

OH

20

Isolated as an off - white solid ( 0 . 267 g , 18 % ) : mp 189 192° C . ; ' H NMR ( 400 MHz , DMSO - d . ) 8 13 . 44 ( brs , 1H ) , 8 . 01 ( s , 1H ) , 7 . 82 ( s , 1H ) , 3 . 52 ( d , J = 8 . 2 Hz , 1H ) , 3 . 29 ( d , J = 8 . 2 Hz , 1H ) ; ESIMS m / z 333 ( [ M - H ] ) .

Isolated as an off - white solid ( 0 . 73 g , 28 % ) : mp 113 - 115° C . ; ' H NMR ( 400 MHz , DMSO - da ) 8 13 . 39 ( brs , 1H ) , 7 . 91 ( s , 1H ) , 7 . 86 ( s , 1H ) , 7 . 84 ( s , 1H ) , 3 . 69 - 3 . 60 ( m , 2H ) ; ESIMS s , m / z 333 ( [ M - H ] ; ) .

trans - 3 - ( 3 , 5 - bis ( trifluoromethyl ) phenyl ) - 2 , 2 - dichlo rocyclopropanecarboxylic acid ( C8 )

trans - 2 , 2 - Dichloro - 3 - ( 3 , 5 - dichloro - 4 - fluorophenyl ) cyclopropanecarboxylic acid ( C11 )

30

CI Clo Ci Ci

F L

35 OH ?? L

F

40

FIF É

Isolated as an off - white solid ( 0 . 539 g , 34 % ) : ' H NMR Isolated as an off - white solid ( 0 . 5 g . 31 % ) : mp 112 - 1140 ( 400 MHZ , DMSO - d ) : 0 13 . 37 ( brs , 1H ) , 7 . 71 ( d , J = 6 . 4 Hz ,

C . : ' H NMR ( 400 MHz . DMSO - d ) 8 13 . 43 ( brs . 1H ) , 8 . 22 + 2H ) , 3 . 42 ( S , 2H ) ; ESIMS m / z 317 ( 1M - H 7 ) . ( s , 2H ) , 8 . 08 ( s , 1H ) , 3 . 80 - 3 . 71 ( m , 2H ) ; ESIMS m / z 365 ( [ M - H ] " ) . trans - 3 - ( 4 - Bromo - 3 , 5 - dichlorophenyl ) - 2 , 2 - dichloro

cyclopropanecarboxylic acid ( C12 ) trans - 2 , 2 - dichloro - 3 - ( 3 , 5 - dibromophenyl ) cyclopro

panecarboxylic acid ( C9 ) Ci Cio

50 50

55 cl clo ??

OH Br

60

Br Isolated as an off - white solid ( 0 . 100 g , 10 % ) : ' H NMR * * ( 400 MHz , DMSO - do ) d 13 . 37 ( brs , 1H ) , 7 . 76 ( s , 3H ) , 3 . 57

Isolated as an off - white solid ( 0 . 5 g , 24 % ) : mp 157 - 159° ( d , J = 8 . 8 Hz , 1H ) , 3 . 48 ( d , J = 8 . 8 Hz , 1H ) ; ESIMS m / z 377 C . ; ' H NMR ( 400 MHz , DMSO - do ) 8 13 . 36 ( brs , 1H ) , 7 . 81 ( [ M - H ] ' ) . el sentimentos sem e mer skaper

US 9 , 795 , 140 B2 46

trans - 3 - ( 3 - Bromo - 5 - chlorophenyl ) - 2 , 2 - dichlorocy trans - 2 , 2 - Dichloro - 3 - ( 3 - chloro - 4 - fluorophenyl ) cy clopropanecarboxylic acid ( C13 ) clopropanecarboxylic acid ( C16 )

45

CI cl CI Clo

Br OH OH 10

Isolated as an off - white solid ( 1 . 0 g , 53 % ) : mp 121 - 123° C . ; 1H NMR ( 400 MHz , DMSO - d . ) 8 13 . 35 ( brs , 1H ) , 7 . 71 Isolated as an off - white solid ( 0 . 4 g , 25 % ) : mp 161 - 163° ( dd , J = 2 . 0 , 7 . 2 Hz , 1H ) , 7 . 53 - 7 . 35 ( m , 2H ) , 3 . 50 - 3 . 41 ( m , C . ; ' H NMR ( 400 MHz , DMSO - do ) & 13 . 38 ( br s , 1H ) , 7 . 70 20 2H ) ; ESIMS m / z 281 ( [ M - H ] ) . ( d , J = 5 . 3 Hz , 2H ) , 7 . 66 - 7 . 52 ( m , 1H ) , 3 . 59 - 3 . 43 ( m , 2H ) ; <

ESIMS m / z 341 ( [ M - H ] - ) . trans - 2 , 2 - Dichloro - 3 - ( 3 - chloro - 5 - methylphenyl ) cy

clopropanecarboxylic acid ( C17 ) trans - 2 , 2 - Dichloro - 3 - ( 3 - chloro - 5 - fluorophenyl ) cy clopropanecarboxylic acid ( C14 ) 25 25

Ciclo

Ciclo OH

OH

CH3

40

Isolated as an off - white solid ( 0 . 700 g , 25 % ) : mp 138 140° C . ; ' H NMR ( 400 MHz , DMSO - do ) 8 13 . 38 ( brs , 1H ) , 7 . 46 ( s , 1H ) , 7 . 42 ( td , J = 2 . 0 , 8 . 7 Hz , 1H ) , 7 . 37 ( d , J = 9 . 8 Hz , 1H ) , 3 . 52 ( q , J = 8 . 5 Hz , 2H ) ; ESIMS m / z 281 ( [ M - H ] - ) .

Isolated as an off - white solid ( 1 . 0 g , 42 % ) : mp 124 - 126° C . , ' H NMR ( 400 MHz , DMSO - do ) & 13 . 33 ( brs , 1H ) , 7 . 30 ( s , 1H ) , 7 . 23 ( s , 1H ) , 7 . 21 ( s , 1H ) , 3 . 38 ( s , 2H ) , 2 . 31 ( s , 3H ) ; ESIMS m / z 277 ( [ M - H ] " ) .

45 trans - 2 , 2 - Dichloro - 3 - ( 3 , 5 - dichloro - 4 - methylphenyl )

cyclopropanecarboxylic acid ( C18 ) trans - 2 , 2 - Dichloro - 3 - ( 4 - chloro - 3 - fluorophenyl ) cy clopropanecarboxylic acid ( C15 )

50

CI CL o Ci Ci 0 .

??

55 F OH

H3C

60

Isolated as an off - white solid ( 0 . 500 g , 20 % ) : mp 140 - Isolated as an off - white solid ( 0 . 8 g , 40 % ) : mp 181 - 183° 142° C . ; H NMR ( 400 MHz , DMSO - do ) 8 13 . 40 ( brs , 1H ) , 65 C . ; " H NMR ( 400 MHz , DMSO - do ) 8 13 . 40 ( s , 1H ) , 7 . 56 ( s , 7 . 59 ( m , 1H ) , 7 . 55 ( d , J = 8 . 4 Hz , 1H ) , 7 . 33 ( dd , J = 2 . 0 , 8 . 4 2H ) , 3 . 53 - 3 . 50 ( m , 1H ) , 3 . 46 - 3 . 43 ( m , 1H ) , 2 . 40 ( s , 3H ) ; Hz , 1H ) , 3 . 55 - 3 . 38 ( m , 2H ) ; ESIMS m / z 281 ( [ M - H ] ) . ESIMS m / z 311 ( [ M - H ] ; ) .

US 9 , 795 , 140 B2 47 un - 22 Debiasa 48

Example 3 trans - 2 , 2 - Dichloro - 3 - ( 3 , 4 - dichloro - 5 - methylphenyl ) cyclopropanecarboxylic acid ( C19 ) mens mong many

Preparation of trans - 1 , 3 - dichloro - 5 - ( 2 , 2 - dichloro - 3 ( 4 - methoxyphenyl ) cyclopropyl ) benzene ( C22 )

CI Clo

?? CH3

10

CH3

25

CI

Isolated as an off - white solid ( 0 . 73 g , 45 % ) : mp 157 - 1590 C . ; ' H NMR ( 400 MHz , DMSO - do ) 8 13 . 40 ( s , 1H ) , 7 . 59 ( d , 20 J = 2 . 0 Hz , 1H ) , 7 . 44 ( d , J = 1 . 6 Hz , 1H ) , 3 . 43 ( q , J = 8 . 5 Hz , 2H ) , 2 . 39 ( s , 3H ) ; ESIMS m / z 311 ( [ M - H ] ) . Aqueous sodium hydroxide ( 50 % , 6 . 8 mL , 130 mmol )

was added to a stirred solution of ( E ) - 1 , 3 - dichloro - 5 - ( 4 trans - 2 , 2 - Dichloro - 3 - ( 4 - ( perfluoroethyl ) phenyl ) cy methoxystyryl ) benzene ( C43 ) ( 2 . 4 g , 8 . 6 mmol ) and N - ben

clopropanecarboxylic acid ( C20 ) zyl - N , N - diethylethanaminium chloride ( 0 . 20 g , 0 . 86 mmol ) in chloroform ( 14 mL , 170 mmol ) at 23° C . The resulting biphasic , dark brown mixture was vigorously stirred at 23° C . for 24 hours . The reaction mixture was diluted with water ( 200 mL ) and extracted with dichloromethane ( 2x100 mL ) . The combined organic layers were dried over magnesium sulfate , filtered , and concentrated to afford the title product as a brown oil ( 2 . 8 g , 90 % ) : ' H NMR ( 400 MHz , CDC13 ) 7 . 34 ( t , J = 1 . 8 Hz , 1H ) , 7 . 21 - 7 . 30 ( m , 4H ) , 6 . 93 ( m , 2H ) , 3 . 83

FF ( s , 3H ) , 3 . 14 ( d , J = 8 . 5 Hz , 1H ) , 3 . 08 ( d , J = 8 . 5 Hz , 1H ) ; IR ( thin film ) 3075 ( w ) , 2934 ( w ) , 2836 ( w ) , 1724 ( w ) , 1640 ( w ) , 1609 ( m ) , 1584 ( m ) , 1568 ( s ) , 1513 ( s ) cm - ' .

The following compounds were prepared in like manner Isolated as an off - white solid ( 0 . 020 g , 10 % ) : mp 116 - to the procedure outlined in Example 3 :

118° C . ; ' H NMR ( 300 MHz , CDC12 ) 8 7 . 63 ( d , J = 8 . 1 Hz , 2H ) , 7 . 42 ( d , J = 8 . 1 Hz , 2H ) , 3 . 53 ( d , J = 8 . 4 Hz , 1H ) , 2 . 94 ( d , J = 8 . 4 Hz , 1H ) ; ESIMS m / z 347 ( [ M - H ] ; ) . trans - 1 , 2 , 3 - Trichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxy

45 phenyl ) cyclopropyl ) benzene ( C23 )

?? fati 3

45

trans - 2 , 2 - dichloro - 3 - ( 4 - ethoxyphenyl ) cyclopropan ecarboxylic acid ( C21 )

Ci Ci CH2 50

CI Clo

OH . 55 55 noti geri HC

60

Isolated as a dark foam ( 4 . 7 g , 100 % ) : ' H NMR ( 400 Isolated as an off - white solid ( 0 . 025 g , 5 % ) : mp 129 - 130° MHz , CDC12 ) 8 7 . 40 ( d , J = 0 . 6 Hz , 2H ) , 7 . 29 - 7 . 22 ( m , 2H ) ,

C . ; ' H NMR ( 400 MHz , CDC1z ) 8 7 . 16 ( d , J = 8 . 4 Hz , 2H ) , 6 . 96 - 6 . 89 ( m , 2H ) , 3 . 83 ( s , 3H ) , 3 . 12 ( d , J = 8 . 8 Hz , 1H ) , 3 . 06 6 . 88 ( d , J = 8 . 31 Hz , 2H ) , 4 . 03 ( q , J = 6 . 8 Hz , 2H ) , 3 . 41 ( d , 65 ( d , J = 8 . 7 Hz , 1H ) ; 13C NMR ( 101 MHz , CDC1 , ) 8 159 . 46 , J = 8 . 0 Hz , 1H ) , 2 . 81 ( d , J = 8 . 0 Hz , 1H ) , 1 . 41 ( t , J = 6 . 8 Hz , 135 . 08 , 134 . 23 , 130 . 91 , 129 . 85 , 129 . 16 , 125 . 42 , 114 . 02 , 3H ) ; ESIMS m / z 273 ( [ M - H ] ; ) . 64 . 67 , 55 . 32 , 39 . 62 , 38 . 48 .

US 9 , 795 , 140 B2 50

trans - 1 , 2 - Dichloro - 4 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxy trans - 1 - ( 2 , 2 - Dichloro - 3 - ( 4 - methoxyphenyl ) cyclopro phenyl ) cyclopropyl ) benzene ( C24 ) pyl ) - 3 - ( trifluoromethyl ) benzene ( C26 )

49

C1 C1 CI CIA CH3 CH3 F story xos 10

Isolated as an orange - red oil ( 7 . 6 g , 99 % ) : ' H NMR ( 400 15 MHz , CDC13 ) 8 7 . 47 ( d , J = 4 . 9 Hz , 1H ) , 7 . 45 ( bs , 1H ) , 7 . 30 - 7 . 23 ( m , 2H ) , 7 . 21 ( dd , J = 8 . 2 , 1 . 9 Hz , 1H ) , 6 . 96 - 6 . 90 Isolated as a brown liquid ( 3 . 5 g , 67 % ) : ' H NMR ( 300

MHz , CDC13 ) 8 7 . 62 - 7 . 50 ( m , 4H ) , 7 . 29 ( d , J = 9 . 0 Hz , 2H ) , ( m , 2H ) , 3 . 83 ( s , 3H ) , 3 . 11 ( app . q , J = 8 . 8 Hz , 2H ) ; 13C NMR 6 . 94 ( d , J = 9 . 0 Hz , 2H ) , 7 . 35 - 7 . 25 ( m , 3H ) , 7 . 97 - 6 . 88 ( m , ( 101 MHz , CDC1z ) 0 159 . 39 , 134 . 90 , 132 . 62 , 131 . 99 , 20 iH ) , 3 . 83 ( s , 3H ) , 3 . 19 ( m . 2H ) : ESIMS m / z 361 ( IM + H1 + ) . 130 . 90 , 130 . 40 , 129 . 90 , 128 . 33 , 125 . 81 , 113 . 98 , 64 . 94 , 55 . 33 , 39 . 52 , 38 . 75 . trans - 2 - Chloro - 4 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxyphenyl )

cyclopropyl ) - 1 - ( trifluoromethoxy ) benzene ( C27 ) 25

Example 4 25

30 CICI CH3

Preparation of trans - 1 - ( 2 , 2 - dichloro - 3 - ( 4 - ( trifluo romethyl ) phenyl ) cyclopropyl ) - 4 - methoxybenzene

( C25 )

1 35 35

Ci Cid 1

CH3 SO 40

1 Isolated as an off - white solid ( 2 . 5 g , 65 % ) : ' H NMR ( 400

MHz , CDC13 ) 8 7 . 57 ( d , J = 2 . 0 Hz , 1H ) , 7 . 44 ( d , J = 8 . 8 Hz , 1H ) , 7 . 35 - 7 . 25 ( m , 3H ) , 7 . 97 - 6 . 88 ( m , 1H ) , 3 . 84 ( s , 3H ) ,

45 3 . 15 - 3 . 05 ( m , 2H ) ; ESIMS m / z 411 ( [ M + H ] + ) .

trans - 1 , 2 , 4 - Trichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxy phenyl ) cyclopropyl ) benzene ( C28 )

50

CH3

To a stirred solution of ( E ) - 1 - methoxy - 4 - ( 4 - ( trifluorom ethyl ) styryl ) benzene ( C46 ) ( 4 . 00 g , 14 . 0 mmol ) and N - ben zyl - N , N - diethylethanaminium chloride ( 0 . 320 g , 14 . 0 mmol ) in chloroform ( 23 . 1 g , 288 mmol ) , was added aque ous sodium hydroxide ( 50 % , 8 . 64 g , 216 mmol ) in water ( 17 mL ) at 23° C . , and the resulting mixture was vigorously stirred at 23° C . for 16 hours . The reaction mixture was diluted with water and extracted with dichloromethane . The combined organic layers were dried over sodium sulfate , filtered , and concentrated . Purification by flash column chromatography provided the title compound as an off - white solid ( 3 . 70 g , 68 % ) : ' H NMR ( 300 MHz , CDC13 ) 8 7 . 65 ( d , J = 8 . 4 Hz , 2H ) , 7 . 49 ( d , J = 8 . 4 Hz , 2H ) , 7 . 29 ( d , J = 8 . 4 Hz , 2H ) , 6 . 94 ( d , J = 8 . 4 Hz , 2H ) , 3 . 83 ( s , 3H ) , 3 . 19 ( s , 2H ) ; ESIMS m / z 361 ( [ M + H ] + ) .

The following compounds were prepared in like manner to the procedure outlined in Example 4 :

60 Hon 65

Isolated as a brown liquid ( 2 . 0 g , 58 % ) : EIMS m / z 394 ( [ M ] + ) .

US 9 , 795 , 140 B2 52

trans - 1 - ( 2 , 2 - Dichloro - 3 - ( 4 - methoxyphenyl ) cyclopro trans - 1 , 3 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxy pyl ) - 3 , 5 - bis ( trifluoromethyl ) benzene ( C29 ) phenyl ) cyclopropyl ) - 2 - fluorobenzene ( C32 )

51

Ci Ci CI Cia CH CH3 - Wyson 10

F

FF

Isolated as a brown liquid ( 3 . 0 g , 61 % ) : EIMS m / z 428 ( [ M ] + ) . Isolated as a brown solid ( 1 . 6 g , 54 % ) : ' H NMR ( 300

20 MHz , CDC1z ) 8 7 . 32 ( d , J = 6 . 0 Hz , 2H ) , 7 . 30 ( d , J = 9 . 0 Hz , 1H ) , 6 . 93 ( d , J = 9 . 0 Hz , 1H ) , 3 . 83 ( s , 3H ) , 3 . 12 - 3 . 05 ( m , 2H ) ; ESIMS m / z 297 ( [ M + H ] + ) . trans - 1 , 3 - Di bromo - 5 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxy

phenyl ) cyclopropyl ) benzene ( C30 ) 25 25 trans - 2 - Bromo - 1 , 3 - dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 4

methoxyphenyl ) cyclopropyl ) benzene ( C33 ) I CI " CH3

30 CI CI CH3 gton Br 35

Br

Isolated as a brown liquid ( 3 . 0 g , 57 % ) : ' H NMR ( 300 40 MHz , CDC1z ) 8 7 . 64 ( s , 1H ) , 7 . 45 ( s , 2H ) , 7 . 25 ( d , J = 9 . 0 Hz , 2H ) , 6 . 92 ( d , J = 9 . 0 Hz , 1H ) , 3 . 83 ( s , 3H ) , 3 . 15 - 3 . 05 ( m , 2H ) ; ESIMS m / z 453 ( [ M + H ] + ) . Isolated as an off - white solid ( 1 . 5 g , 44 % ) : ' H NMR ( 300

MHz , CDC1z ) 8 7 . 36 ( d , J = 9 . 0 Hz , 2H ) , 7 . 20 ( s , 2H ) , 6 . 93 45 ( d , J = 9 . 0 Hz , 2H ) , 3 . 83 ( s , 3H ) , 3 . 15 - 3 . 05 ( m , 2H ) ; ESIMS

trans - 1 - Chloro - 3 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxyphenyl ) m / z 439 ( [ M + H ] + ) . cyclopropyl ) - 5 - ( trifluoromethyl ) benzene ( C31 )

trans - 1 - Bromo - 3 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 4 methoxyphenyl ) cyclopropyl ) benzene ( C34 ) 50 50

CI CI OCHz CH3 X ullo 7 )

CH3 I

55

8

Isolated as a brown solid ( 4 . 0 g , 74 % ) : ' H NMR ( 300 Isolated as an off - white solid ( 2 . 5 g , 50 % ) : ' H NMR ( 400 MHz , CDC1 , ) 8 7 . 64 ( s , 1H ) , 7 . 45 ( s , 1H ) , 7 . 42 ( s , 1H ) , 7 . 26 65 MHz , CDC12 ) 8 7 . 49 ( s , 1H ) , 7 . 30 ( s , 1H ) , 7 . 28 - 7 . 24 ( m , ( d , J = 9 . 0 Hz , 2H ) , 6 . 93 ( d , J = 9 . 0 Hz , 1H ) , 3 . 83 ( s , 3H ) , 3H ) , 6 . 92 ( d , J = 8 . 0 Hz , 2H ) , 3 . 92 ( s , 3H ) , 3 . 01 ( q , J = 8 . 8 Hz , 3 . 15 - 3 . 05 ( m , 2H ) ; ESIMS m / z 395 ( [ M + H ] + ) . 2H ) ; ESIMS m / z 405 ( [ M + H ] + ) .

53 US 9 , 795 , 140 B2

54 trans - 1 - Chloro - 3 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxyphenyl ) Isolated as an off - white solid ( 3 . 0 g , 47 % ) : ' H NMR ( 400

cyclopropyl ) - 5 - fluorobenzene ( C35 ) MHz , CDC13 ) 8 7 . 27 ( d , J = 8 . 8 Hz , 2H ) , 7 . 14 ( s , 2H ) , 7 . 06 ( s , 1H ) , 6 . 92 ( d , J = 8 . 8 Hz , 2H ) , 3 . 82 ( s , 3H ) , 3 . 10 ( q , J = 8 . 8 Hz , 2H ) , 2 . 36 ( s , 3H ) ; ESIMS m / z 341 ( [ M + H ] + ) .

5 CI CI CH3 trans - 1 , 3 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxy

phenyl ) cyclopropyl ) - 2 - methylbenzene ( C39 )

10

Ci Cia CH3

15

Isolated as a brown liquid ( 3 . 5 g , 67 % ) : ESIMS m / z 345 ( [ M + H ] + ) . HC com pion Sama semana trans - 1 - Chloro - 4 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxyphenyl )

cyclopropyl ) - 2 - fluorobenzene ( C36 ) 20

CH3

Isolated as a brown liquid ( 2 . 5 g , 80 % ) : ' H NMR ( 400 MHz , CDC13 ) 8 7 . 25 ( d , J = 8 . 0 Hz , 2H ) , 7 . 17 ( d , J = 8 . 8 Hz , 1H ) , 6 . 92 ( d , J = 8 . 0 Hz , 2H ) , 6 . 88 ( d , J = 8 . 8 Hz , 1H ) , 3 . 82 ( s , 3H ) , 3 . 12 - 3 . 03 ( m , 2H ) , 2 . 47 ( s , 3H ) ; ESIMS m / z 375 ( [ M + H ] + ) .

25

30 30 trans - 1 , 2 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxy

phenyl ) cyclopropyl ) - 3 - methylbenzene ( C40 )

Isolated as an off - white solid ( 2 . 5 g , 65 % ) : ESIMS m / z 345 ( [ M + H ] + ) .

35 35 trans - 2 - Chloro - 4 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxyphenyl )

cyclopropyl ) - 1 - fluorobenzene ( C37 )

40

CICI - CH3 CH3

45 Asenten Isolated as a Brown liquid ( 4 . 0 g , 90 % ) : ESIMS m / z 375 ( [ M + H ] + ) .

F

245 50 Isolated as a brown liquid ( 2 . 0 g , 58 % ) : ESIMS m / z 345 ( [ M + H ] + ) .

trans - 1 - ( 2 , 2 - Dichloro - 3 - ( 4 - ( perfluoroethyl ) phenyl ) cyclopropyl ) - 4 - methoxybenzene ( C41 )

trans - 1 - Chloro - 3 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxyphenyl ) cyclopropyl ) - 5 - methylbenzene ( C38 )

CH2 55

CI Ci F CH3 tomon 60 60 oson F F

CH3 Isolated as an off - white solid ( 0 . 5 g , 46 % ) : ' H NMR ( 400

65 MHz , CDC1z ) 8 7 . 60 - 7 . 50 ( m , 4H ) , 7 . 47 ( d , J = 8 . 0 Hz , 2H ) , 6 . 92 ( d , J = 8 . 0 Hz , 2H ) , 3 . 82 ( s , 3H ) , 3 . 20 ( s , 2H ) ; ESIMS m / z 411 ( [ M + H ] + ) .

US 9 , 795 , 140 B2 55 56

trans - 4 , 4 ' - ( 3 , 3 - Dichlorocyclopropane - 1 , 2 - diyl ) bis ( E ) - 1 , 2 , 3 - Trichloro - 5 - ( 4 - methoxystyryl ) benzene ( ethoxybenzene ) ( C42 ) ( C44 )

5 5 CH3

CH3 1 ci

10

HzC

15 Isolated as an off - white solid ( 3 . 7 g , 31 % ) : ' H NMR ( 400

MHz , CDC13 ) 8 7 . 49 - 7 . 46 ( m , 2H ) , 7 . 47 - 7 . 39 ( m , 2H ) , 7 . 04 Isolated as an off - white solid ( 1 . 5 g , 45 % ) : ' H NMR ( 400 ( d , J = 16 . 3 Hz , 1H ) , 6 . 93 - 6 . 89 ( m , 2H ) , 6 . 78 ( d , J = 16 . 3 Hz ,

MHz , CDC13 ) 8 7 . 27 ( d , J = 8 . 0 Hz , 4H ) , 6 . 90 ( d , J = 8 . 0 Hz , 1H ) , 3 . 84 ( s , 3H ) ; 13C NMR ( 101 MHz , CDC13 ) & 159 . 46 , 4H ) , 4 . 04 ( q , J = 6 . 8 Hz , 4H ) , 3 . 09 ( s , 2H ) , 1 . 42 ( t , J = 6 . 8 Hz , 20135 . 08 , 134 . 23 , 130 . 91 , 129 . 85 , 129 . 16 , 125 . 42 , 114 . 02 , 6H ) ; ESIMS m / z 351 ( [ M + H ] + ) . 64 . 67 , 55 . 32 , 39 . 62 , 38 . 48 ; EIMS m / z 313 ( [ M ] + ) .

( E ) - 1 , 2 - Dichloro - 4 - ( 4 - methoxystyryl ) benzene ( C45 ) Example 5

25

- CH3 Preparation of ( E ) - 1 , 3 - dichloro - 5 - ( 4 - methoxystyryl ) benzene ( C43 )

CH 30 30

CH3

3 5 Isolated as an off - white solid ( 6 . 0 g , 53 % ) : mp 91 - 94° C . ; ' H NMR ( 400 MHz , CDC13 ) 8 7 . 56 ( d , J = 2 . 0 Hz , 1H ) , 7 . 46 - 7 . 42 ( m , 2H ) , 7 . 39 ( d , J = 8 . 4 Hz , 1H ) , 7 . 29 ( dd , J = 8 . 4 , 2 . 1 Hz , 1H ) , 7 . 04 ( d , J = 16 . 2 Hz , 1H ) , 6 . 93 - 6 . 88 ( m , 2H ) , 6 . 85 ( d , J = 16 . 3 Hz , 1H ) , 3 . 84 ( s , 3H ) ; 13C NMR ( 101 MHz ,

20 CDC12 ) 8 159 . 75 , 137 . 86 , 132 . 72 , 130 . 58 , 130 . 49 , 130 . 12 , 129 . 33 , 127 . 96 , 127 . 77 , 125 . 37 , 123 . 98 , 114 . 24 , 55 . 35 ; EIMS m / z 279 ( [ M ] + ) .

50

CH3

Example 6 Sodium methoxide powder ( 98 % , 0 . 63 g , 11 mmol ) was 45 added to a stirred solution of 3 , 5 - dichlorobenzaldehyde ( 2 . 0 > > Preparation of ( E ) - 1 - methoxy - 4 - ( 4 - ( trifluoromethyl )

g , 11 mmol ) and diethyl 4 - methoxybenzylphosphonate ( 2 . 0 styryl ) benzene ( C46 ) mL , 11 mmol ) in dry N , N - dimethylformamide ( 38 mL ) at 23° C . The resulting heterogeneous dark blue mixture was heated to 80° C . , resulting in a dark brown mixture , and stirred for 24 hours . The cooled reaction mixture was diluted with water ( 500 mL ) and extracted with diethyl ether ( 3x100 mL ) . The combined organic layers were diluted with hexane 55 ( 150 mL ) and washed with water ( 300 mL ) . The organic layer was dried over magnesium sulfate , filtered , and con centrated to afford the title product as a light brown oil ( 2 . 4 g , 75 % ) : ' H NMR ( 400 MHz , CDC13 ) 8 7 . 44 ( m , 2H ) , 7 . 34 60 To a stirred solution of diethyl 4 - methoxybenzyl phos ( d , J = 2 Hz , 2H ) , 7 . 20 ( t , J = 2 Hz , 1H ) , 7 . 06 ( d , J = 16 . 5 Hz , phonate ( 8 . 89 g , 34 . 0 mmol ) in N , N - dimethylformamide ( 30 1H ) , 6 . 91 ( m , 2H ) , 6 . 82 ( d , J = 16 . 5 Hz , 1H ) , 3 . 84 ( s , 3H ) ; IR mL ) was added sodium methoxide powder ( 1 . 86 g , 34 . 0 ( thin film ) 2934 ( w ) . 2835 ( w ) . 1724 ( w ) . 1637 ( w ) . 1605 mmol ) . The reaction mixture was stirred at room tempera

ture for 1 hour . The reaction mixture was cooled to 0° C . and ( m ) , 1581 ( m ) , 1558 ( m ) , 1511 ( s ) cm - . 65 4 - ( trifluoromethyl ) benzaldehyde ( 5 . 00 g , 28 . 0 mmol ) in The following compounds were prepared in like manner N , N - dimethylformamide ( 30 mL ) was added dropwise . The

to the procedure outlined in Example 5 : reaction mixture was stirred at 60° C . for 2 hours . The

58 US 9 , 795 , 140 B2

57 reaction mixture was poured in ice cold water , filtered , and ( E ) - 1 , 3 - Dibromo - 5 - ( 4 - methoxystyryl ) benzene ( C50 ) dried to afford the title compound as an off - white solid ( 3 . 60 g , 80 % ) : ' H NMR ( 300 MHz , CDC13 ) 8 7 . 61 - 7 . 52 ( m , 4H ) , 7 . 47 ( d , J = 9 . 0 Hz , 2H ) , 7 . 14 ( d , J = 16 . 5 Hz , 1H ) , 6 . 97 ( d , J = 16 . 5 Hz , 1H ) , 6 . 91 ( d , J = 9 . 0 Hz , 2H ) , 3 . 84 ( s , 3H ) ; ESIMS 5 m / z 279 ( [ M + H ] + ) .

The following compounds were prepared in like manner to the procedure outlined in Example 6 :

CH3

10

( E ) - 1 - ( 4 - Methoxystyryl ) - 3 - ( trifluoromethyl ) benzene ( C47 ) Br

- CH3

TI VI Isolated as an off - white solid ( 2 . 2 g , 54 % ) : ' H NMR ( 300 MHz , CDC13 ) 8 7 . 53 ( s , 1H ) , 7 . 50 ( s , 2H ) , 7 . 43 ( d , J = 9 . 0 Hz , 2H ) , 7 . 05 ( d , J = 16 . 2 Hz , 1H ) , 6 . 90 ( d , J = 9 . 0 Hz , 2H ) , 6 . 79 ( d , J = 16 . 2 Hz , 1H ) , 3 . 80 ( s , 3H ) ; ESIMS m / z 367 ( [ M + H ] + ) .

( E ) - 1 - Chloro - 3 - ( 4 - methoxystyryl ) - 5 - ( trifluorom ethyl ) benzene ( C51 )

25 Isolated as an off - white solid ( 4 . 0 g , 85 % ) : H NMR ( 400 MHz , CDC1z ) 8 7 . 72 ( s , 1H ) , 7 . 64 ( d , J = 6 . 8 Hz , 1H ) , 7 . 50 - 7 . 44 ( m , 4H ) , 7 . 12 ( d , J = 16 . 0 Hz , 1H ) , 6 . 98 ( d , J = 16 . 0 Hz , 1H ) , 6 . 91 ( d , J = 8 . 8 Hz , 2H ) , 3 . 84 ( s , 3H ) ; ESIMS m / z 279 ( M + H ] + ) . - CH3

30 30 F ( E ) - 2 - Chloro - 4 - ( 4 - methoxystyryl ) - 1 - ( trifluo

romethoxy ) benzene ( C48 )

35

40 -

F

Isolated as an off - white solid ( 4 . 3 g , 58 % ) : ' H NMR ( 300 MHz , CDC1z ) 8 7 . 62 ( s , 1H ) , 7 . 58 ( s , 1H ) , 7 . 48 - 7 . 42 ( m , 3H ) , 7 . 12 ( d , J = 16 . 2 Hz , 1H ) , 6 . 95 - 6 . 85 ( m , 3H ) , 3 . 84 ( s , 3H ) ; ESIMS m / z 313 ( [ M + H ] + ) .

Isolated : ESIMS m / z 329 ( [ M + H ] + ) . 45 ( E ) - 2 - Bromo - 1 , 3 - dichloro - 5 - ( 4 - methoxystyryl ) ben

zene ( C52 ) ( E ) - 1 - ( 4 - Methoxystyryl ) - 3 , 5 - bis ( trifluoromethyl ) benzene ( C49 )

50

CH3 . F

55

Br Br

8 FF

Isolated as an off - white solid ( 4 . 0 g , 56 % ) : ' H NMR ( 300 Isolated as an off - white solid ( 2 . 8 g , 40 % ) : ' H NMR ( 300 MHz , CDC12 ) 8 7 . 88 ( s , 2H ) , 7 . 70 ( s , 1H ) , 7 . 49 ( d , J = 8 . 4 Hz , 65 MHz , CDC13 ) d 7 . 46 ( s , 2H ) , 7 . 43 ( d , J = 9 . 0 Hz , 2H ) , 7 . 07 2H ) , 7 . 19 ( d , J = 16 . 5 Hz , 1H ) , 6 . 99 ( d , J = 16 . 5 Hz , 1H ) , 6 . 92 ( d , J = 13 . 5 Hz , 1H ) , 6 . 90 ( d , J = 9 . 0 Hz , 1H ) , 6 . 73 ( d , J = 13 . 5 ( d , J = 8 . 4 Hz , 2H ) , 3 . 84 ( m , 3H ) ; ESIMS m / z 347 ( [ M + H ] + ) . Hz , 1H ) , 3 . 84 ( s , 3H ) ; ESIMS m / z 358 ( [ M + H ] + ) .

US 9 , 795 , 140 B2 59

( E ) - 1 - Bromo - 3 - chloro - 5 - ( 4 - methoxystyryl ) benzene ( E ) - 2 - Chloro - 1 - fluoro - 4 - ( 4 - methoxystyryl ) benzene ( C53 ) ( C56 )

60

" CH3 CH3 Br gur . Door 10

F

Isolated as an off - white solid ( 6 . 0 g , 72 % ) : ESIMS m / z 15 263 ( [ M + H ] + ) .

Isolated as an off - white solid ( 4 . 0 g , 63 % ) : ' H NMR ( 300 MHz , CDC1z ) 8 7 . 49 ( s , 1H ) , 7 . 43 ( d , J = 8 . 4 Hz , 2H ) , 7 . 38 ( s , 1H ) , 7 . 35 ( s , 1H ) , 7 . 05 ( d , J = 16 . 5 Hz , 1H ) , 6 . 91 ( d , J = 8 . 4 Hz , 2H ) , 6 . 80 ( d , J = 16 . 5 Hz , 1H ) , 3 . 82 ( s , 3H ) ; ESIMS m / z 323 ( [ M + H ] + ) .

( E ) - 1 - Chloro - 3 - ( 4 - methoxystyryl ) - 5 - methylbenzene ( C57 )

20

CH3 ( E ) - 1 - Chloro - 3 - fluoro - 5 - ( 4 - methoxystyryl ) benzene ( C54 )

25 puen OCH3 CH3

30 men Isolated as an off - white solid ( 5 . 0 g , 60 % ) : ' H NMR ( 300 MHz , CDC13 ) 8 7 . 44 ( d , J = 8 . 4 Hz , 2H ) , 7 . 28 ( s , 1H ) , 7 . 15 ( s , 1H ) , 7 . 05 - 7 . 00 ( m , 2H ) , 6 . 91 - 6 . 83 ( m , 3H ) , 3 . 83 ( s , 3H ) ,

35 2 . 24 ( s , 3H ) ; ESIMS m / z 259 ( [ M + H ] + ) . ( E ) - 1 - Methoxy - 4 - ( 4 - ( perfluoroethyl ) styryl ) benzene

( C58 )

Isolated as an off - white solid ( 5 . 0 g , 60 % ) : ' H NMR ( 400 40 MHz , CDC13 ) 8 7 . 45 ( d , J = 8 . 4 Hz , 2H ) , 7 . 10 - 7 . 0 ( m , 3H ) , 6 . 96 - 6 . 80 ( m , 4H ) , 3 . 80 ( s , 3H ) ; ESIMS m / z 263 ( [ M + H ] + ) . OCH3

( Cho 2 na samostan solon ( E ) - 1 - Chloro - 2 - fluoro - 4 - ( 4 - methoxystyryl ) benzene ( C55 )

45 too o u FX F F

50 CH3 mo Isolated as an off - white solid ( 0 . 5 g , 42 % ) : ' H NMR ( 400

MHz , CDC13 ) 8 7 . 60 - 7 . 50 ( m , 4H ) , 7 . 47 ( d , J = 8 . 8 Hz , 2H ) , 7 . 15 ( d , J = 16 . 8 Hz , 1H ) , 6 . 98 ( d , J = 16 . 8 Hz , 1H ) , 6 . 92 ( d , J = 8 . 8 Hz , 2H ) , 3 . 82 ( s , 3H ) ; ESIMS m / z 329 ( [ M + H ] + ) .

55 ( E ) - 1 , 2 - bis ( 4 - ethoxyphenyl ) ethene ( C59 )

0 CH3 400 60 Isolated as an off - white solid ( 7 . 0 g , 84 % ) : ' H NMR ( 400

MHz , CDC13 ) 8 7 . 44 ( d , J = 8 . 0 Hz , 2H ) , 7 . 35 - 7 . 31 ( m , 1H ) , 7 . 28 - 7 . 24 ( m , 1H ) , 7 . 17 ( dd , J = 1 . 6 , 8 . 0 Hz , 1H ) , 7 . 03 ( d , J = 16 . 0 Hz , 1H ) , 6 . 90 ( d , J = 8 . 0 Hz , 1H ) , 7 . 49 ( d , J = 8 . 0 Hz , 65 HzC6 1H ) , 6 . 86 ( d , J = 16 . 0 Hz , 1H ) , 3 . 82 ( s , 3H ) ; ESIMS m / z 263 ( [ M + H ] + ) .

novou

US 9 , 795 , 140 B2 61 62

( E ) - 1 , 2 - Dichloro - 5 - ( 4 - methoxystyryl ) - 3 - methyl ben zene ( C62 )

Isolated as an off - white solid ( 1 . 7 g , 34 % ) : ' H NMR ( 300 MHz , CDC13 ) 8 7 . 40 ( d , J = 9 . 0 Hz , 4H ) , 6 . 91 ( s , 2H ) , 6 . 87 ( d , J = 9 . 0 Hz , 4H ) , 4 . 05 ( q , J = 6 . 9 Hz , 4H ) , 1 . 42 ( t , J = 6 . 9 Hz , 6H ) ; ESIMS m / z 269 ( [ M + H ] + ) .

5

Example 7 CH3

Preparation of ( E ) - 1 , 3 - dichloro - 2 - fluoro - 5 - ( 4 methoxystyryl ) benzene ( C60 ) poor 10

CH3

CH3 15 Isolated as an off - white solid ( 3 . 0 g , 55 % ) : ' H NMR ( 300 MHz , CDC1z ) 8 7 . 50 - 7 . 40 ( m , 3H ) , 7 . 24 ( s , 1H ) , 7 . 02 ( d , J = 15 . 9 Hz , 1H ) , 6 . 90 ( d , J = 9 . 0 Hz , 2H ) , 6 . 81 ( d , J = 15 . 9 Hz , 1H ) , 3 . 83 ( s , 3H ) , 2 . 42 ( s , 3H ) ; ESIMS m / z 293 ( [ M + H ] + ) .

20 Example 8

25

Cl 30

CI

Preparation of ( E ) - 1 , 2 , 4 - trichloro - 5 - ( 4 - methox ystyryl ) benzene ( C63 )

A stirred mixture of 5 - bromo - 1 , 3 - dichloro - 2 - fluoroben - , zene ( 2 . 00 g , 8 . 20 mmol ) , 1 - methoxy - 4 - vinylbenzene ( 1 . 32 g , 9 . 80 mmol ) , and triethylamine ( 20 mL ) under argon was CH3 degassed for 5 minutes . Palladium ( II ) acetate ( 0 . 0368 g , 0 . 164 mmol ) and 1 , 1 ' - bis ( diphenylphosphino ) ferrocene ( 0 . 181 g , 0 . 328 mmol ) were added and the reaction was heated to 90° C . for 16 hours . The reaction mixture was poured into water and extracted with ethyl acetate . The combined organic layers were dried over sodium sulfate , 26 To a sealed tube were added 1 - bromo - 2 , 4 , 5 - trichloroben filtered , and concentrated . Purification by flash column zene ( 3 . 0 g , 12 mmol ) , 1 , 2 - dimethoxyethane : water ( 10 : 1 , 30 chromatography provided the title compound as an off - white mL ) , ( E ) - 2 - ( 4 - methoxystyryl ) - 4 , 4 , 5 , 5 - tetramethyl - 1 , 3 , 2 - di

oxaborolane ( C64 ) ( 3 . 7 g , 14 mmol ) , and potassium carbon solid ( 1 . 60 g , 67 % ) : ' H NMR ( 300 MHz , CDC1z ) 8 7 . 41 ( d , ate ( 3 . 2 g , 24 mmol ) . The reaction mixture was degassed for J = 8 . 8 Hz , 2H ) , 7 . 31 ( s , 1H ) , 7 . 37 ( s , 1H ) , 6 . 96 ( d , J = 16 . 0 Hz , 10 minutes with argon , followed by addition of tetrakis 1H ) , 6 . 89 ( d , J = 8 . 8 Hz , 2H ) , 6 . 76 ( d , J = 16 . 0 Hz , 1H ) , 3 . 84 ( triphenylphosphine ) palladium ( 0 ) ( 0 . 55 g , 0 . 48 mmol ) . The

reaction mixture was degassed for 10 minutes then heated at ( s , 3H ) ; ESIMS m / z 297 ( [ M + H ] + ) . 90° C . for 16 hours . The reaction mixture was poured in to The following compounds were prepared in like manner water and extracted with ethyl acetate . The combined

to the procedure outlined in Example 7 : organic layers were dried over sodium sulfate , filtered , and concentrated . Purification by flash column chromatography provided the title compound as an off - white solid ( 3 . 0 g ,

( E ) - 1 , 3 - Dichloro - 5 - ( 4 - methoxystyryl ) - 2 - methylben 80 % ) : ' H NMR ( 400 MHz , CDC12 ) 8 7 . 73 ( s , 1H ) , 7 . 50 - 7 . 45 zene ( C61 ) ( m , 3H ) , 7 . 20 ( d , J = 16 . 0 Hz , 1H ) , 7 . 02 ( d , J = 16 Hz , 1H ) ,

6 . 92 ( d , J = 8 . 0 Hz , 2H ) , 3 . 84 ( m , 3H ) ; ESIMS m / z 313 50 ( [ M + H ] + ) .

45

Example 9 CH3

55 55 Preparation of ( E ) - 2 - ( 4 - methoxystyryl ) - 4 , 4 , 5 , 5 - te

tramethyl - 1 , 3 , 2 - dioxaborolane ( C64 ) poo H3C

CH3 60

H3CO H3C - Y H3C Isolated as an off - white solid ( 2 . 5 g , 67 % ) : H NMR ( 300

MHz , CDC13 ) d 7 . 43 ( d , J = 8 . 7 Hz , 2H ) , 7 . 38 ( s , 2H ) , 7 . 02 ( d , J = 16 . 5 Hz , 1H ) , 6 . 90 ( d , J = 8 . 7 Hz , 2H ) , 6 . 79 ( d , J = 1 . 5 Hz , 1H ) , 3 . 82 ( s , 3H ) , 2 . 42 ( s , 3H ) ; ESIMS m / z 293 ( [ M + H ] + ) .

65 H3C CH3

US 9 , 795 , 140 B2 63 64

To a 50 mL round - bottomed flask were added 1 - ethynyl - To a stirred solution of 1 - ( 4 - bromophenyl ) - 2 , 2 , 2 - trifluo 4 - methoxybenzene ( 4 . 0 g , 30 mmol ) , 4 , 4 , 5 , 5 - tetramethyl - 1 , roethanone ( 5 . 00 g , 19 . 7 mmol ) in dichloromethane under 3 , 2 - dioxaborolane ( 3 . 3 g , 36 mmol ) , zirconocene hydrochlo argon were added 4 - tert - butyl - 2 , 6 - dimethylphenylsulfur tri

fluoride ( 2 . 90 g , 11 . 8 mmol ) and hydrogen fluoride pyridine ride ( 1 . 2 g , 4 . 0 mmol ) , and triethylamine ( 2 . 8 mL , 15 mmol ) 5 complex ( 0 . 190 g . 9 . 80 mmol ) at 0° C . The reaction mixture at 0° C . The reaction mixture was then stirred at 65° C . for was allowed to warm to room temperature and stirred for 16 16 hours . The reaction mixture was poured in water and hours . The reaction mixture was poured into water and extracted with ethyl acetate . The combined organic layers extracted with ethyl acetate . The combined organic extracts were dried over sodium sulfate , filtered , and concentrated . 10 were dried over sodium sulfate , filtered , and concentrated .

10 Purification by flash column chromatograph provided the Purification by flash column chromatography provided the title compound as colorless liquid ( 1 . 00 g , 20 % ) : ' H NMR title compound as an off - white semi solid ( 3 . 0 g , 38 % ) : ' H ( 300 MHz , CDC13 ) 8 7 . 65 ( d , J = 9 . 0 Hz , 2H ) , 7 . 47 ( d , J = 9 . 0 NMR ( 400 MHz , CDC13 ) 8 7 . 43 ( d , J = 8 . 8 Hz , 2H ) , 7 . 35 ( d , Hz , 2H ) ; EIMS m / z 274 ( [ M ] + ) . J = 18 . 0 Hz , 1H ) , 6 . 86 ( d , J = 8 . 8 Hz , 2H ) , 6 . 01 ( d , J = 18 . 0 Hz , 15 1H ) , 3 . 81 ( s , 3H ) , 1 . 30 ( s , 12H ) . Example 12

Example 10

Preparation of 3 , 4 , 5 - trichlorobenzaldehyde ( C65 ) 20 Preparation of trans - 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 dichlorophenyl ) cyclopropanecarboxamido ) benzoic

acid ( C67 )

25 1 CI

OH

N 30

In an oven dried , nitrogen flushed , 500 mL round - bot tomed flask equipped with a pressure equalizing addition funnel , 5 - bromo - 1 , 2 , 3 - trichlorobenzene ( 10 . 0 g , 38 . 4 mmol ) was dissolved in tetrahydrofuran ( 100 mL ) , and the resulting 35 solution was cooled in an ice bath under nitrogen . Isopropyl To a solution of trans - 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophenyl ) magnesium chloride ( 2 M solution tetrahydrofuran , 21 . 1 cyclopropanecarboxylic acid ( C1 ) ( 0 . 300 g , 1 . 00 mmol ) in mL , 42 . 3 mmol ) was added dropwise with good stirring over dichloromethane ( 5 . 00 mL ) stirred at 0° C . , were added 15 minutes via the addition funnel . After 0 . 5 hours , N , N - 10 N , N - dimethylformamide ( 1 drop ) followed by oxalyl chlo dimethylformamide ( 3 . 72 mL , 48 . 0 mmol ) was added to the ride ( 0 . 131 mL , 1 . 50 mmol ) over 2 minutes . The ice batch dark solution with stirring . After an additional 0 . 5 hours , was removed and the reaction allowed to warm to room hydrochloric acid ( 1 N , 100 mL ) was added with stirring . temperature over 90 minutes . The reaction was then con The layers were separated , and the organic layer was washed as centrated to yield a yellow - orange semi - solid . The semi with brine . The combined aqueous layers were extracted solid was dissolved in dichloromethane ( 3 . 5 mL ) , and the with ether , and the combined organics were dried over solution was added slowly to a cooled solution of 5 - amino sodium sulfate , filtered , and concentrated to afford the title 2 - chlorobenzoic acid ( 0 . 206 g , 1 . 20 mmol ) and triethylam compound as a white solid ( 10 : 1 mixture of title compound ine ( 0 . 209 mL , 1 . 50 mmol ) in dichloromethane ( 7 mL ) . The to 1 , 2 , 3 - trichlorobenzene , 7 . 96 g , 99 % ) : ' H NMR ( CDC13 ) ice bath was removed and the reaction was allowed to warm 8 9 . 91 ( s , 1H ) , 7 . 88 ( s , 2H ) ; EIMS m / z 209 ( [ M ] + ) . to room temperature over 90 minutes . The reaction was

diluted with dichloromethane ( 10 mL ) and washed with Example 11 hydrochloric acid ( 0 . 1 N ) . The resulting slurry was filtered

Preparation of 1 - bromo - 4 - ( perfluoroethyl ) benzene and the solid washed with water . The precipitated solid was ( C66 ) dried in a vacuum oven at 40° C . to provide the title

compound as a light brown solid ( 0 . 421 g , 93 % ) : mp 234 - 236° C . ; ' H NMR ( 400 MHz , DMSO - do ) d 13 . 47 ( s , 1H ) , 10 . 90 ( s , 1H ) , 8 . 16 ( d , J = 2 . 3 Hz , 1H ) , 7 . 78 ( dd , J = 8 . 7 , 2 . 4 Hz , 1H ) , 7 . 59 ( m , 4H ) , 3 . 56 ( dd , J = 49 . 8 , 8 . 5 Hz , 2H ) , 1 . 09 ( m , 1H ) ; 13C NMR ( 101 MHz , DMSO - do ) 8 166 . 26 , 165 . 77 , 162 . 61 , 137 . 57 , 137 . 27 , 134 . 04 , 132 . 18 , 131 . 44 ,

F F 131 . 22 , 127 . 88 , 127 . 66 , 126 . 40 , 125 . 92 , 122 . 88 , 121 . 17 , 102 . 37 , 62 . 11 , 38 . 41 , 36 . 83 ; ESIMS m / z 454 ( [ M + H ] + ) .

65

US 9 , 795 , 140 B2 65 66

Example 13 trans - 3 - ( 2 , 2 - Dichloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclo propane - 1 - carboxamido ) - N - ( 2 , 2 , 2 - trifluoroethyl )

benzamide ( F3 ) Preparation of trans - 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 dichlorophenyl ) cyclopropane - 1 - carboxamido ) - N

methylbenzamide ( F1 )

" C1 Clo

N 10 CI NH Clo

ZI CH3 NH

15

Isolated as a white solid ( 0 . 155 g , 62 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 2 - trifluo

roethyl ) benzamide ( F4 ) 20

cl clo Byxocet IZ

30

5 - Amino - 2 - chloro - N - methylbenzamide ( C68 ) ( 0 . 072 g , 0 . 39 mmol ) and 4 - dimethylaminopyridine ( 0 . 052 g , 0 . 42 , mmol ) were sequentially added to a stirred mixture of trans - 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropanecar boxylic acid ( C1 ) ( 0 . 097 g , 0 . 33 mmol ) and 1 - ethyl - 3 - ( 3 dimethylaminopropyl ) carbodiimide ( 0 . 093 g , 0 . 49 mmol ) in 1 , 2 - dichloroethane ( 3 . 3 mL ) at room temperature . The reac tion was stirred at room temperature for 20 hours . Dichlo romethane was added and the mixture was washed with saturated aqueous sodium bicarbonate and hydrochloric acid 35 ( 1 N ) . The organic phase was dried over magnesium sulfate , filtered , and concentrated . Purification by flash column chromatography using 0 - 100 % ethyl acetate / hexanes as elu ent provided the title compound as a yellow oil ( 0 . 047 g , 30 % ) .

The following compounds were prepared in like manner to the procedure outlined in Example 13 :

Isolated as a yellow solid ( 0 . 081 g , 44 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 - oxo - 2 - | ( 2 , 2 ,

2 - trifluoroethyl ) amino ) ethyl ) benzamide ( F5 )

40

CICI

CI . NH 45 45 F o seu trans - 5 - ( 2 , 2 - Dichloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclo

propane - 1 - carboxamido ) - N - methyl - 2 - ( trifluorom ethyl ) benzamide ( F2 )

50 Isolated as a yellow solid ( 0 . 065 g , 39 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( pyridin - 3

ylmethyl ) benzamide ( F6 ) L

I

Ci Ci 55 ZI I

CH3 Ciclo pu 60 cl pio

65

Isolated as a yellow solid ( 0 . 051 g , 32 % ) . Isolated as a tan powder ( 0 . 091 g , 67 % ) .

US 9 , 795 , 140 B2 67 68

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 4 , 5 - trichloro trans - N - ( Allyloxy ) - 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 4 , phenyl ) cyclopropane - 1 - carboxamido ) - N - ( pyridin - 3 5 - trichlorophenyl ) cyclopropane - 1 - carboxamido )

ylmethyl ) benzamide ( F7 ) benzamide ( F11 )

Cl . Cl 0 Cl . Cl 0 ???????? LZ CH

10 C

C1

15 Isolated as a tan powder ( 0 . 051 g , 59 % ) . Isolated as a tan semi - solid ( 0 . 021 g , 26 % ) .

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe ny1 ) cyclopropane - 1 - carboxamido ) - N - ( pyridin - 2

ylmethyl ) benzamide ( F8 ) trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe ny1 ) cyclopropane - 1 - carboxamido ) - N - ( pyridin - 4

ylmethyl ) benzamide ( F12 ) 20

Cl . Cl 0

? C1 C1 - 25 ???? ??? ????? T

3 )

Isolated as an off - white powder ( 0 . 036 g , 26 % ) . Isolated as a tan powder ( 0 . 100 g , 74 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 4 , 5 - trichloro

phenyl ) cyclopropane - 1 - carboxamido ) - N - ( pyridin - 2 - yimethyl ) benzamide ( F9 )

35 trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 4 , 5 - trichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( pyridin - 4

ylmethyl ) benzamide ( F13 )

40 ) Cl . Cl ? Cl . Cl ( ??? ??? ?

C , 45 ?

Isolated as an off - white powder ( 0 . 017 g , 20 % ) . 50 56 )

Isolated as an off - white powder ( 0 . 062 g , 72 % ) . trans - N - ( Allyloxy ) - 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 dichlorophenyl ) cyclopropane - 1 - carboxamido ) benz

amide ( F10 ) trans - N - ( Allyloxy ) - 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 4 dichlorophenyl ) cyclopropane - 1 - carboxamido ) benz

amide ( F14 ) 55

Cl . Cl 0 Cl . CH2 60 CH , Cl 0 ? ??? ?????? ???? ??? CH ,

? LZ ?

65 C /

Isolated as an off - white semi - solid ( 0 . 034g , 27 % ) . Isolated as a white powder ( 0 . 062 2 , 49 % ) .

70 US 9 , 795 , 140 B2

69 trans - N - 2 - Chloro - N - ( cyclopropylmethoxy ) - 5 - ( 2 , 2 trans - N - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro dichloro - 3 - ( 3 , 4 , 5 - trichlorophenyl ) cyclopropane - 1 phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 4 - fluoro

carboxamido ) benzamide ( F15 ) phenethyl ) benzamide ( F19 )

CI Clo Ciclo position defina Cl

10

15 Isolated as a white foam ( 0 . 056 g , 56 % ) . Isolated as an off - white powder ( 0 . 119 g , 83 % ) . trans - N - 2 - Chloro - N - ( cyclopropylmethoxy ) - 5 - ( 2 , 2 dichloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - 1

carboxamido ) benzamide ( F16 ) trans - N - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 4 , 5 - trichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 4 - fluoro

phenethyl ) benzamide ( F20 ) 20

CI Clo Ci Cl .

25 pxigir og hafa @

IZ

CY Cl 30

Isolated as a white powder ( 0 . 066 g , 50 % ) . Isolated as a tan powder ( 0 . 097 g , 71 % ) .

35 trans - N - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro - phenyl ) cyclopropane - 1 - carboxamido ) - N - ( ( 4 - fluo

robenzyl ) oxy ) benzamide ( F17 ) trans - N - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( ( 2 , 2 - dif

luorocyclopropyl ) methoxy ) benzamide ( F21 )

40

Ciclo N ???? NH ??? CI . NH

F 45

Isolated as a tan foam ( 0 . 063 g , 44 % ) . 50

Isolated as a brown glass ( 0 . 130 g , 70 % ) . trans - N - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 4 , 5 - trichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( ( 4 - fluo

robenzyl ) oxy ) benzamide ( F18 ) trans - N - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 4 - dichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( ( 2 , 2 - dif

luorocyclopropyl ) methoxy ) benzamide ( F22 ) 55

cl Clo ??? ?? ?? IZ " C1

Isolated as a tan foam ( 0 . 048 g , 35 % ) . Isolated as a brown glass ( 0 . 150 g , 81 % ) .

US 9 , 795 , 140 B2 72

Example 14 trans - N - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 4 , 5 - trichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( ( 2 , 2 - dif

luorocyclopropyl ) methoxy ) benzamide ( F23 ) Preparation of trans - N - benzyl - 2 - chloro - 5 - ( 2 , 2 - di chloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - 1 - car

boxamido ) benzamide ( F27 )

N 2

CICLO CI ????? IZ

NH =

?

Isolated as a tan foam ( 0 . 130 g , 73 % ) . trans - N - 2 - Chloro - N - ( 2 - cyclopropylethyl ) - 5 - ( 2 , 2 dichloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - 1

carboxamido ) benzamide ( F24 ) To a solution of phenylmethanamine ( 0 . 024 g , 0 . 23 mmol )

in dichloromethane ( 2 mL ) were added in sequence 1 - ethyl 3 - ( 3 - dimethylaminopropyl ) carbodiimide ( 0 . 054 g , 0 . 28 mmol ) , 4 - dimethylaminopyridine ( 0 . 027 g , 0 . 23 mmol ) , and trans - 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophenyl ) cy clopropanecarboxamido ) benzoic acid ( C67 ) ( 0 . 085 g , 0 . 19

os mmol ) . The reaction mixture was stirred at room tempera ture for 16 hours . Purification by flash column chromatog raphy using 0 - 20 % ethyl acetate / hexanes as eluent provided the title compound as a white solid ( 0 . 075 g , 74 % ) .

The following compounds were prepared in like manner 30 to the procedure outlined in Example 14 :

25

IZ ?????? trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 4 - fluoroben

zyl ) benzamide ( F28 ) Isolated as a tan powder ( 0 . 136 g , 78 % ) . 35

trans - N - 2 - Chloro - N - ( 2 - cyclopropylethyl ) - 5 - ( 2 , 2 dichloro - 3 - ( 3 , 4 - dichlorophenyl ) cyclopropane - 1

carboxamido ) benzamide ( F25 ) CI . Clo

40 Ci

ci Clo

Cl By Sofi pecivo 45

Isolated as a white solid ( 0 . 072 g , 68 % ) . Example 15

50 Isolated as a tan powder ( 0 . 134 g , 77 % ) . trans - N - 2 - Chloro - N - ( 2 - cyclopropylethyl ) - 5 - ( 2 , 2 dichloro - 3 - ( 3 , 4 , 5 - trichlorophenyl ) cyclopropane - 1

carboxamido ) benzamide ( F26 )

Preparation of trans - 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 dichlorophenyl ) cyclopropane - 1 - carboxamido ) - N

phenoxybenzamide ( F29 )

55

HN C1 . EZ 60 ?????? N

To a solution of trans - 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 dichlorophenyl ) cyclopropanecarboxamido ) benzoic acid Isolated as a white powder ( 0 . 128 g , 77 % ) .

74

L

US 9 , 795 , 140 B2 73

( C67 ) ( 0 . 300 g , 0 . 661 mmol ) in dichloromethane ( 5 mL ) trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe stirred at 0° C . , were added N , N - dimethylformamide ( 1 nyl ) cyclopropane - 1 - carboxamido ) - N - ( 3 , 4 - difluo drop ) followed by oxalyl chloride ( 0 . 0870 mL , 0 . 992 mmol ) . robenzyl ) benzamide ( F32 ) The ice batch was removed and the reaction was allowed to warm to room temperature over 90 minutes . The reaction 5 was concentrated and the resultant acid chloride was dis solved in dichloromethane ( 5 mL ) and cooled in an ice bath . Ciclo A solution of O - phenylhydroxylamine ( 0 . 108 g , 0 . 992 mmol ) and triethylamine ( 0 . 230 mL , 1 . 65 mmol ) in dichlo romethane ( 3 mL ) was added dropwise . The mixture was 10 Cla removed from the ice bath and warmed to room temperature over 1 hour . The reaction mixture was allowed to stir at room temperature for 16 hours . Purification by flash column chromatography using 0 - 35 % ethyl acetate / hexanes as elu ent followed by trituration with dichloromethane , filtration , 15 and drying in a vacuum oven at 40° C . overnight provided Isolated as a white solid ( 0 . 085 g , 85 % ) . the title compound as a white solid ( 0 . 0981 g , 27 % ) .

Example 16 trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - pentylbenz

Preparation of trans - 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 amide ( F33 ) dichlorophenyl ) cyclopropane - 1 - carboxamido ) - N

isobutylbenzamide ( F30 )

????? NH

20

Ciclo 25 25

Ciclo CH3 CH3 N

CH3 plec plain 30 30 30

Isolated as a white solid ( 0 . 072 g , 79 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 4 - dime

thoxybenzyl ) benzamide ( F34 )

al Clo CH3

35

To a solution of trans - 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 dichlorophenyl ) cyclopropanecarboxamido ) benzoic acid ( C67 ) ( 0 . 0750 g , 0 . 165 mmol ) in dichloromethane ( 1 mL ) were added 1 - [ bis ( dimethylamino ) methylene ) - 1H - 1 , 2 , 3 - tri azolo [ 4 , 5 - b ] pyridinium 3 - oxid hexafluorophosphate ( 0 . 0690 40 g , 0 . 182 mmol ) followed by diisopropylethylamine ( 0 . 0280 g , 0 . 215 mmol ) , and the resulting pale - yellow solution was stirred for 15 minutes , treated with 2 - methylpropan - 1 - amine ( 0 . 0150 g , 0 . 198 mmol ) , and stirred at room temperature for approximately 18 hours . The solution was washed with hydrochloric acid ( 1 N ) , and the phases were separated and 45 dried by passing them through a phase separator cartridge . The organic phase was concentrated , purified by flash col umn chromatography , and dried under vacuum to provide the title compound as a sticky , viscous , oil that slowly solidifies upon scratching ( 0 . 0810 g , 100 % ) .

The following compounds were prepared in like manner to the procedure outlined in Example 16 :

NH H3c

Isolated as a pale - yellow solid ( 0 . 084 g , 84 % ) . 50

trans - 2 - Chloro - N - ( cyclopropylmethyl ) - 5 - ( 2 , 2 - di chloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - 1 - car

boxamido ) benzamide ( F35 ) trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - hexylbenz

amide ( F31 ) 55

Ciclo CI Clo Xalqining the _ CHz 60 CI

65

Isolated as a white solid ( 0 . 067 g , 75 % ) . Isolated as a white solid ( 0 . 074 g , 84 % ) .

US 9 , 795 , 140 B2 75 76

trans - N - ( 4 - ( tert - Butylbenzyl ) - 2 - chloro - 5 - ( 2 , 2 - di chloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - 1 - car

boxamido ) benzamide ( F36 ) H3C

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 3 , 3 , 3 - trifluo

ropropy1 ) benzamide ( F40 )

5 Cl Clo

CH3 CH ?

Cl . Cl ???? o =

Z 10 CI F

Isolated as a white solid ( 0 . 061 g , 51 % ) . 15 15 trans - 2 - Chloro - N - ( 2 - cyanoethyl ) - 5 - ( 2 , 2 - dichloro - 3 ( 3 , 5 - dichlorophenyl ) cyclopropane - 1 - carboxamido )

benzamide ( F37 )

Isolated as a white solid ( 0 . 077g , 81 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 4 - ( trifluorom

ethyl ) benzyl ) benzamide ( F41 ) 20

Cl . Cl ?

F 25 Cl Clo ?????? ?????? 3 )

Isolated as a white solid ( 0 . 072g , 82 % ) .

35 35 trans - 2 - Chloro - N - 3 - cyanopropyl ) - 5 - ( 2 , 2 - dichloro 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - 1 - carboxamido )

benzamide ( F38 )

Isolated as a white solid ( 0 . 087g , 82 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 - methyl - 1

( methylsulfonyl ) propan - 2 - y1 ) benzamide ( F42 )

Cl . Clo *

CH3 ? C1 C1 0 = S = 0 ??? ??????? 45 Cl ???? LZ

6 H?C CH

Isolated as a white solid ( 0 . 081 g , 90 % ) . 50

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 3 - ( 2 , 2 , 2 - trif

luoroethoxypropyl ) benzamide ( F39 )

Isolated as a white solid ( 0 . 090 g , 88 % ) . trans - 2 - Chloro - N - ( 2 - ( cyclopropylmethoxyethyl ) - 5 ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - 1

carboxamido ) benzamide ( F43 ) 55

Cl . Cl ? Cl . Cl0 F 60 ? / ???? ??????? LZ - C Z

65

Isolated as a white solid ( 0 . 082 g , 79 % ) . Isolated as a white solid ( 0 . 042 g , 44 % ) .

US 9 , 795 , 140 B2 77 78

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 3 - fluoropro

pyl ) benzamide ( F44 )

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 - difluoro

ethyl ) benzamide ( F48 ) CI cl , Co .

?? ??? F

10 CI NH

Isolated as a white solid ( 0 . 053 g , 59 % ) . 15 trans - N - Butyl - 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - di chlorophenyl ) cyclopropane - 1 - carboxamido ) benz

amide ( F45 ) Isolated as a white solid ( 0 . 065 g , 76 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 3 , 3 , 3 - pen

tafluoropropyl ) benzamide ( F49 ) 20

cl , Clo CH3 pxequi , - CI NH 25 F F

1 Xin I

T

30

Isolated as a white solid ( 0 . 067 g , 76 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ethylbenz

amide ( F46 ) 35 35 Isolated as a white solid ( 0 . 070 g , 72 % ) .

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 4 - ( dimethyl

amino ) butyl ) benzamide ( F50 )

CUCI

CHZ ciclo NH

ci N - CH3 NH CH3 W

Isolated as a white solid ( 0 . 065 g , 82 % ) . 50

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( prop - 2 - yn - 1

yl ) benzamide ( F47 )

Isolated as a white solid ( 0 . 031 g , 34 % ) . trans - 2 - Chloro - N - ( 2 - chloroethyl ) - 5 - ( 2 , 2 - dichloro - 3 ( 3 , 5 - dichlorophenyl ) cyclopropane - 1 - carboxamido )

benzamide ( F51 ) 55

CI Clo CICI

N ECH N 60 CI

65

Isolated as a white solid ( 0 . 043 g , 53 % ) . Isolated as a white solid ( 0 . 073 g , 86 % ) .

79 US 9 , 795 , 140 B2

80 trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe trans - N - ( 2 - Acetamidoethyl ) - 2 - chloro - 5 - ( 2 , 2 - di

nyl ) cyclopropane - 1 - carboxamido ) - N - 2 - ( methylthio ) chloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - 1 - car ethyl ) benzamide ( F52 ) boxamido ) benzamide ( F55 )

N ? ??? ??????? CH , ' s NH CHZ

15

Isolated as a tan solid ( 0 . 063 g , 71 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - propylbenz

amide ( F56 ) Isolated as a white solid ( 0 . 255 g , 88 % ) . 20

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 - methoxy

ethyl ) benzamide ( F53 ) clo

25 14 CI CH3

?? ? CH3

IZ 30

35

Isolated as a white solid ( 0 . 074 g , 90 % ) . trans - 2 - Chloro - N - ( 3 - chloropropyl ) - 5 - ( 2 , 2 - dichloro 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - 1 - carboxamido )

benzamide ( F57 ) Isolated as a white solid ( 0 . 064 g , 76 % ) .

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 - ethoxyethyl )

benzamide ( F54 ) 4 40

Ci Clo 45

CH3 Biroqu pdf 50 50 Isolated as a white solid ( 0 . 084 g , 96 % ) .

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 3 - ( 2 - methoxy

ethoxy ) propyl ) benzamide ( F58 ) Isolated as a white solid ( 0 . 066 g , 76 % ) .

CI clo IZ CHZ

NH

Isolated as a white solid ( 0 . 071 g , 75 % ) .

US 9 , 795 , 140 B2 82

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - methyl - N - ( 2 , 2 , nyl ) cyclopropane - 1 - carboxamido ) - N - ethyl - N - meth

2 - trifluoroethyl ) benzamide ( F59 ) ylbenzamide ( F63 ) Cl CICO CH ; F 5

Xect Xhe ciclo CH3 N CH

10 CL NH

Isolated as a white solid ( 0 . 056 g , 62 % ) . 15

Isolated as a white solid ( 0 . 077 g , 94 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 3 , 3 , 4 , 4 , 4 - pen

tafluorobutyl ) benzamide ( F60 ) 20

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - methyl - N - ( 3 , 3 ,

3 - trifluoropropyl ) benzamide ( F64 )

ci Clo F

CI Clo XF 25 perguntou que F F

30

Isolated as a white solid ( 0 . 093 g , 94 % ) . CI

Isolated as a white solid ( 0 . 083 g , 89 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 3 , 3 , 4 , 4 , 4 -

heptafluorobutyl ) benzamide ( F61 ) 35

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - methyl - N

( prop - 2 - yn - 1 - yl ) benzamide ( F65 )

CICIO F F F H V ciclo CH3 CH3 pero custo F F 2CH

Isolated as a white solid ( 0 . 054 g , 52 % ) . 50

Isolated as a tan solid ( 0 . 035 g , 42 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - methyl - N - pro

pylbenzamide ( F62 ) trans - 2 - Chloro - N - ( cyanomethyl ) - 5 - ( 2 , 2 - dichloro - 3 ( 3 , 5 - dichlorophenyl ) cyclopropane - 1 - carboxamido )

N - methylbenzamide ( F66 ) 55

C1 Ciclo Ciclo CH3

CHz 60 CM paçon des NH

65

Isolated as a white solid ( 0 . 071 g , 84 % ) . Isolated as a light yellow solid ( 0 . 023 g , 28 % ) .

US 9 , 795 , 140 B2 83 84

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 - methoxy

ethyl ) - N - methylbenzamide ( F67 )

trans - 2 , 2 - Dichloro - N - ( 4 - chloro - 3 - ( 3 , 3 - difluoropyrro lidine - 1 - carbonyl ) phenyl ) - 3 - ( 3 , 5 - dichlorophenyl )

cyclopropane - 1 - carboxamide ( F71 )

Cl . Clo C C1 CH ; C

NH 10

Isolated as a light yellow solid ( 0 . 064 g , 74 % ) . 15 15

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - methyl - N - ( 2

( methylthio ) ethyl ) benzamide ( F68 )

Isolated as a white solid ( 0 . 079 g , 88 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nylcyclopropane - 1 - carboxamido ) - N - ( 4 , 4 , 4 - trifluo

robutyl ) benzamide ( F72 ) 20

ClO CICLO puidum , plagunt N 25 e Ci ,

30

Isolated as a white solid ( 0 . 069 g , 77 % ) . Isolated as a white solid ( 0 . 090 g , 97 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( ( 3 , 3 - difluoro

cyclobutyl ) methyl ) - N - methylbenzamide ( F73 ) trans - 2 - Chloro - N - ( cyclopropylmethyl ) - 5 - ( 2 , 2 - di chloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - 1 - car

boxamido ) - N - methylbenzamide ( F69 ) 35 35

CI . Clo CH al Clo CH3 40 laçast N

NH 45

Isolated as a white solid ( 0 . 087 g , 92 % ) . Example 17a Isolated as a colorless oil ( 0 . 066 g , 77 % ) . 50

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( ( 3 , 3 - difluoro

cyclobutyl ) methyl ) benzamide ( F70 )

Preparation of trans - 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 dichlorophenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 ( methylsulfinyl ) ethyl ) benzamide ( F74 ) and trans - 2

chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2

( methylsulfonyl ) ethyl ) benzamide ( F75 ) 55

F74

ciclo NH ???? 0

O =

Isolated as a white solid ( 0 . 074 g , 80 % ) .

US 9 , 795 , 140 B2 85 85 86

- continued 5 - Amino - N - methyl - 2 - ( trifluoromethyl ) benzamide ( C69 ) F75

ci Clo 5 5

NO CH3 10

HN

To a solution of trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 dichlorophenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 - ( meth - Isolated as a white solid ( 0 . 067 g . 75 % ) : 1H NMR ( 400 ylthio ) ethyl ) benzamide ( F52 ) ( 0 . 179 g , 0 . 340 mmol ) in 13 MHz , CDC13 ) 8 7 . 43 ( d , J = 8 . 5 Hz , 1H ) , 6 . 74 ( d , J = 2 . 4 Hz , acetic acid ( 4 mL ) was added sodium perborate tetrahydrate ate tetrahydrate 1 H ) , 6 . 71 6 . 66 ( m , 1H ) , 5 . 76 ( s , 1H ) , 4 . 07 ( s , 2H ) , 2 . 98 ( d ,

J = 4 . 9 Hz , 3H ) ; IR ( thin film ) 3465 , 3350 , 1612 cm - ? ; EIMS ( 0 . 0840 g , 0 . 540 mmol ) , and the colorless mixture was m / z 218 ( [ M ] + ) . warmed to 55° C . and stirred for about 3 hours . The reaction 5 - Amino - 2 - chloro - N - ( 2 , 2 , 2 - trifluoroethyl ) benzamide mixture was diluted with dichloromethane ( 50 mL ) and 20 ( C70 ) neutralized by the slow addition of saturated aqueous sodium bicarbonate . The phases were separated and the aqueous phase was extracted with dichloromethane , and the combined organic layers were washed with brine , dried by passing through a phase separator cartridge , and concen trated . Purification by flash column chromatography using 0 - 100 % ethyl acetate / hexanes followed by 1 : 1 dichlo romethane / methanol as eluent and drying in a vacuum oven so ( house vacuum ) at 47° C . overnight provided ( F74 ) as a Isolated as a white solid ( 0 . 067 g , 75 % ) : ' H NMR ( 400

MHz , DMSO - do ) 88 . 98 ( t , J = 6 . 3 Hz , 1H ) , 7 . 08 ( d , J = 8 . 5 Hz , white solid ( 0 . 048 g , 26 % ) and ( F75 ) as a white solid ( 0 . 135 1H ) , 6 . 64 6 . 52 ( m , 2H ) , 5 . 46 ( s , 2H ) , 4 . 01 ( qd , J = 9 . 7 , 6 . 5 Hz , g , 71 % ) . 2H ) ; IR ( thin film ) 3428 , 3281 , 1656 cm - 1 ; ESIMS m / z 254

HON

30

35 ( M + H ] + ) . Example 17b 5 - Amino - 2 - chloro - N - ( 2 - oxo - 2 - ( ( 2 , 2 , 2 - trifluoroethyl )

amino ) ethyl ) benzamide ( C71 ) Preparation of 5 - amino - 2 - chloro - N - methylbenzamide ( C68 ) 40

H2N 45 45 NH Id

HN - CH3

Isolated as a white solid ( 0 . 067 g , 75 % ) : ' H NMR ( 400 MHz , CDC1 , ) 8 8 . 03 ( t . J = 6 . 3 Hz , 1H ) , 7 . 69 ( t , J = 5 . 2 Hz ,

To a solution of 2 - chloro - N - methyl - 5 - nitrobenzamide 1H ) , 6 . 68 6 . 58 ( m , 2H ) , 6 . 51 ( d , J = 6 . 4 Hz , 1H ) , 4 . 27 ( s , 2H ) , ( C81 ) ( 0 . 280 g . 1 . 31 mmol ) in methanol ( 8 . 70 mL ) and 3 . 96 3 . 70 ( m , 4H ) ; IR ( thin film ) 3307 , 2941 , 1693 . 1647 water ( 4 . 35 mL ) were added iron powder ( 0 . 364 g , 6 . 52 cm - ? ; ESIMS m / z 311 ( [ M + H ] + ) . cm mmol ) and ammonium chloride ( 0 . 209 g , 3 . 91 mmol ) . The Example 18 reaction was heated at 60° C . for 2 hours . The reaction was 55 filtered through Celite® . The filtrate was diluted with Preparation of 5 - amino - 2 - chloro - N - ( pyridin - 3 - ylm dichloromethane and extracted with hydrochloric acid ( 1N ) . ethyl ) benzamide ( C72 ) The combined aqueous phases were neutralized with satu rated aqueous sodium bicarbonate and extracted with dichlo romethane . The combined organic phases were dried over 60 magnesium sulfate , filtered , and concentrated to give the title compound as a yellow solid ( 0 . 0720 g , 22 % ) : ' H NMR ( 400 MHz , CDC1 . ) 8 7 . 09 ( d , J = 8 . 5 Hz , 1H ) , 6 . 89 ( d , J = 2 . 9

HON Hz , 1H ) , 6 . 61 ( dd , J = 8 . 6 , 2 . 9 Hz , 1H ) , 6 . 53 ( s , 1H ) , 3 . 92 ( s , 2H ) , 2 . 96 ( d , J = 4 . 9 Hz , 3H ) ; EIMS m / z 185 ( [ M ] + ) . 65

The following compounds were prepared in like manner to the procedure outlined in Example 17b :

87

m

to 10

US 9 , 795 , 140 B2 88

1 - Ethyl - 3 - ( 3 - dimethylaminopropyl ) - carbodiimide hydro - ( m , 2H ) , 7 . 17 ( d , J = 8 . 5 Hz , 1H ) , 7 . 08 ( d , J = 3 Hz , 1H ) , 6 . 79 chloride ( 0 . 840 g , 4 . 40 mmol ) and 4 - dimethylaminopyridine ( br s , 1H ) , 6 . 69 ( dd , J = 8 . 5 , 3 Hz , 1H ) , 4 . 67 ( d , J = 6 Hz , 2H ) , ( 0 . 460 g , 3 . 80 mmol ) were sequentially added to a stirred 3 . 81 ( br s , 2H ) ; IR ( thin film ) 3428 ( w ) , 3240 ( m ) , 3056 ( w ) ,

1651 ( s ) , 1596 ( s ) , 1543 ( s ) , 1478 ( s ) , 1416 ( s ) cm - ? ; ESIMS mixture of 5 - amino - 2 - chlorobenzoic acid ( 0 . 500 g , 2 . 90 5 m / z 262 ( [ M + H ] + ) . mmol ) and pyridin - 3 - ylmethanamine ( 0 . 360 mL , 3 . 50 mmol ) in dichloromethane ( 12 mL ) at 23° C . The resulting 5 - Amino - 2 - chloro - N - ( 4 - fluorophenethyl ) benzamide heterogeneous pink reaction mixture was stirred at 23° C . for ( C75 ) 2 hours . N , N - Dimethylformamide ( 6 mL ) was added to improve solubility and the resulting homogeneous orange solution was stirred at 23° C . for 70 hours . The reaction mixture was concentrated , and the residue was purified by reverse phase column chromatography using 5 - 100 % acetonitrile / water as eluent to provide the title compound as a light brown powder ( 0 . 650 g , 86 % ) : mp 133 - 136° C . ; ' H NMR ( 400 MHz , DMSO - do ) 8 8 . 89 ( br t , J = 6 Hz , 1H ) , 8 . 55 ( d , J = 1 . 5 Hz , 1H ) , 8 . 47 ( dd , J = 5 , 1 . 5 Hz , 1H ) , 7 . 73 ( dt , J = 8 , 20 Isolated as a white solid ( 0 . 067 g , 75 % ) : ' H NMR ( 400 1 . 5 Hz , 1H ) , 7 . 37 ( ddd , J = 8 , 5 , 0 . 8 Hz , 1H ) , 7 . 07 ( d , J = 8 Hz , 2 MHz , CDC1z ) 88 . 32 ( br t , J = 5 . 5 Hz , 1H ) , 7 . 28 ( m , 2H ) , 7 . 12 1H ) , 6 . 55 - 6 . 62 ( m , 2H ) , 5 . 41 ( br s , 2H ) , 4 . 42 ( d , J = 6 Hz , ( m , 2H ) , 7 . 03 ( d , J = 8 . 5 Hz , 1H ) , 6 . 56 ( dd , J = 8 . 5 , 3 Hz , 1H ) , 2H ) ; IR ( thin film ) 3432 ( m ) , 3340 ( m ) , 3195 ( m ) , 3025 ( m ) , 6 . 51 ( d , J = 3 Hz , 1H ) , 5 . 37 ( br s , 2H ) , 3 . 39 ( m , 2H ) , 2 . 79 ( t , 1654 ( s ) , 1626 ( s ) , 1602 ( s ) , 1559 ( s ) , 1474 ( s ) , 1439 ( s ) , s J = 7 . 2 Hz , 2H ) ; IR ( thin film ) 3482 ( w ) , 3366 ( w ) , 3302 ( m ) , 1428 ( s ) cm - 1 ; ESIMS m / z 262 ( [ M + H ] " ) . 3070 ( w ) , 2946 ( w ) , 1637 ( s ) , 1596 ( m ) , 1544 ( m ) , 1508 ( m ) , The following compounds were prepared in like manner to the procedure outlined in Example 18 : 1474 ( m ) , 1436 ( m ) cm - 1 ; ESIMS m / z 293 ( [ M + H ] + ) .

5 - Amino - 2 - chloro - N - ( 2 - cyclopropylethyl ) benzamide 5 - Amino - 2 - chloro - N - ( pyridin - 2 - ylmethyl ) benzamide 30 ( C76 )

( C73 )

15 HN HN

35

N H N

HON

40

Isolated as a white solid ( 0 . 067 g , 75 % ) : ' H NMR ( 400 Isolated as a white solid ( 0 . 067 g . 75 % ) : ' H NMR ( 400 M Hz , DMSO - do ) 8 8 . 23 ( br t , J = 6 Hz , 1H ) , 7 . 04 ( d , J = 9 Hz ,

MHz , CDC13 ) 8 8 . 55 ( br d , J = 5 Hz , 1H ) , 7 . 69 ( td , J = 7 . 5 , 2 1H ) , 6 . 53 - 6 . 59 ( m , 2H ) , 5 . 36 ( br s , 2H ) , 3 . 23 ( td , J = 7 , 6 Hz , 2H ) , 1 . 38 ( q , J = 7 Hz , 2H ) , 0 . 74 ( m , 1H ) , 0 . 38 - 0 . 44 ( m , 2H ) , Hz , 1H ) , 7 . 52 ( br s , 1H ) , 7 . 35 ( d , J = 7 . 5 Hz , 1H ) , 7 . 21 ( dd , 45 lad , 45 0 . 03 - 0 . 08 ( m , 2H ) ; IR ( thin film ) 3281 ( m ) , 3076 ( w ) , 3000

J = 7 . 5 , 5 Hz , 1H ) , 7 . 16 ( d , J = 8 . 5 Hz , 1H ) , 7 . 04 ( d , J = 3 Hz , ( w ) , 2914 ( w ) , 1634 ( s ) , 1595 ( m ) , 1579 ( m ) , 1552 ( m ) , 1476 1H ) , 6 . 67 ( dd , J = 8 . 5 , 3 Hz , 1H ) , 4 . 78 ( d , J = 5 Hz , 2H ) , 3 . 77 ( m ) , 1433 ( m ) cm - ? ; ESIMS m / z 239 ( [ M + H ] + ) . ( br s , 2H ) ; IR ( thin film ) 3340 ( m ) , 3223 ( m ) , 3055 ( w ) , 1640 Example 19 ( s ) , 1594 ( s ) , 1571 ( s ) , 1520 ( s ) , 1474 ( s ) , 1435 ( s ) cm ' ; se ESIMS m / z 262 ( [ M + H ] + ) . Preparation of

N - ( allyloxy ) - 5 - amino - 2 - chlorobenzamide ( C77 )

50

5 - Amino - 2 - chloro - N - ( pyridin - 4 - ylmethyl ) benzamide ( C74 ) 55

CH HN . 60

HON

1 - Ethyl - 3 - ( 3 - dimethylaminopropyl ) - carbodiimide hydro chloride ( 0 . 840 g , 4 . 40 mmol ) and 4 - dimethylaminopyridine

65 ( 0 . 460 g , 3 . 80 mmol ) were sequentially added to a stirred Isolated as a white solid ( 0 . 067 g , 75 % ) : mp 122 - 125° C . ; mixture of 5 - amino - 2 - chlorobenzoic acid ( 0 . 500 g , 2 . 90

' H NMR ( 400 MHz , CDC13 ) 8 8 . 56 - 8 . 60 ( m , 2H ) , 7 . 28 - 7 . 31 mmol ) , 0 - allylhydroxylamine hydrochloride ( 0 . 380 g , 3 . 50

90 m

US 9 , 795 , 140 B2 89

mmol ) , and triethylamine ( 0 . 490 mL , 3 . 50 mmol ) in dichlo 1 - Ethyl - 3 - ( 3 - dimethylaminopropyl ) - carbodiimide hydro romethane ( 15 mL ) at 23° C . The resulting homogeneous chloride ( 0 . 900 g , 4 . 70 mmol ) and 4 - dimethylaminopyridine gray solution was stirred at 23° C . for 48 hours . The reaction mixture was concentrated , and the residue was purified by ( 0 . 500 g , 4 . 10 mmol ) were sequentially added to a stirred reverse phase flash column chromatography using 5 - 100 % 5 mixture of 5 - amino - 2 - chlorobenzoic acid ( 0 . 535 g , 3 . 10 acetonitrile / water as eluent to provide the title compound as mmol ) . O - ( ( 2 . 2 - difluorocyclopropyl methyl ) hydroxylamine a light brown oil ( 0 . 440 g , 67 % ) : ' H NMR ( 400 MHz , CDC13 ) 87 . 13 ( d , J = 9 Hz , 1H ) , 6 . 95 ( d , J = 2 . 5 Hz , 1H ) , 6 . 66 hydrochloride ( 0 . 500 g , 3 . 10 mmol ) , and triethylamine ( dd , J = 9 , 2 . 5 Hz , 1H ) , 6 . 05 ( m , 1H ) , 5 . 32 - 5 . 45 ( m , 2H ) , 4 . 53 ( 0 . 520 mL , 3 . 70 mmol ) in dichloromethane ( 16 mL ) at 23° ( d , J = 6 Hz , 2H ) , 3 . 79 ( br s , 2H ) ; IR ( thin film ) 3346 ( w ) , 10 C . The resulting homogeneous light pink solution was 3214 ( w ) , 2935 ( w ) , 1629 ( s ) , 1598 ( s ) , 1575 ( s ) , 1474 ( s ) , stirred at 23° C . for 24 hours . The reaction mixture was 1433 ( m ) , 1330 ( m ) , 1271 ( m ) cm - l ; ESIMS m / z 227 concentrated , and the residue was purified by reverse phase ( [ M + H ] + ) . flash column chromatography using 5 - 100 % acetonitrile )

The following compounds were prepared in like manner 15 water as eluent to provide the title compound as a brown to the procedure outlined in Example 19 : semi - solid ( 0 . 560 g , 65 % ) : ' H NMR ( 400 MHz , DMSO - do )

5 - Amino - 2 - chloro - N - ( cyclopropylmethoxy ) benzamide 8 11 . 51 ( br s , 1H ) , 7 . 06 ( d , J = 8 . 3 Hz , 1H ) , 6 . 55 - 6 . 61 ( m , 2H ) , ( C78 ) 5 . 41 ( br s , 2H ) , 3 . 96 ( m , 1H ) , 3 . 85 ( m , 1H ) , 2 . 08 ( m , 1H ) ,

20 1 . 67 ( m , 1H ) , 1 . 39 ( m , 1H ) ; IR ( thin film ) 3343 ( w ) , 3211 ( w ) , 2937 ( w ) , 1645 ( m ) , 1600 ( s ) , 1527 ( m ) , 1472 ( s ) , 1437 ( m ) cm - ? ; ESIMS m / z 277 ( [ M + H ] + ) .

N 25 HN Example 21

30 Preparation of 2 - chloro - N - methyl - 5 - nitrobenzamide ( C81 )

Isolated as a white solid ( 0 . 067 g , 75 % ) : ' H NMR ( 400 3 MHz , CDC13 ) 8 7 . 13 ( d , J = 8 . 5 Hz , 1H ) , 6 . 95 ( d , J = 2 . 5 Hz , 1H ) , 6 . 67 ( dd , J = 8 . 5 , 2 . 5 Hz , 1H ) , 3 . 88 ( br d , J = 7 Hz , 2H ) , 3 . 81 ( br s , 2H ) , 1 . 21 ( m , 1H ) , 0 . 57 - 0 . 66 ( m , 2H ) , 0 . 32 - 0 . 39 ( m , 2H ) ; IR ( thin film ) 3344 ( w ) , 3215 ( w ) , 2936 ( w ) , 1644 ( s ) , 1599 ( s ) , 1526 ( m ) , 1474 ( s ) , 1431 ( m ) cm - ' ; ESIMS m / z 241 ( [ M + H ] + ) .

35

5 - Amino - 2 - chloro - N - ( ( 4 - fluorobenzyl ) oxy ) benz amide ( C79 ) mas elemente en . Yeye CH3

14 H2N1

Isolated as a white solid ( 0 . 067 g , 75 % ) . Example 20

Preparation of 5 - amino - 2 - chloro - N - ( ( 2 , 2 - difluorocy clopropyl ) methoxy ) benzamide ( C80 )

2 - Chloro - 5 - nitrobenzoic acid ( 0 . 500 g , 2 . 48 mmol ) , diiso propylethylamine ( 0 . 650 mL , 3 . 72 mmol ) , and 4 - dimethyl

50 aminopyridine ( 0 . 545 g , 4 . 47 mmol ) were sequentially added to a stirred mixture of methanamine hydrochloride ( 0 . 251 g , 3 . 72 mmol ) and 1 - ethyl - 3 - ( 3 - dimethylaminopro pyl ) - carbodiimide hydrochloride ( 0 . 951 g , 4 . 96 mmol ) in

55 1 , 2 - dichloroethane ( 25 mL ) at room temperature . The reac tion mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate and hydrochlo ric acid ( 1 N ) . The organic phase was dried over magnesium

60 sulfate , filtered , and concentrated to give the title compound as a white solid ( 0 . 283 g , 50 % ) : ' H NMR ( 400 MHz , CDC13 ) 8 8 . 53 ( d , J = 2 . 7 Hz , 1H ) , 8 . 22 ( dd , J = 8 . 8 , 2 . 8 Hz , 1H ) , 7 . 60 ( d , J = 8 . 8 Hz , 1H ) , 6 . 21 ( s , 1H ) , 3 . 08 ( d , J = 4 . 9 Hz , 3H ) ; EIMS m / z 215 ( [ M ] + ) .

The following compounds were prepared in like manner to the procedure outlined in Example 21 :

??? H N F

US 9 , 795 , 140 B2 91

N - Methyl - 5 - nitro - 2 - ( trifluoromethyl ) benzamide ( C82 ) Maison Martin 92

Example 22

5 Preparation of

2 - chloro - 5 - nitro - N - ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( C84 ) F

10 - CH3

I

I

Isolated as a white solid ( 0 . 067 g , 75 % ) : ' H NMR ( 400 MHz , CDC13 ) 8 8 . 41 - 8 . 34 ( m , 2H ) , 7 . 92 ( d , J = 8 . 4 Hz , 1H ) , 5 . 87 ( s , 1H ) , 3 . 06 ( d , J = 4 . 9 Hz , 3H ) ; EIMS m / z 248 ( [ M ] + ) . 2 - Chloro - 5 - nitrobenzoic acid ( 0 . 500 g , 2 . 48 mmol ) and

2 - Chloro - 5 - nitro - N - ( 2 - oxo - 2 - ( ( 2 , 2 , 2 - trifluoroethyl ) 4 - dimethylaminopyridine ( 0 . 394 g , 3 . 22 mmol ) were amino ) ethyl ) benzamide ( C83 ) sequentially added to a stirred mixture of 2 , 2 , 2 - trifluoroeth

20 anamine ( 0 . 295 g , 2 . 98 mmol ) and 1 - ethyl - 3 - ( 3 - dimethyl aminopropyl ) - carbodiimide hydrochloride ( 0 . 713 g , 3 . 72 mmol ) in 1 , 2 - dichloroethane ( 12 mL ) at room temperature , and the mixture was stirred at room temperature for 1 day . The reaction mixture was diluted with dichloromethane and 25 washed with saturated aqueous sodium bicarbonate fol lowed by hydrochloric acid ( 1 N ) to provide the title compound as a white solid ( 0 . 379 g , 51 % ) : ' H NMR ( 400 MHz , DMSO - da ) 9 . 42 ( t , J = 6 . 2 Hz , 1H ) , 8 . 32 ( dd , J = 8 . 8 ,

Isolated as a white solid ( 0 . 067 g , 75 % ) : ' H NMR ( 400 30 40 Hz 30 2 . 8 Hz , 1H ) , 8 . 25 ( d , J = 2 . 7 Hz , 1H ) , 7 . 86 ( d , J = 8 . 8 Hz , 1H ) , MHz , DMSO - d ) 89 . 04 ( t , J = 5 . 9 Hz , 1H ) , 8 . 70 ( t , J = 6 . 3 Hz , 4 . 13 ( qd , J = 9 . 7 , 6 . 4 Hz , 2H ) ; IR ( thin film ) 3378 , 2964 , 1H ) , 8 . 34 8 . 28 ( m , 2H ) , 7 . 83 ( d , J = 8 . 6 Hz , 1H ) , 4 . 03 3 . 92 ( m , 1739 , 1675 cm - ? ; ESIMS m / z 284 ( [ M + H ] + ) . 4H ) ; IR ( thin film ) 3293 , 3089 , 1694 , 1654 cm - 1 ; ESIMS The following molecules in Table 1 may be prepared m / z 341 ( [ M + H ] + ) . according to the procedures disclosed in

TABLE P1

Query 1 1 Structure and preparation method for prophetic molecules

| 3 | Structure Prep *

13 , 16 Br Bro

N IZ ?????

P2 13 , 16 CI Clo ZE

N CH3

US 9 , 795 , 140 B2 93 93 94

TABLE P1 - continued Structure and preparation method for prophetic molecules

No . No . Structure Prep *

P3 13 , 16

1 ??? T

11 CH3

P4 13 , 16 , 17a Ci Cio .

ZA O =

N O CH

P5 13 , 16 , 17a 1 . CI — 1 ]

T

N

1

CH3 0

P6 13 , 16 , 17a CI Clo

D = 0 1 ]

presion ??? poteft

O = CH30

P7 13 , 16 , 17a CI Clo

CHZ

P8 13 , 16 C1 Clo

IZ NH

US 9 , 795 , 140 B2

95 US 9 , 793 , 140 B2 95 TABLE P1 - continued

Structure and preparation method for prophetic molecules

No . Structure Prep *

P9 C ] 13 , 16 | C1

?????? ???

P10 ) 13 , 16 Cl . Cl o

CH3

P11 13 , 16

Cl ?????? ???

P12 13 , 16 Cl . Cl

?

P13 13 , 16 ? Cl Cl

N N ?? ????? ?????? "

P14 13 , 16 Cl . Cl 0 NH2 -

US 9 , 795 , 140 B2 97 98

TABLE P1 - continued Structure and preparation method for prophetic molecules

No . Structure Structure Prep * P15 13 , 16 1 . Cl 0

N ??? ya que P16 13 , 16 Cl . Clo ??

Prep * means prepare according to Example or Scheme

The following compounds were prepared in like manner to the procedure outlined in Example 2 :

3 . 50 ( d , J = 8 . 4 Hz , 1H ) , 2 . 91 ( d , J = 8 . 4 Hz , 1H ) ; 19F NMR ( 376 MHz , CDC13 ) 8 - 115 . 52 ; ESIMS m / z 313 ( [ M - H ] ) .

30 trans - 2 , 2 - Dichloro - 3 - ( 3 - chloro - 5 - ( difluoromethyl ) phenyl ) cyclopropane - 1 - carboxylic acid ( C85 )

trans - 2 , 2 - Dichloro - 3 - ( 3 - ( difluoromethyl ) - 5 - fluoro phenyl ) cyclopropane - 1 - carboxylic acid ( C87 )

35 CICLO CI Clo

F

?? " OH F

40

-

45 Isolated as an off - white solid ( 2 . 6 g , 63 % ) : ' H NMR ( 300 MHz , CDC13 ) missing COOH signal 8 7 . 49 ( s , 1H ) , 7 . 38 ( s , 1H ) , 7 . 30 ( s , 1H ) , 6 . 63 ( t , J = 56 . 0 Hz , 1H ) , 3 . 50 ( d , J = 8 . 4 Hz , 1H ) , 2 . 91 ( d , J = 8 . 0 Hz , 1H ) ; 19F NMR ( 282 MHz , CDC13 ) 8 - 112 . 04 ; ESIMS m / z 313 ( [ M - H ] " ) .

Isolated as an off - white solid ( 5 g , 38 % ) : ' H NMR ( 400 MHz , CDC13 ) missing COOH signal 8 7 . 23 - 7 . 21 ( m , 2H ) , 7 . 11 ( d , J = 8 . 8 Hz , 1H ) , 6 . 64 ( t , J = 55 . 6 Hz , 1H ) , 3 . 51 ( d , J = 8 . 4 Hz , 1H ) , 2 . 91 ( d , J = 8 . 0 Hz , 1H ) ; 19F NMR ( 376 MHz ,

50 CDC1z ) d - 110 . 37 ; ESIMS m / z 297 . 19 ( [ M - H ] ) ) .

trans - 2 , 2 - Dichloro - 3 - ( 4 - chloro - 3 - ( difluoromethyl ) phenyl ) cyclopropane - 1 - carboxylic acid ( C86 )

trans - 2 , 2 - Dichloro - 3 - ( 3 - ( difluoromethyl ) - 4 - fluoro phenyl ) cyclopropane - 1 - carboxylic acid ( C88 )

55

CI Clo CI CI

?? ?? 60

CI F F

Isolated as an off - white solid ( 6 . 2 g , 69 % ) : ' H NMR ( 400 65 Isolated as an off - white solid ( 6 . 0 g , 77 % ) : ' H NMR ( 400 MHz , CDC13 ) 8 10 . 5 ( br s , 1H ) , 7 . 55 ( s , 1H ) , 7 . 46 ( d , J = 8 . 0 MHz , CDC13 ) missing COOH signal 8 7 . 49 ( d , J = 6 . 0 Hz , Hz , 1H ) , 7 . 34 ( d , J = 8 . 4 Hz , 1H ) , 6 . 95 ( t , J = 54 . 8 Hz , 1H ) , 1H ) , 7 . 40 ( br s , 1H ) , 7 . 17 ( t , J = 9 . 2 Hz , 1H ) , 6 . 90 ( t , J = 54 . 8

99 US 9 , 795 , 140 B2

100 Hz , 1H ) , 3 . 49 ( d , J = 8 . 0 Hz , 1H ) , 2 . 89 ( d , J = 8 . 4 Hz , 1H ) ; 19F trans - 2 , 2 - Dichloro - 3 - ( 4 - ( difluoromethyl ) phenyl ) NMR ( 376 MHz , CDC1z ) 8 - 114 . 47 , - 119 . 69 ; ESIMS m / z cyclopropane - 1 - carboxylic acid ( C92 ) 297 ( [ M - H ] ) .

5 trans - 2 , 2 - Dichloro - 3 - ( 3 - chloro - 4 - ( difluoromethyl ) phenyl ) cyclopropane - 1 - carboxylic acid ( C89 ) CI CI o

OH

1 CI 10

OH

15

Isolated as an off - white solid ( 7 g , 61 % ) : ' H NMR ( 300 MHz , CDC1Z ) 8 7 . 53 ( d , J = 8 . 0 Hz , 2H ) , 7 . 37 ( d , J = 8 . 0 Hz , 2H ) , 6 . 66 ( t , J = 56 . 4 Hz , 1H ) , 3 . 52 ( d , J = 8 . 4 Hz , 1H ) , 2 . 92 ( d , J = 8 . 0 Hz , 1H ) ; 19F NMR ( 282 MHz , CDC1z ) 8 - 112 . 20 ;

Isolated as an off - white solid ( 3 . 5 g , 42 % ) : ' H NMR ( 400 20 ESIMS m / z 279 . 30 ( M - H ] - ) . MHz , CDC1z ) missing COOH signal 8 7 . 68 ( d , J = 7 . 6 Hz , 1H ) , 7 . 35 ( s , 1H ) , 7 . 29 ( d , J = 8 . 4 Hz , 1H ) , 6 . 94 ( t , J = 54 . 8 Hz , 1H ) , 3 . 48 ( d , J = 8 . 4 Hz , 1H ) , 2 . 91 ( d , J = 8 . 4 Hz , 1H ) ; 19F trans - 2 , 2 - Dichloro - 3 - ( 3 , 5 - difluoro - 4 - methoxyphe NMR ( 376 MHz , CDC13 ) 8 - 115 . 46 ; ESIMS m / z 313 nyl ) cyclopropane - 1 - carboxylic acid ( C93 ) ( [ M - H ] ) . 25

trans - 2 , 2 - Dichloro - 3 - ( 4 - ( difluoromethyl ) - 3 - fluoro phenyl ) cyclopropane - 1 - carboxylic acid ( C90 ) CI Clo

30 ??

ciclo limpse OH 35

F Isolated as a tan solid ( 0 . 440 g , 53 % ) : ' H NMR ( 400

MHz , CDC1z ) 8 10 . 72 ( s , 1H ) , 6 . 89 - 6 . 77 ( m , 2H ) , 4 . 02 ( t , 40 J = 1 . 2 Hz , 3H ) , 3 . 39 ( d , J = 8 . 3 Hz , 1H ) , 2 . 80 ( d , J = 8 . 3 Hz ,

1H ) ; 19F NMR ( 376 MHz , CDC13 ) 8 - 127 . 43 , - 127 . 43 , Isolated as an off - white solid ( 4 . 4 g . 77 % ) : 1H NMR ( 400 - 127 . 44 ; ESIMS m / z 296 ( [ M - H ] " ) .

MHz , CDC1z ) 8 7 . 62 ( t , J = 7 . 6 Hz , 1H ) , 7 . 18 ( d , J = 7 . 6 Hz , 1H ) , 7 . 06 ( d , J = 10 . 0 Hz , 1H ) , 6 . 89 ( t , J = 54 . 8 Hz , 1H ) , 3 . 50 cis / trans - 2 , 2 - Dichloro - 3 - ( 3 , 4 , 5 - trifluorophenyl ) cy ( d , J = 8 . 4 Hz , 1H ) , 2 . 90 ( d , J = 8 . 4 Hz , 1H ) ; 1°F NMR ( 376 45 clopropane - 1 - carboxylic acid ( C94 ) MHz , CDC1z ) 8 - 114 . 42 , - 118 . 63 ; ESIMS m / z 297 . 15 ( [ M - H ] ) .

CICLO trans - 2 , 2 - Dichloro - 3 - ( 3 - ( difluoromethyl ) phenyl ) cyclopropane - 1 - carboxylic acid ( C91 )

50

OH

ci Clo 55

F OH

Isolated as a white solid ( 0 . 411 g , 53 % ) : ' H NMR ( 400 MHz , CDC13 ) 8 7 . 72 ( s , 1H ) , 7 . 06 - 6 . 74 ( m , 2H ) , 3 . 46 - 3 . 23 ( m , 1H ) , 3 . 01 - 2 . 74 ( m , 1H ) ; 19F NMR ( 376 MHz , CDC12 ) 8

Isolated as an off - white solid ( 6 . 2 g 53 % ) : 1H NMR ( 300 - 132 . 88 , - 132 . 94 , - 133 . 81 , - 133 . 87 , - 159 . 60 , - 159 . 65 . MHz , CDC1z ) 8 7 . 49 ( br s , 2H ) , 7 . 41 ( br s , 2H ) , 6 . 66 ( t . - 159 . 71 , - 160 . 34 , - 160 . 39 , - 160 . 45 ; ESIMS m / z 284 ( [ M J = 56 . 0 Hz , 1H ) , 3 . 53 ( d , J = 8 . 4 Hz , 1H ) , 2 . 92 ( d , J = 8 . 0 Hz , 65 H ] ) . 1H ) ; 19F NMR ( 282 MHz , CDC13 ) 8 - 111 . 20 ; ESIMS m / z The following compounds were prepared in like manner 279 . 20 ( [ M - H ] ) ) . to the procedure outlined in Example 4 :

US 9 , 795 , 140 B2 101 102

trans - 1 - Chloro - 3 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxyphenyl ) trans - 4 - ( 2 , 2 - Dichloro - 3 - ( 4 - methoxyphenyl ) cyclopro cyclopropyl ) - 5 - ( difluoromethyl ) benzene ( C95 ) pyl ) - 2 - ( difluoromethyl ) - 1 - fluorobenzene ( C98 )

Ci Ci Cici CH3 -

F soxar . boxon 10 F

F

15

Isolated as an off - white solid ( 10 . 0 g , 55 % ) : ESIMS m / z 374 ( M + H ] ) . Isolated as a yellow liquid ( 11 . 5 g . 69 % ) : 1H NMR ( 300

MHz , CDC1z ) : 8 7 . 47 ( s , 2H ) , 7 . 39 ( s , 1H ) , 7 . 28 ( d , J = 8 . 7 20 Hz , 2H ) , 6 . 93 ( d , J = 8 . 7 Hz , 2H ) , 6 . 64 ( t , J = 56 . 1 Hz , 1H ) , 3 . 83 ( s , 3H ) , 3 . 16 ( q , J = 8 . 7 Hz , 2H ) .

trans - 2 - Chloro - 4 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxyphenyl ) cyclopropyl ) - 1 - ( difluoromethyl ) benzene ( C99 )

25 trans - 1 - Chloro - 4 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxyphenyl ) cyclopropyl ) - 2 - ( difluoromethyl ) benzene ( C96 ) ci ci CH3

CI CI 30 CH3 boxenon F

35

Isolated as a pale yellow solid ( 10 . 7 g , 83 % ) : ' H NMR ( 400 MHz , CDC13 ) 8 7 . 65 ( s , 1H ) , 7 . 46 - 7 . 41 ( m , 2H ) , 7 . 28 ( d , J = 8 . 4 Hz , 2H ) , 7 . 10 - 6 . 83 ( m , 3H ) , 3 . 83 ( s , 3H ) , 3 . 18 - 3 . 13 ( m , 2H ) .

Isolated as an off - white solid ( 10 . 0 g , 34 % ) : ' H NMR 40 ( 400 MHz , CDC13 ) 8 7 . 68 ( d , J = 8 . 0 Hz , 1H ) , 7 . 43 ( s , 1H ) ,

7 . 38 ( d , J = 8 . 4 Hz , 1H ) , 7 . 28 - 7 . 25 ( m , 2H ) , 7 . 09 - 6 . 92 ( m , 3H ) , 3 . 83 ( s , 3H ) , 3 . 15 ( q , J = 12 . 0 Hz , 2H ) ; ESIMS m / z 376 ( [ M + H ] + ) .

45

trans - 2 - Fluoro - 4 - ( 2 , 2 - dichloro - 3 - ( 4 - methoxyphenyl ) cyclopropyl ) - 1 - ( difluoromethyl ) benzene ( C100 ) trans - 1 - ( 2 , 2 - Dichloro - 3 - ( 4 - methoxyphenyl ) cyclopro

pyl ) - 3 - ( difluoromethyl ) - 5 - fluorobenzene ( C97 ) 50

CI cl CH3 O - CICI CH3

55 F byxon non

F 60

Isolated as a pale yellow liquid ( 6 . 9 g , 58 % ) : ' H NMR Isolated as an off - white solid ( 16 . 5 g , 64 % ) : ' H NMR ( 400 MHz , CDC13 ) 8 7 . 31 ( t , J = 7 . 6 Hz , 1H ) , 7 . 27 ( d , J = 9 . 2

( 400 MHz , CDC13 ) 87 . 29 ( d , J = 8 . 8 Hz , 2H ) , 7 . 20 ( d , J = 8 . 8 65 Hz , 2H ) , 7 . 14 ( d , J = 10 . 8 Hz , 1H ) , 7 . 04 - 6 . 76 m , 4H ) , 3 . 83 Hz , 2H ) , 6 . 93 ( d , J = 8 . 8 Hz , 2H ) , 6 . 65 ( t , J = 56 . 0 Hz , 2H ) , ( s , 3H ) , 3 . 16 ( t , J = 8 . 8 Hz , 2H ) ; 19F NMR ( 376 MHz , CDC13 ) 3 . 83 ( s , 3H ) , 3 . 16 ( s , 2H ) . 8 - 114 . 14 , - 114 . 32 , - 119 . 30 .

US 9 , 795 , 140 B2 103 104

trans - 1 - ( 2 , 2 - Dichloro - 3 - ( 4 - methoxyphenyl ) cyclopro trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 - chloro - 4 - fluoro pyl ) - 3 - ( difluoromethyl ) benzene ( C101 ) phenyl ) cyclopropane - 1 - carboxamido ) benzoic acid

( C104 )

CI CI CH3 Ciclo

OH Byxor 10 N

F

15 Isolated as a pale yellow solid ( 6 . 3 g , 95 % ) : ' H NMR ( 400 MHz , CDC13 ) 8 7 . 50 ( br s , 4H ) , 7 . 29 ( d , J = 8 . 8 Hz , 2H ) , 6 . 93 ( d , J = 8 . 0 Hz , 2H ) , 6 . 67 ( t , 1H ) , 3 . 83 ( s , 3H ) , 3 . 19 ( s , 2H ) ; 197 NMR ( 376 MHz , CDC13 ) - 110 . 87 , - 111 . 02 .

trans - 1 - ( 2 , 2 - Dichloro - 3 - ( 4 - ( difluoromethyl ) phenyl ) cyclopropyl ) - 4 - methoxybenzene ( C102 )

Isolated as a white solid ( 6 . 589 g , 93 % ) : mp 207 - 210° C . ; ' H NMR ( 400 MHz , DMSO - do ) d 13 . 50 ( s , 1H ) , 10 . 95 ( s , 1H ) , 8 . 18 ( d , J = 2 . 5 Hz , 1H ) , 7 . 80 ( dd , J = 8 . 7 , 2 . 5 Hz , 1H ) ,

20 7 . 71 ( d , J = 7 . 2 Hz , 1H ) , 7 . 51 ( dd , J = 28 . 2 , 8 . 8 Hz , 3H ) , 3 . 59 ( d , J = 8 . 4 Hz , 1H ) , 3 . 43 ( d , J = 8 . 5 Hz , 1H ) ; 13C NMR ( 101 MHz , DMSO - da ) 8 166 . 22 , 162 . 68 , 158 . 01 , 155 . 55 , 137 . 53 , 131 . 37 , 131 . 17 , 131 . 00 , 130 . 95 , 130 . 91 , 129 . 74 , 129 . 67 , 125 . 86 , 122 . 82 , 121 . 12 , 119 . 49 , 119 . 32 , 116 . 91 , 116 . 70 ,

of 62 . 21 , 38 . 49 , 36 . 58 ; °F NMR ( 376 MHz , DMSO - do ) 8 - 117 . 26 ; ESIMS m / z 438 ( [ M + H ] + ) . CI CI CH3

trans - 2 , 3 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1 - carboxamido ) benzoic acid

( C105 ) 30

! Ciclo

OH Isolated as a white solid ( 14 g , 69 % ) : ' H NMR ( 400 MHz , 35 CDC1z ) 8 7 . 54 ( d , J = 8 . 0 Hz , 2H ) , 7 . 46 ( d , J = 8 . 0 Hz , 2H ) , 7 . 28 ( t , J = 8 . 4 Hz , 2H ) , 6 . 93 ( d , J = 8 . 0 Hz , 2H ) , 6 . 67 ( t , J = 56 . 8 Hz , 1H ) , 3 . 83 ( s , 3H ) , 3 . 18 ( s , 2H ) .

The following compounds were prepared in like manner to the procedure outlined in Example 12 : 40

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro - 4 methoxyphenyl ) cyclopropane - 1 - carboxamido ) ben

zoic acid ( C103 ) 45

Isolated as a tan solid ( 1 . 685 g , 79 % ) : mp 231 - 235° C . ; ' H NMR ( 400 MHz , DMSO - do ) 13 . 82 ( s , 1H ) , 11 . 05 ( s , 1H ) , 8 . 13 ( d , J = 2 . 4 Hz , 1H ) , 7 . 97 ( d , J = 2 . 4 Hz , 1H ) , 7 . 63 ( s , 1H ) , 7 . 56 ( s , 2H ) , 3 . 63 ( d , J = 8 . 5 Hz , 1H ) , 3 . 50 ( d , J = 8 . 5 Hz , 1H ) ; 13C NMR ( 101 MHz , DMSO - da ) 8 165 . 84 , 162 . 96 , 138 . 00 , 137 . 09 , 134 . 14 , 133 . 98 , 133 . 01 , 127 . 83 , 127 . 64 , 123 . 41 , 122 . 15 , 119 . 27 , 61 . 94 , 38 . 37 , 36 . 78 ; HRMS - ESI ( m / z )

50 [ M + ] * calcd for C17H , C1 , NO3 , 484 . 8714 ; found , 484 . 8711 . CI Clo

0 trans - 2 , 4 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1 - carboxamido ) benzoic acid

( C106 ) HCO 55

C1 C1

OH

NH

Isolated as a cream - colored solid ( 1 . 565 g , 90 % ) : mp 227 - 231° C . ; ' H NMR ( 400 MHz , DMSO - do ) 13 . 48 ( s , 1H ) , 10 . 89 ( s , 1H ) , 8 . 16 ( d , J = 2 . 4 Hz , 1H ) , 7 . 78 ( dd , J = 8 . 7 , 60 2 . 4 Hz , 1H ) , 7 . 61 ( s , 2H ) , 7 . 53 ( d , J = 8 . 7 Hz , 1H ) , 3 . 84 ( s , 3H ) , 3 . 57 ( d , J = 8 . 4 Hz , 1H ) , 3 . 45 ( d , J = 8 . 5 Hz , 1H ) ; 13C NMR ( 101 MHz , DMSO - da ) 8 166 . 27 , 162 . 66 , 151 . 18 , 137 . 58 , 131 . 44 , 131 . 42 , 131 . 22 , 129 . 72 , 128 . 18 , 125 . 90 , 122 . 87 , 121 . 16 , 62 . 19 , 60 . 64 , 38 . 51 , 36 . 44 ; HRMS - ESI 65 ( m / z ) [ M + ] * calcd for C18H12C1 - N04 , 480 . 9209 ; found , 480 . 9216 .

US 9 , 795 , 140 B2 105 106

Isolated as a light - yellow solid ( 0 . 855 g , 42 % ) : mp trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe 263 - 266° C . ; H NMR ( 500 MHz , DMSO - da ) 8 13 . 67 ( s , nyl ) cyclopropane - 1 - carboxamido ) - N — ( ( R ) - 1 - ( 2 , 2 , 1H ) , 10 . 37 ( s , 1H ) , 8 . 37 ( s , 1H ) , 7 . 85 ( s , 1H ) , 7 . 63 ( s , 1H ) , 2 - trifluoroethyl ) thio ) propan - 2 - yl ) benzamide ( PF3 ) 7 . 53 ( d , J = 1 . 6 Hz , 2H ) , 3 . 82 ( d , J = 8 . 6 Hz , 1H ) , 3 . 63 ( d , J = 8 . 5 Hz , 1H ) ; 13C NMR ( 126 MHz , DMSO - da ) 8 165 . 41 , 163 . 35 , 5 137 . 17 , 133 . 95 , 133 . 66 , 131 . 17 , 129 . 96 , 128 . 80 , 128 . 24 , 127 . 74 , 127 . 60 , 126 . 63 , 62 . 37 , 37 . 24 , 37 . 09 ; HRMS - ESI CI . Clo ( m / z ) [ M + ] * calcd for C , H , CIGNO3 , 484 . 8714 ; found , 484 . 8715 .

The following compounds were prepared in like manner 10 © CH2 to the procedure outlined in Example 13 :

Cl . 10

trans - 2 - Chloro - 5 - ( 2 , 2 - dibromo - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 2 - trifluo

roethyl ) benzamide ( PF1 ) 15 15 Isolated as a white solid ( 0 . 306 g , 91 % ) .

Br Bro F F trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 - ( ( furan - 2

ylmethyl ) thio ) ethyl ) benzamide ( PF9 ) 20

NH

CI Clo 25 25 IZ

cl N Isolated as a white solid ( 0 . 100 g , 32 % ) The following

compounds were prepared in like manner to the procedure outlined in Example 15 : C1

30

Isolated as a tan solid ( 0 . 064 g , 65 % ) . 2 - Chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 - ( 4 - fluoro

phenyl ) propan - 2 - yl ) benzamide ( F97 ) 35 35

trans - Methyl - 2 - ( 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 dichlorophenyl ) cyclopropane - 1 - carboxamido ) ben

zamido ) - 4 - ( methylthio ) butanoate ( PF10 )

CI Clo 40 Cl . Clo boxoxoxlayhi IZ

0 H3C CH3 - CH2

45

S - CH3 Isolated as a white foam ( 0 . 086 g , 63 % ) . The following compounds were prepared in like manner

to the procedure outlined in Example 16 : Isolated as a light green solid ( 0 . 052 g , 52 % ) . 50

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N — ( ( R ) - 1 - ( ( 3 , 3 , 3 - trifluoropropyl ) thio ) propan - 2 - yl ) benzamide ( PF2 )

trans - N - ( 4 - ( 1H - 1 , 2 , 4 - Triazol - 1 - yl ) benzyl ) - 2 - chloro 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane

1 - carboxamido ) benzamide ( PF11 ) 55

Cl . Clo F ci Clo F

60 ????? ?????? N CH CH3

65

Isolated as a white solid ( 0 . 311 mg , 91 % ) . Isolated as a tan solid ( 0 . 077 g , 76 % ) .

US 9 , 795 , 140 B2 107 108

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 - ( thiazol - 2 nyl ) cyclopropane - 1 - carboxamido ) - N - ( 3 , 3 , 3 - trif

y1 ) ethyl ) benzamide ( PF12 ) luoro - 2 - hydroxypropyl ) benzamide ( PF16 )

Cl . Cl 0 Cl Clo 0H ??? 10 CI

15

Isolated as a white solid ( 0 . 032g , 34 % ) . trans - N - ( 2 - 1H - Pyrazol - 1 - y1 ) ethyl ) - 2 - chloro - 5 - ( 2 , 2

dichloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - 1 carboxamido ) benzamide ( PF13 )

Isolated as a white solid ( 0 . 055g , 59 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 - hydroxypro

py1 ) benzamide ( F78 ) 20 20

Cl . Clo Cl . Cl 0 0H 25

Cl , CH3

3 )

Isolated as a white solid ( 0 . 061 g , 68 % ) . 35 trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe

nyl ) cyclopropane - 1 - carboxamido ) - N - ( 3 - sulfamoyl propy1 ) benzamide ( PF14 ) . Isolated as a white solid ( 0 . 036 g , 43 % ) .

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe ny1 ) cyclopropane - 1 - carboxamido ) - N - ( 2 - ( 2 - oxoimi

dazolidin - 1 - y1 ) ethyl ) benzamide ( F79 )

4 {

Cl Clo Cl Clo H2N

Lz NH 45

50 ) Isolated as a white solid ( 0 . 023 g , 24 % ) .

trans - N - ( 2 - ( Benzo [ b ] thiophen - 3 - y1 ) ethyl ) - 2 - chloro 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane

1 - carboxamido ) benzamide ( PF15 )

Isolated as a white solid ( 0 . 038 g , 41 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro - 4 methoxyphenyl ) cyclopropane - 1 - carboxamido ) - N

propylbenzamide ( F84 ) 55

Cl Clo Cl Clo ???????? CH , = =

0 - MC ?

65

Isolated as a tan solid ( 0 . 064g , 63 % ) . Isolated as a white solid ( 0 . 125g , 92 % ) .

US 9 , 795 , 140 B2 109 110

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro - 4 trans - 2 , 3 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro methoxyphenyl ) cyclopropane - 1 - carboxamido ) - N phenyl ) cyclopropane - 1 - carboxamido ) - N - ethylbenz

ethylbenzamide ( F85 ) amide ( F91 )

Cl Cl

? ????? LZ C1 Cl o 10

H0 ?

CH , ?

Isolated as a white solid ( 0 . 126g , 95 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro - 4

methoxyphenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 fluoroethyl ) benzamide ( F86 ) 20

Isolated as a white solid ( 0 . 038 g , 43 % ) .

Cl Clo

LZ 25 25 trans - 2 , 3 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 - fluoro

ethyl ) benzamide ( F92 ) Cl ??? Ha (

3 )

Cl . Cl ? Isolated as a white solid ( 0 . 119g , 87 % ) . ? 35 CI Cl trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro - 4 - methoxyphenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 ,

2 , 2 - trifluoroethyl ) benzamide ( F87 ) ??? 40 )

Cl . Cl - F

Isolated as a white solid ( 0 . 037g , 40 % ) . ???? 45 H , C trans - 2 , 3 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 2 - trif

luoroethyl ) benzamide ( F93 ) Isolated as a white solid ( 0 . 128g , 88 % ) . 50 )

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro - 4 methoxyphenyl ) cyclopropane - 1 - carboxamido ) - N - ( 3 ,

3 , 3 - trifluoropropyl ) benzamide ( F88 ) Cl . Cl 0 55

Cl Cl

F 60 ?????? ????? ??? F ? ?? H

65

Isolated as a white solid ( 0 . 138 g , 92 % ) . Isolated as a white solid ( 0 . 013g , 13 % ) .

111 US 9 , 795 , 140 B2

112 trans - 2 , 3 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro trans - 2 , 4 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 3 , 3 , 3 - trif phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 - fluoro

luoropropyl ) benzamide ( F94 ) ethyl ) benzamide ( F99 )

CI

10 C1 N ????? ????? N -

F

15

Isolated as a white solid ( 0 . 047 g , 51 % ) . trans - 2 , 4 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 2 - trif

luoroethyl ) benzamide ( F100 ) 20

Isolated as a white solid ( 0 . 046 g , 46 % ) .

C . Ciclo trans - 2 , 3 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - propylben -

zamide ( F95 ) 25

1 N

30

Ciclo N

- CH3 35 puisque Isolated as a white solid ( 0 . 041 g , 43 % ) . trans - 2 , 4 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - propylben

zamide ( F101 )

40 CI ci Clo

CI . CHZ Isolated as a white solid ( 0 . 061 g , 68 % ) .

45 en een gery posite trans - 2 , 4 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - ethylbenz

amide ( F98 ) 50 Isolated as a white solid ( 0 . 037 g , 40 % ) .

trans - 2 , 4 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 3 , 3 , 3 - trif

luoropropyl ) benzamide ( F102 ) CI CICI 55

CH3

]

60 ????? - C1 1 AL 65

Isolated as a white solid ( 0 . 052 g , 57 % ) . Isolated as a white solid ( 0 . 046 g , 48 % ) .

US 9 , 795 , 140 B2 113 114

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 - chloro - 4 - fluoro trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 - chloro - 4 - fluoro phenyl ) cyclopropane - 1 - carboxamido ) - N - ethylbenz phenyl ) cyclopropane - 1 - carboxamido ) - N - propylben

amide ( F103 ) zamide ( F106 )

CiClo Ciclo IT

- CH3 10 ???????? CH3 ?? N

15

Isolated as a white solid ( 0 . 077 g , 85 % ) . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 - chloro - 4 - fluoro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 3 , 3 , 3 - trif

luoropropyl ) benzamide ( F107 ) 20 Isolated as a white solid ( 0 . 061 g , 68 % ) .

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 - chloro - 4 - fluoro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 - fluoro

ethyl ) benzamide ( F104 ) CI CI ? . 25

30 F CI CI ? . Melayu Xirdiging

F Isolated as a white solid ( 0 . 068 mg , 65 % ) . The following compounds were prepared in like manner

35 to the procedure outlined in Example 17a : . . . trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N — ( R ) - 1 - ( ( 3 , 3 , 3 - trifluoropropyl ) sulfonyl ) propan - 2 - yl ) benzamide

( PF4 ) 40

Isolated as a white solid ( 0 . 063 g , 69 % ) . Ci ci

45 Support trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 - chloro - 4 - fluoro phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 2 - trif

luoroethyl ) benzamide ( F105 ) © CH , ?

50

Isolated as a white solid ( 0 . 0137 g , 54 % ) .

Ci Clo F 55 F

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( ( 2R ) - 1 - ( ( 3 , 3 , 3 - trifluoropropyl ) sulfinyl ) propan - 2 - yl ) benzamide

( PF5 ) NH Ciclo

Oleguas " peloinnit 60 I CI

© CHz

65

Isolated as a white solid ( 0 . 069 g , 71 % ) . Isolated as a white solid ( 0 . 109 g , 44 % ) .

US 9 , 795 , 140 B2 115 116

trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N — ( ( R ) - 1 - ( 2 , 2 ,

2 - trifluoroethyl ) sulfonyl ) propan - 2 - yl ) benzamide ( PF6 )

and concentrated under vacuum on a rotary evaporator to provide the title compound as a clear , colorless oil ( 0 . 058 g , 44 % ) .

5 Example 24

Preparation of 2 - chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( 3 , 4 difluorophenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 ,

2 , 2 - trifluoroethyl ) benzamide ( F108 ) Ciclo LF 10

NH Po = h = O I ]

CH , OP C1 C1

15 NH

Isolated as a white solid ( 0 . 107 g , 45 % ) . F

20 trans - 2 - Chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2R ) - 1 - ( ( 2 , 2 ,

2 - trifluoroethyl ) sulfinyl ) propan - 2 - yl ) benzamide ( PF7 )

Ciclo

To a solution of 5 - amino - 2 - chloro - N - ( 2 , 2 , 2 - trifluoro ethyl ) benzamide ( C70 ) ( 0 . 071 g , 0 . 281 mmol ) and trans - 2 , 2 - dichloro - 3 - ( 3 , 4 - difluorophenyl ) cyclopropanecarboxylic acid ( C124 ) ( 0 . 075 g , 0 . 281 mmol ) in ethyl acetate ( 3 mL ) were added sequentially pyridine ( 0 . 068 mL , 0 . 843 mmol ) and 2 , 4 , 6 - tripropyl - 1 , 3 , 5 , 2 , 4 , 6 - trioxatriphosphorinane - 2 , 4 , 6 - trioxide ( 50 % solution in ethyl acetate , 0 . 357 g , 0 . 562 mmol ) , and the resulting pale - yellow solution was stirred at room temperature for approximately 14 hours . The solution was concentrated under a stream of nitrogen , and purified by silica gel flash column chromatography with a mobile phase of hexanes / ethyl acetate . The pure fractions were combined and concentrated under vacuum on a rotary evaporator to provide the title compound as a white foam ( 0 . 083 g , 56 % ) .

The following compounds were prepared in like manner to the procedure outlined in Example 24 :

? CH ; O = 30

Isolated as a white solid ( 0 . 120 g , 52 % ) . 35

Example 23

Preparation of 2 - chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( 3 , 5 dichlorophenyl ) cyclopropane - 1 - carboxamido ) - N - ( 1 -

( 4 - fluorophenyl ) ethyl ) benzamide ( F96 )

5 - ( trans - 3 - ( 3 - Bromo - 4 - chlorophenyl ) - 2 , 2 - dichloro cyclopropane - 1 - carboxamido ) - 2 - chloro - N - ( 2 , 2 , 2

trifluoroethyl ) benzamide ( F109 ) 40

CICI F 45 HN F BP CL Clo

14 CIT

50 © CH3 50 Isolated as a white foam ( 0 . 100 g , 75 % ) .

2 - Chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( 3 , 4 - dibromophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 2 - trifluo

roethyl ) benzamide ( F111 ) sj 55 .

C C CI

To a solution of trans - 2 - chloro - 5 - ( 2 , 2 - dichloro - 3 - ( 3 , 5 dichlorophenyl ) cyclopropane carboxamido ) benzoic acid ( C67 ) ( 0 . 100 g , 0 . 220 mmol ) and 1 - ( 4 - fluorophenyl ) ethan 1 - amine ( 0 . 037 g , 0 . 220 mmol ) in ethyl acetate ( 3 mL ) were added sequentially pyridine ( 0 . 054 mL , 0 . 661 mmol ) and 60 2 , 4 , 6 - tripropyl - 1 , 3 , 5 , 2 , 4 , 6 - trioxatriphosphorinane - 2 , 4 , 6 - tri oxide ( 50 % solution in ethyl acetate , 0 . 281 g 0 . 441 mmol ) , and the resulting pale - yellow solution was stirred at room temperature for approximately 12 hours . The solution was concentrated under a stream of nitrogen , and purified by 65 silica gel flash column chromatography with a mobile phase of hexanes / ethyl acetate . The pure fractions were combined

Dolgut N Br

Isolated as a white solid ( 0 . 090 g , 71 % ) .

US 9 , 795 , 140 B2 117 118

2 - Chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( 3 - fluoro - 4 - ( trif 2 - Chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( 3 - chloro - 4 - ( trif luoromethyl ) phenyl ) cyclopropane - 1 - carboxamido ) luoromethyl ) phenyl ) cyclopropane - 1 - carboxamido )

N - ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F112 ) N - ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F116 )

C1 C1 CICI . F HN

10 E F

15

Isolated as a white foam ( 0 . 073 g , 53 % ) . Isolated as a white foam ( 0 . 081 g , 60 % ) .

5 - ( trans - 3 - ( 4 - Bromo - 3 - fluorophenyl ) - 2 , 2 - dichloro cyclopropane - 1 - carboxamido ) - 2 - chloro - N - ( 2 , 2 , 2

trifluoroethyl ) benzamide ( F113 ) 20 20

2 - Chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( 4 - chloro - 3 - ( trif luoromethyl ) phenyl ) cyclopropane - 1 - carboxamido )

N - ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F117 )

Ci Ci 25 25 F CICI F Xiu Xiut F

Br 30

Isolated as a white foam ( 0 . 086 g , 64 % ) . Isolated as a white foam ( 0 . 097 g , 72 % ) . 35 5 - ( trans - 3 - ( 3 - Bromo - 4 - ( trifluoromethyl ) phenyl ) - 2 , 2

dichlorocyclopropane - 1 - carboxamido ) - 2 - chloro - N ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F114 )

5 - ( trans - 3 - ( 3 - Bromo - 4 - fluorophenyl ) - 2 , 2 - dichloro cyclopropane - 1 - carboxamido ) - 2 - chloro - N - ( 2 , 2 , 2

trifluoroethyl ) benzamide ( F118 ) 40

C C

CICI

NH 45 Br N F F F

50 Isolated as a white foam ( 0 . 085 g , 66 % ) . Isolated as a white foam ( 0 . 113 g , 83 % ) .

5 - ( trans - 3 - ( 4 - Bromo - 3 - ( trifluoromethyl ) phenyl ) - 2 , 2 dichlorocyclopropane - 1 - carboxamido ) - 2 - chloro - N

( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F115 )

2 - Chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( 4 - fluoro - 3 - ( trif luoromethyl ) phenyl ) cyclopropane - 1 - carboxamido )

N - ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F119 ) 55

C1 C1 CICI

F 60 K F Volt Xoxloqu NH

65

Isolated as a white foam ( 0 . 095 g , 74 % ) . Isolated as a gold foam ( 0 . 111 g , 81 % ) .

119 US 9 , 795 , 140 B2

120 2 - Chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( 4 - chloro - 3 - fluoro 5 - ( trans - 3 - ( 3 - Bromo - 5 - ( trifluoromethyl ) phenyl ) - 2 , 2 phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 2 - trif dichlorocyclopropane - 1 - carboxamido ) - 2 - chloro - N

luoroethyl ) benzamide ( F120 ) ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F124 )

?? ??

F F ????? ? ????? N 10 Bra NH CI

CF3 Isolated as a white foam ( 0 . 120 g , 83 % ) . 15

Isolated as a clear colorless oil ( 0 . 102 g , 80 % ) . 2 - Chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( 3 , 5 - difluorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 2 - trifluo

roethyl ) benzamide ( F121 ) 2 - Chloro - 5 - trans - ( 2 , 2 - dichloro - 3 - ( 3 , 5 - difluoro - 4 methoxyphenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 ,

2 , 2 - trifluoroethyl ) benzamide ( F125 ) 20 20

CL

F CI ??? 25 F ???? - N

H3Cmo 30

Isolated as a white foam ( 0 . 058 g , 39 % ) .

Isolated as a white foam ( 0 . 075 g , 80 % ) . 2 - Chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( 3 - fluoro - 5 - ( trif luoromethyl ) phenyl ) cyclopropane - 1 - carboxamido )

N - ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F122 ) 35 2 - Chloro - 5 - trans - ( 2 , 2 - dichloro - 3 - ( 3 , 4 , 5 - trifluorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 2 - trifluo

roethyl ) benzamide ( F126 ) CICI

F 40

CI Clo po telemet FF

F T

Isolated as a white foam ( 0 . 112 g , 82 % ) .

Isolated as a clear colorless oil ( 0 . 052 g , 54 % ) . 5 - ( trans - 3 - ( 3 - Bromo - 5 - fluorophenyl ) - 2 , 2 - dichloro cyclopropane - 1 - carboxamido ) - 2 - chloro - N - ( 2 , 2 , 2

trifluoroethyl ) benzamide ( F123 ) 55

2 - Chloro - 5 - cis - ( 2 , 2 - dichloro - 3 - ( 3 , 4 , 5 - trifluorophe nyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 2 - trifluo

roethyl ) benzamide ( F127 ) CI CI ?? ??

O F IF 60 F yoxloqit pohy

Br of F

Isolated as a white solid ( 0 . 097 g , 72 % ) . Isolated as a clear colorless oil ( 0 . 017 g , 18 % ) .

US 9 , 795 , 140 B2 121 122

2 - Chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( 3 - chloro - 5 - dif 2 - Chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - 3 - chloro - 4 - dif luoromethylphenyl ) cyclopropane - 1 - carboxamido ) luoromethylphenyl ) cyclopropane - 1 - carboxamido ) -

N - ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F128 ) N - ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F132 )

Cl . Cl o Cl . Cl ? F

F F F ??? ???? 10 )

15

Isolated as a yellow oil ( 0 . 063 g , 73 % ) .

2 - Chloro - 5 - trans - 2 , 2 - dichloro - 3 - ( 4 - chloro - 3 - ( dif luoromethylphenyl ) cyclopropane - 1 - carboxamido ) -

N - ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F129 )

Isolated as a yellow foam ( 0 . 068 g , 78 % ) . 2 - Chloro - 5 - trans - 2 , 2 - dichloro - 3 - ( 4 - ( difluorom ethyl ) - 3 - fluorophenyl ) cyclopropane - 1 - carbox

amido ) - N - ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F133 ) 20

? Cl Cl 25 F

| \ / ???? ????? 1

30 )

Isolated as a pale yellow oil ( 0 . 063 g , 73 % ) . ?? 2 - Chloro - 5 - trans - 2 , 2 - dichloro - 3 - 3 - ( difluorom

ethyl ) - 5 - fluorophenyl ) cyclopropane - 1 - carbox amido ) - N - ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F130 )

Isolated as a yellow foam ( 0 . 059g , 70 % ) . 2 - Chloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( 3 - ( difluoromethyl ) phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 2 - trif

luoroethyl ) benzamide ( F134 )

40 )

Cl . Cl o F F ? C1 C1 F ZL ?? ????? ????? 45 F

Isolated as a white foam ( 0 . 058 g , 71 % ) . 5 (

Isolated as a yellow foam ( 0 . 051 g , 61 % ) . 2 - Chloro - 5 - trans - 2 , 2 - dichloro - 3 - ( 3 - ( difluorom ethyl ) - 4 - fluorophenyl ) cyclopropane - 1 - carbox

amido ) - N - ( 2 , 2 , 2 - trifluoroethyl ) benzamide ( F131 )

2 - Chloro - 5 - trans - 2 , 2 - dichloro - 3 - ( 4 - ( difluoromethyl ) phenyl ) cyclopropane - 1 - carboxamido ) - N - ( 2 , 2 , 2 - trif

luoroethyl ) benzamide ( F135 ) 55 55

? Cl Cl

Cl . Cl F F F 60 ??????? ???? F

F " F 65

Isolated as a white foam ( 0 . 059 g , 70 % ) . Isolated as a white foam ( 0 . 057g , 70 % ) .

US 9 , 795 , 140 B2 124 123

Example 25

Preparation of ( E ) - 1 - chloro - 3 - ( difluoromethyl ) - 5 - ( 4 methoxystyryl ) benzene ( C107 )

Isolated as an off - white solid ( 20 g , 75 % ) ; ' H NMR ( 300 MHz , CDC1Z ) 7 . 46 ( d , J = 8 . 0 Hz , 2H ) , 7 . 38 ( s , 1H ) , 7 . 28 ( s , 1H ) , 7 . 08 ( t , J = 16 . 2 Hz , 2H ) , 6 . 92 ( t , J = 15 . 6 Hz , 3H ) , 6 . 63 ( t , J = 56 . 0 Hz , 1H ) , 3 . 84 ( s , 3H ) ; ESIMS m / z 279 ( [ M + H ] + ) . lt

À 0 - CH3 ( E ) - 2 - ( Difluoromethyl ) - 1 - fluoro - 5 - ( 4 - methoxystyryl )

benzene ( C110 )

10

CH3

F

F

To a stirred solution of ( E ) - 3 - chloro - 5 - ( 4 - methoxystyryl ) benzaldehyde ( C115 ) ( 13 g , 47 . 79 mmol ) in dichlorometh - 15 ane ( 130 mL ) was added diethylaminosulfur trifluoride ( 31 . 5 mL , 238 . 97 mmol ) at - 78° C . The resulting solution was stirred for 20 hours at room temperature . The reaction mixture was cooled to 0° C . , and a solution of saturated aqueous sodium bicarbonate was added dropwise . The lay ers were separated and the aqueous layer was extracted with dichloromethane ( 3x75 mL ) . The combined organic layer was washed with water and brine , dried over sodium sulfate , and concentrated . The crude material was purified by flash se column chromatography using 10 - 20 % ethyl acetate in hexanes as the eluent to afford the title compound as a pale yellow oil ( 13 . 1 g , 94 % ) : ' H NMR ( 400 MHz , CDC1z ) 8 7 . 55 ( s , 1H ) , 7 . 45 ( d , J = 8 . 8 Hz , 3H ) , 7 . 34 ( s , 1H ) , 7 . 10 ( d , J = 16 Hz , 1H ) , 6 . 90 ( t , J = 8 . 4 Hz , 3H ) , 6 . 61 ( t , J = 56 . 4 Hz , 20 1H ) , 3 . 80 ( s , 3H ) ; 19F NMR ( 376 MHz , CDC1z ) 8 - 111 . 72 .

The following compounds were prepared in like manner to the procedure outlined in Example 25 :

Isolated as an off - white solid ( 14 . 0 g , 70 % ) : ' H NMR ( 300 MHz , CDC13 ) 87 . 69 ( d , J = 9 . 0 Hz , 1H ) , 7 . 57 - 7 . 53 ( m , 1H ) , 7 . 45 ( d , J = 9 . 9 Hz , 2H ) , 7 . 13 - 7 . 06 ( m , 2H ) , 7 . 00 - 6 . 89 ( m , 4H ) , 3 . 85 ( s , 3H ) ; ESIMS m / z 279 ( [ M + H ] + ) .

( E ) - 2 - Chloro - 1 - ( Difluoromethyl ) - 4 - ( 4 - methox ystyryl ) benzene ( C111 )

CH3

( E ) - 1 - Chloro - 2 - ( difluoromethyl ) - 4 - ( 4 - methox ystyryl ) benzene ( C108 ) 35 35

CH3 40

F ?? Isolated as an off - white solid ( 18 . 0 g , 90 % ) : ' H NMR ( 400 MHz , CDC1z ) 8 7 . 61 ( d , J = 8 . 0 Hz , 1H ) , 7 . 51 ( s , 1H ) , 7 . 47 - 7 . 43 ( m , 3H ) , 7 . 14 - 7 . 07 ( m , 1H ) , 6 . 94 - 6 . 80 ( m , 4H ) , 3 . 85 ( s , 3H ) ; ESIMS m / z 294 ( [ M + H ] + ) . 45

( E ) - 1 - ( Difluoromethyl ) - 2 - fluoro - 4 - ( 4 - methoxystyryl ) benzene ( C112 )

Isolated as an off - white solid ( 12 g , 94 % ) : ' H NMR ( 300 MHz , CDC13 ) 8 7 . 75 ( s , 1H ) , 7 . 51 - 7 . 44 ( m , 3H ) , 7 . 37 ( d , J = 8 . 4 Hz , 1H ) , 7 . 13 ( d , J = 6 . 6 Hz , 1H ) , 7 . 06 ( s , 1H ) , 6 . 95 - 6 . 89 ( m , 3H ) , 3 . 95 ( s , 3H ) ; 19F NMR ( 282 MHz , 50 CDC1z ) 8 - 115 . 31 ; ESIMS m / z 295 ( [ M + H ] * ) .

OCH3 ( E ) - 1 - ( Difluoromethyl ) - 3 - fluoro - 5 - ( 4 - methoxystyryl ) benzene ( C109 ) F

55

F CH3 F 60

Isolated as a pale yellow solid ( 9 g , 55 % ) : ' H NMR ( 400 MHz , CDC1z ) 8 7 . 54 ( t , J = 8 . 0 Hz , 1H ) , 7 . 46 ( d , J = 8 . 8 Hz , 2H ) , 7 . 32 ( d , J = 8 . 0 Hz , 1H ) , 7 . 22 ( d , J = 11 . 6 Hz , 1H ) , 7 . 11

65 ( d , J = 16 . 4 Hz , 1H ) , 7 . 01 - 6 . 83 ( m , 4H ) , 3 . 95 ( s , 3H ) ; 19F NMR ( 376 MHz , CDC1z ) 8 - 113 . 57 , - 114 . 25 , - 120 . 33 ; ESIMS m / z 279 ( [ M + H ] + ) .

L

US 9 , 795 , 140 B2 125 126

( E ) - 1 - ( Difluoromethyl ) - 3 - ( 4 - methoxystyryl ) benzene 5 - 10 % ethyl acetate in petroleum ether as the eluent to afford ( C113 ) the title compound as a yellow solid ( 13 . 5 g , 54 % ) : ' H NMR

( 300 MHz , CDC1z ) 8 9 . 99 ( s , 1H ) , 7 . 85 ( s , 1H ) , 7 . 69 ( s , 2H ) , 7 . 47 ( d , J = 8 . 4 Hz , 2H ) , 7 . 16 ( d , J = 16 . 2 Hz , 1H ) , 6 . 94 ( t ,

5 J = 8 . 4 Hz , 3H ) , 3 . 84 ( s , 3H ) ; ESIMS m / z 273 ( [ M + H ] + ) . The following compounds were prepared in like manner

to the procedure outlined in Example 26 : ) CH3 -

F 10 ( E ) - 2 - Chloro - 5 - ( 4 - methoxystyryl ) benzaldehyde

( C116 )

Isolated as a pale yellow solid ( 6 g , 68 % ) : ' H NMR ( 300 MHz , CDC1Z ) 8 7 . 62 - 7 . 56 ( m , 2H ) , 7 . 48 - 7 . 34 ( m , 4H ) , 7 . 11 15 ( d , J = 16 . 5 Hz , 1H ) , 7 . 00 ( s , 1H ) , 6 . 95 - 6 . 89 ( t , 2H ) , 6 . 66 ( t , 1H ) , 3 . 95 ( s , 3H ) ; 19F NMR ( 282 MHz , CDC1z ) 8 - 110 . 84 ; ESIMS m / z 261 ( [ M + H ] + ) .

CH3

( E ) - 1 - ( Difluoromethyl ) - 4 - ( 4 - methoxystyryl ) benzene ( C114 )

20

CH3 Isolated as a pale yellow solid ( 11 . 8 g , 27 % ) : ' H NMR

25 ( 300 MHz , CDC13 ) 8 10 . 45 ( s , 1H ) , 8 . 02 ( s , 1H ) , 7 . 62 ( d , J = 6 . 4 Hz , 1H ) , 7 . 46 - 7 . 40 ( m , 3H ) , 7 . 12 ( d , J = 16 . 4 Hz , 1H ) , 6 . 95 - 6 . 90 ( m , 3H ) , 3 . 95 ( s , 3H ) ; ESIMS m / z 273 ( [ M + H ] + ) .

30 ( E ) - 3 - Fluoro - 5 - ( 4 - methoxystyryl ) benzaldehyde

( C117 ) T

- CH3 Isolated as an off - white solid ( 15 . 4 g , 75 % ) ; ' H NMR

( 300 MHz , CDC13 ) 8 7 . 57 - 7 . 45 ( m , 6H ) , 7 . 12 ( d , J = 15 . 9 Hz , 1H ) , 7 . 00 - 6 . 89 ( m , 3H ) , 6 . 64 ( t , J = 57 Hz , 1H ) , 3 . 92 ( s , 3H ) ; ESIMS m / z 260 . 17 ( [ M + H ] + ) . buen Example 26

40

Preparation of ( E ) - 3 - chloro - 5 - ( 4 - methoxystyryl ) benzaldehyde ( C115 )

0 - CH3

45 Isolated as a pale yellow solid ( 25 g , 57 % ) : 1H NMR ( 300 MHz , CDC1z ) 8 10 ( s , 1H ) , 7 . 77 ( s , 1H ) , 7 . 48 - 7 . 40 ( m , 4H ) , 7 . 16 ( d , J = 16 . 2 Hz , 1H ) , 6 . 94 ( t , J = 15 . 6 Hz , 3H ) , 3 . 84 ( s , 3H ) ; ESIMS m / z 275 ( [ M + H ] + ) .

H 50 50 ( E ) - 2 - Fluoro - 5 - ( 4 - methoxystyryl ) benzaldehyde ( C118 )

55

0 - CH3 To a stirred solution of 3 - bromo - 5 - chlorobenzaldehyde ( 20 . 0 g , 91 . 32 mmol ) in dimethylacetamide , 1 - methoxy - 4 vinylbenzene ( 18 . 3 g , 136 . 9 mmol ) and triethylamine ( 50 . 5 mL , 273 . 96 mmol ) were added , and the reaction mixture was degassed with argon for 5 minutes . Palladium ( II ) acetate 60 ( 410 mg , 1 . 83 mmol ) and tri - o - tolylphosphine ( 1 . 11 g , 3 . 65 mmol ) were added , and the resulting reaction mixture was heated to 100° C . for 16 hours . The reaction mixture was poured into water and extracted with ethyl acetate . The Isolated as an off - white solid ( 0 . 25 g , 20 % ) : ' H NMR combined organic layer was dried over sodium sulfate and 65 ( 400 MHz , CDC12 ) 8 10 . 43 ( s , 1H ) , 7 . 90 ( d , J = 8 . 4 Hz , 1H ) , concentrated under reduced pressure . The resulting crude 7 . 54 - 7 . 46 ( m , 4H ) , 7 . 20 ( d , J = 16 . 0 Hz , 1H ) , 6 . 94 - 6 . 90 ( m , material was purified by flash column chromatography using 3H ) , 3 . 85 ( s , 3H ) ; ESIMS m / z 274 ( [ M + H ] + ) .

oscana sus 29 . US 9 , 795 , 140 B2 127 128

( E ) - 2 - Chloro - 4 - ( 4 - methoxystyryl ) benzaldehyde ( E ) - 4 - ( 4 - Methoxystyryl ) benzaldehyde ( C122 ) ( C119 )

- CH3 CH3 vond 10

15

Isolated as an off - white solid ( 8 . 0 g , 57 % ) : ' H NMR ( 400 MHz , CDC1z ) 8 10 . 41 ( s , 1H ) , 7 . 97 ( dd , J = 2 . 4 , 6 . 8 Hz , 1H ) , 7 . 71 - 7 . 67 ( m , 1H ) , 7 . 44 ( d , J = 8 . 0 Hz , 2H ) , 7 . 18 - 7 . 13 ( m , TH ) , 7 . 08 - 7 . 04 ( m , TH ) , 6 . 95 - 6 . 90 ( m , 3H ) , 3 . 89 ( s , 3H ) ; ESIMS m / z 257 ( [ M + H ] + ) .

Isolated as a light brown solid ( 9 g , 47 % ) : ' H NMR ( 400 MHz . CDCI . ) 8 10 ( s . 1H ) . 7 . 84 ( d . J = 8 . 0 Hz , 2H ) , 7 . 61 ( d . J = 7 . 6 Hz , 2H ) , 7 . 48 ( d , J = 8 . 0 Hz , 2H ) , 7 . 23 ( t , J = 7 . 6 Hz , 1H ) , 7 . 00 ( d , J = 16 . 0 Hz , 1H ) , 6 . 92 ( d , J = 8 . 8 Hz , 2H ) , 3 . 84 ( s , 3H ) .

20

( E ) - 2 - Fluoro - 4 - ( 4 - methoxystyryl ) benzaldehyde ( C120 ) Example 27

25

Preparation of trans - 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1carboxylic acid ( C1 )

CH3 30

C1 C10

35

0 - CH3

Isolated as a brown solid ( 15 g , 78 % ) : ' H NMR ( 400 40 MHz , CDC12 ) 8 10 . 35 ( s , 1H ) , 7 . 83 ( t , J = 7 . 6 Hz , 1H ) , 7 . 48 ( d , J = 8 . 8 Hz , 2H ) , 7 . 35 ( d , J = 8 . 4 Hz , 1H ) , 7 . 23 - 7 . 18 ( m , 2H ) , 6 . 96 - 6 . 91 ( m , 3H ) , 3 . 95 ( s , 3H ) ; 19F NMR ( 376 MHz , CDC13 ) d - 122 . 26 ; 5 Sodium permanganate ( 40 % aqueous ) ( 84 g , 236 mmol ) ESIMS m / z 257 ( [ M + H ] * ) . was added dropwise to a stirred mixture of trans - 2 , 2 - di

chloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - 1 - carbaldehyde ( C115 ) ( 58 . 7 g , 196 mmol ) in acetone ( 982 mL ) at 15° C . ( E ) - 3 - ( 4 - Methoxystyryl ) benzaldehyde ( C121 ) The resulting mixture was stirred at 20° C . for 2 hours . The

50 reaction mixture was diluted with isopropyl alcohol ( 20 mL ) and concentrated to remove the acetone . Celite® and aque ous hydrochloric acid ( 1 N , 295 mL , 295 mmol ) were added to the brown residue . The resulting mixture was diluted with ethyl acetate ( 500 mL ) and filtered through Celite® . The

55 filtrate was washed with brine ( 200 mL ) . The organic layer was dried over sodium sulfate , filtered and concentrated . The resulting slurry was diluted with heptane ( ~ 200 mL ) and allowed to solidify at 20° C . The solid was collected , washed with heptane and dried to afford the title product as a white

60 solid ( 54 . 68 g , 91 % ) : ' H NMR ( 300 MHz , CDC1z ) 8 7 . 36 ( t , J = 1 . 9 Hz , 1H ) , 7 . 17 ( dd , J = 1 . 9 , 0 . 7 Hz , 2H ) , 3 . 48 - 3 . 37 ( m ,

Isolated as a brown solid ( 18 0 . 46 % ) : 1H NMR ( 400 1H ) , 2 . 87 ( d , J = 8 . 3 Hz , 1H ) ; - C NMR ( 400 MHz , CDC12 ) MHz . CDC1 . ) 8 10 . 15 ( s . 11 ) . 8 . 00 ( s . 11 ) . 7 . 73 ( d . J = 72 . d 135 . 44 , 135 . 28 , 128 . 66 , 127 . 30 , 39 . 68 , 36 . 88 ; ESIMS Hz , 2H ) , 7 . 53 - 7 . 46 ( m , 3H ) , 7 . 17 ( d , J = 16 . 8 Hz , 1H ) , 7 . 01 65 m / z = 298 . 9 ( M - H ] ) - . . ( d , J = 16 . 0 Hz , 1H ) , 6 . 92 ( d , J = 8 . 8 Hz , 2H ) , 3 . 84 ( s , 3H ) ; The following compounds were prepared in like manner ESIMS m / z 239 ( [ M + H ] + ) . to the procedure outlined in Example 27 :

H

US 9 , 795 , 140 B2 129 130

trans - 2 , 2 - Dichloro - 3 - ( 3 , 4 , 5 - trichlorophenyl ) cyclo trans - 2 , 2 - Dichloro - 3 - ( 3 , 5 - dichloro - 4 - methoxyphe propane - 1 - carboxylic acid ( C2 ) nyl ) cyclopropanecarboxylic acid ( C123 )

CI Clo ci . Co

OH OH

10

H3C

15 Isolated as a white solid ( 2 . 78 g , 95 % ) : ' H NMR ( 400

MHz , DMSO - do ) d 13 . 41 ( s , 1H ) , 7 . 81 ( d , J = 0 . 6 Hz , 2H ) , 3 . 62 ( d , J = 8 . 6 Hz , 1H ) , 3 . 52 ( d , J = 8 . 6 Hz , 1H ) ; ESIMS m / z 332 ( [ M - H ] ) .

trans - 2 , 2 - Dichloro - 3 - ( 3 , 4 - dichlorophenyl ) cyclopro pane - 1 - carboxylic acid ( C3 )

Isolated as an off - white solid ( 1 . 33 g , 96 % ) : mp 161 - 164° C . ; ' H NMR ( 400 MHz , DMSO - d ) 8 13 . 35 ( s , 1H ) , 7 . 63 ( s , 2H ) , 3 . 83 ( s , 3H ) , 3 . 52 ( d , J = 8 . 6 Hz , 1H ) , 3 . 45 ( d , J = 8 . 6 Hz , 1H ) ; 13C NMR ( 126 MHz , DMSO - do ) 8 166 . 81 , 151 . 02 , 131 . 07 , 129 . 63 , 128 . 03 , 61 . 93 , 60 . 52 , 37 . 22 , 36 . 54 ; ESIMS m / z 329 [ ( M - H ) ] .

25 Ci Example 28 Ci .

Preparation of trans - 2 , 2 - dichloro - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1 - carbaldehyde ( C140 ) OH

30

CI Clo

Isolated as a white solid ( 124 g , 82 % ) : mp 133 - 135º C . : H NMR ( 500 MHz , DMSO - d ) d 13 . 39 ( s , 1H ) , 7 . 76 ( d , 35

J = 2 . 0 Hz , 1H ) , 7 . 64 ( d , J = 8 . 3 Hz , 1H ) , 7 . 44 ( dd , J = 8 . 4 , 2 . 1 Hz , 1H ) , 3 . 49 ( s , 2H ) . 13C NMR ( 126 MHz , DMSO - do ) 166 . 34 , 133 . 35 , 130 . 47 , 130 . 33 , 130 . 09 , 129 . 77 , 128 . 81 , 61 . 43 , 37 . 00 , 36 . 06 . 40

trans - 2 , 2 - Dichloro - 3 - ( 3 - chloro - 4 - fluorophenyl ) cy clopropane - 1 - carboxylic acid ( C16 )

??

F

45 Aqueous hydrochloric acid ( 2 N , 237 mL ) was added to cl clo a stirred solution of 1 , 3 - dichloro - 5 - ( ( trans - 2 , 2 - dichloro - 3

( diethoxymethyl ) cyclopropyl ) benzene ( C145 ) ( 85 . 7 g , 227 mmol ) in acetonitrile ( 1184 mL ) . The mixture was stirred at

50 20° C . for 16 hours . The resulting mixture was diluted with water ( 200 mL ) and concentrated to remove the acetonitrile . The resulting aqueous mixture was extracted with hexanes ( 600 mL ) . The organic layer was washed water ( 300 mL ) ,

Isolated as a white solid ( 165 g , 71 % ) : " H NMR ( 400 55 dried over anhydrous sodium sulfate , filtered and concen MHz , CDC13 ) d 11 . 57 ( s , 1H ) , 7 . 42 ( dd , J = 8 . 2 , 7 . 6 Hz , 1H ) , trated . The crude product was purified by chromatography to 7 . 11 - 6 . 98 ( m , 2H ) , 3 . 46 ( d , J = 8 . 2 Hz , 1H ) , 2 . 85 ( d , J = 8 . 3 Hz , 1H ) ; 19F NMR ( 376 MHz , CDC12 ) - 114 . 07 ; ESIMS m / z afford the title product as a yellow oil ( 58 . 7 g , 86 % , purity 282 ( [ M - H ] ) . 95 % ) : ' H NMR ( 400 MHz , CDC13 ) 89 . 54 ( d , v = 4 . 0 Hz , 1H ) ,

In another preparation , isolated as a white powder ( 10 . 385 60 7 . 46 - 7 . 09 ( m , 3H ) , 3 . 51 ( d , J = 8 . 0 Hz , 1H ) , 2 . 92 ( dd , J = 8 . 0 , g , 77 % ) : 119 - 121° C . ; ' H NMR ( 400 MHz , CDC12 ) 8 11 . 83 4 . 0 Hz . 1H ) : 13C NMR ( 126 MHZ . CDC1 . ) 8 193 . 41 . 135 . 33 . ( s , 1H ) , 7 . 32 ( d , J = 6 . 9 Hz , 1H ) , 7 . 16 ( d , J = 6 . 7 Hz , 2H ) , 3 . 45 135 . 09 , 128 . 78 , 127 . 34 , 42 . 89 , 39 . 31 ; IR ( thin film ) 3077 . 79 , ( d , J = 8 . 3 Hz , 1H ) , 2 . 85 ( d , J = 8 . 3 Hz , 1H ) ; 13C NMR ( 101 MHz , CDC13 ) S 172 . 18 , 159 . 26 , 156 . 77 , 130 . 95 , 129 . 26 , 2847 . 30 , 1713 . 57 , 1590 . 66 , 1566 . 39 , 1416 . 76 , 1387 . 06 . IR : 129 . 22 , 128 . 57 , 128 . 50 , 121 . 52 , 121 . 34 , 116 . 94 , 116 . 73 , 65 3078 , 2847 , 1714 , 1590 , 1566 , 1417 , 1387 . 61 . 59 , 39 . 64 , 37 . 30 ; 19F NMR ( 376 MHz , CDC13 ) . The following compounds were prepared in like manner - 115 . 16 ; ESIMS m / z 281 [ ( M - H ) ] . to the procedure outlined in Example 28 :

una 2 delom US 9 , 795 , 140 B2

131 132 trans - 2 , 2 - Dichloro - 3 - ( 3 , 4 - dichlorophenyl ) cyclopro trans - 2 , 2 - Dichloro - 3 - ( 3 - chloro - 4 - fluorophenyl ) cy

pane - 1 - carbaldehyde ( C141 ) clopropane - 1 - carbaldehyde ( C144 ) belompo mons2 Cl . Clo cl clo

10

15

Isolated as orange oil ( 143 g , 98 % ) : ' H NMR ( 400 MHz , CDC13 ) d 9 . 53 ( d , J = 4 . 1 Hz , 1H ) , 7 . 47 ( d , J = 8 . 3 Hz , 1H ) , 7 . 37 ( dd , J = 2 . 2 , 0 . 7 Hz , 1H ) , 7 . 12 ( ddd , J = 8 . 3 , 2 . 2 , 0 . 7 Hz , 1H ) , 3 . 51 ( dd , J = 7 . 9 , 0 . 8 Hz , 1H ) , 2 . 90 ( dd , J = 8 . 0 , 4 . 1 Hz , 1H ) .

Isolated as a yellow oil ( 12 . 496 g , 71 % ) : ' H NMR ( 400 MHz , CDC1z ) : 9 . 52 ( d , J = 4 . 1 Hz , 1H ) , 7 . 33 ( d , J = 7 . 2 Hz , 1H ) , 7 . 16 ( dd , J = 6 . 8 , 1 . 0 Hz , 2H ) , 3 . 53 ( d , J = 7 . 9 Hz , 1H ) , 2 . 90 ( dd , J = 7 . 9 , 4 . 1 Hz , 1H ) ; 13C NMR ( 101 MHz , CDC13 )

20 8 193 . 77 , 159 . 27 , 156 . 78 , 131 . 03 , 129 . 04 , 129 . 00 , 128 . 66 , 128 . 59 , 121 . 49 , 121 . 31 , 116 . 95 , 116 . 74 , 61 . 68 , 43 . 10 , 39 . 25 ; 19F NMR ( 376 MHz , CDC1z ) 8 - 115 . 01 ; EIMS m / z 266 . trans - 2 , 2 - Dichloro - 3 - ( 3 , 4 , 5 - trichlorophenyl ) cyclo

propane - 1 - carbaldehyde ( C142 ) 25 Example 29

ci Clo Preparation of 1 , 3 - dichloro - 5 - ( trans - 2 , 2 - dichloro - 3 ( diethoxymethyl ) cyclopropyl ) benzene ( C145 )

30

a CI o CH3 35

O CH3

Isolated as a yellow solid ( 2 . 8 g , 69 % ) : ' H NMR ( 400 MHz , CDC1z ) 8 9 . 55 ( d , J = 3 . 9 Hz , 1H ) , 7 . 30 ( d , J = 0 . 7 Hz , 2H ) , 3 . 48 ( dt , J = 8 . 0 , 0 . 8 Hz , 1H ) , 2 . 92 ( dd , = 7 . 9 , 3 . 9 Hz , 1H ) .

CLCI

HC - o

A 1 L 4 - neck flask equipped with a mechanical stirrer , trans - 2 , 2 - Dichloro - 3 - ( 3 , 5 - dichloro - 4 - methoxyphe condenser , temperature probe and nitrogen inlet was charged nyl ) cyclopropane - 1 - carbaldehyde ( C143 ) with ( E ) - 1 , 3 - dichloro - 5 - ( 3 , 3 - diethoxyprop - 1 - en - 1 - yl ) ben zene ( C150 ) ( 40 g , 138 mmol ) and CHC1z ( 447 mL ) . Tetrabutylammonium hexafluorophosphate ( V ) ( 1 . 081 g ,

50 2 . 76 mmol ) was added . The light yellow solution was heated to 45° C . With vigorous stirring ( ~ 400 rpm ) , aqueous sodium hydroxide ( 50 % , 182 mL ) was added dropwise via addition funnel ( over 1 hour ) . After 20 hours , the mixture was allowed to cool . The mixture was diluted with hexane ( 200 mL ) . The organic top layer was decanted ( off the aqueous lower suspension ) through Celite® , washing the filtercake with hexane ( 200 mL ) . The filtrate was washed with brine ( ~ 200 mL ) , dried over sodium sulfate , filtered and concentrated to provide the title compound as a brown oil

ou ( 50 . 2 g , 97 % , purity 95 % ) : ' H NMR ( 300 MHz , CDC12 ) 8 Isolated as a light - yellow oil ( 1 . 346 o 74 % ) : 1H NMR 7 . 31 ( t , J = 1 . 9 Hz , 1H ) , 7 . 15 ( dd , J = 1 . 9 , 0 . 7 Hz , 2H ) , 4 . 59 ( d .

( 400 MHZ . CDC1 . ) 8 . 9 . 52 ( d . J = 4 . 0 HZ . 11 ) . 7 . 22 ( s . 21 ) . J = 6 . 2 Hz , 1H ) , 3 . 80 - 3 . 57 ( m , 4H ) , 2 . 77 ( d , J = 8 . 5 Hz , 1H ) . 3 . 90 ( s , 3H ) , 3 . 48 ( d , J = 8 . 0 Hz , 1H ) , 2 . 91 ( dd , J = 8 . 0 , 4 . 0 Hz , 2 . 25 ( dd , J = 8 . 5 , 6 . 2 Hz , 1H ) , 1 . 30 ( t , J = 7 . 0 Hz , 3H ) , 1 . 20 ( t , 1H ) ; 13C NMR ( 101 MHz , CDC1 , ) 8 191 . 67 , 150 . 58 . 65 . JET . 1 Hz , 3H ) . 127 . 74 , 127 . 54 , 127 . 35 , 59 . 76 , 58 . 94 , 41 . 14 , 37 . 13 ; EIMS The following compounds were prepared in like manner m / z 314 . to the procedure outlined in Example 29 :

US 9 , 795 , 140 B2 133 134

1 , 2 - Dichloro - 4 - ( trans - 2 , 2 - dichloro - 3 - ( diethoxym 2 - Chloro - 4 - ( trans - 2 , 2 - dichloro - 3 - ( diethoxymethyl ) ethyl ) cyclopropyl ) benzene ( C146 ) cyclopropyl ) - 1 - fluorobenzene ( C149 )

Cl , CI CO Cl 0 CH3 CH3

- CH3 - CH3 10

F

Isolated as a brown oil ( 63 g , 96 % ) : ' H NMR ( 400 MHz , 15 CDC13 ) d 7 . 44 ( dd , J = 7 . 0 , 2 . 2 Hz , 1H ) , 7 . 29 - 7 . 22 ( m , 1H ) , Isolated as a brown oil ( 184 g , 99 % ) : ' H NMR ( 400 MHz , 7 . 09 ( t . J = 8 . 7 Hz , 1H ) , 6 . 62 ( dd . J = 16 . 1 , 1 . 2 Hz , 1H ) , 6 . 14

CDC12 ) 8 7 . 43 ( d , J = 8 . 2 Hz , 1H ) , 7 . 36 ( dd , J = 2 . 2 , 0 . 7 Hz , ( dd . J = 16 . 1 . 5 . 0 Hz , 1H ) , 5 . 05 ( dd . J = 4 . 9 . 1 . 2 Hz , 1H ) , 3 . 70 1H ) , 7 . 10 ( ddd , J = 8 . 3 , 2 . 1 , 0 . 7 Hz , 1H ) , 4 . 59 ( d , J = 6 . 2 Hz , ( dq , J = 9 . 3 , 7 . 0 Hz , 2H ) , 3 . 56 ( dq , J = 9 . 4 , 7 . 1 Hz , 2H ) , 1 . 25 1H ) , 3 . 82 - 3 . 55 ( m , 4H ) , 2 . 77 ( d , J = 8 . 5 Hz , 1H ) , 2 . 24 ( dd , m ( t . J = 7 . 1 Hz , 6H ) ; 13C NMR ( 101 MHz , CDC1 , ) 8 158 . 91 . J = 8 . 5 , 6 . 3 Hz , 1H ) , 1 . 30 ( t , J = 7 . 0 Hz , 3H ) , 1 . 20 ( t , J = 7 . 1 Hz , 156 . 42 , 133 . 65 , 133 . 62 , 130 . 47 , 128 . 65 , 128 . 07 , 128 . 05 , 3H ) . 126 . 39 , 126 . 32 , 121 . 26 , 121 . 08 , 116 . 72 , 116 . 51 , 100 . 93 ,

61 . 17 , 15 . 24 ; 19F NMR ( 376 MHz , CDC13 ) 8 - 116 . 36 . 1 , 2 , 3 - Trichloro - 5 - ( trans - 2 , 2 - dichloro - 3 - ( diethoxym In another preparation , isolated as an amber oil ( 22 . 38 g ,

ethyl ) cyclopropyl ) benzene ( C147 ) 25 88 % ) : ' H NMR ( 400 MHz , CDC12 ) 8 7 . 31 ( m , 1H ) , 7 . 13 ( m , 2H ) , 4 . 59 ( d , J = 6 . 3 Hz , 1H ) , 3 . 69 ( m , 4H ) , 2 . 78 ( d , J = 8 . 5 Hz , 1H ) , 2 . 23 ( dd , J = 8 . 5 , 6 . 3 Hz , 1H ) , 1 . 30 ( t , J = 7 . 1 Hz , 3H ) , 1 . 20 ( t , J = 7 . 1 Hz , 3H ) ; 19F NMR ( 376 MHz , CDC1 , ) - 116 . 48 ; EIMS m / z 295 [ M - OEt ] . CI CO CH3 30

Example 30 CH ;

Preparation of ( E ) - 1 , 3 - dichloro - 5 - ( 3 , 3 - diethoxy prop - l - en - 1 - yl ) benzene ( C150 )

35

0 CH3 CI Isolated as a brown oil ( 146 g , 93 % ) : ' H NMR ( 400 MHz ,

CDC1z ) 8 7 . 29 ( d , J = 0 . 7 Hz , 2H ) , 4 . 59 ( d , J = 6 . 1 Hz , 1H ) , 3 . 82 - 3 . 54 ( m , 4H ) , 2 . 75 ( d , J = 8 . 5 Hz , 1H ) , 2 . 23 ( dd , J = 8 . 5 , 6 . 1 Hz , 1H ) , 1 . 30 ( t , J = 7 . 0 Hz , 3H ) , 1 . 20 ( t , J = 7 . 0 Hz , 3H ) .

0 CH3

45

CH3

H3C -

trans - 1 , 3 - Dichloro - 5 - ( 2 , 2 - dichloro - 3 - ( diethoxym ethyl ) cyclopropyl ) - 2 - methoxybenzene ( C148 )

Step la : Acetaldehyde ( 120 g , 2688 mmol ) was added to a stirred mixture of 3 , 5 - dichlorobenzaldehyde ( 96 g , 538

50 mmol ) in toluene ( 400 mL ) at 0° C . A solution of potassium a CI O CHZ hydroxide ( 3 . 35 g , 53 . 8 mmol ) in methyl alcohol ( 10 mL )

was added dropwise via addition funnel . The resulting mixture was stirred at 0° C . for 4 hours until all of the 3 , 5 - dichlorobenzaldehyde was consumed by thin layer chro

55 matography . Step 1b : Ethyl acetate ( 500 mL ) and concen trated hydrochloric acid ( 37 % aqueous , 44 . 1 mL , 538 mmol ) were added to the reaction mixture . The resulting mixture was heated at 80° C . , and a colorless liquid was allowed to distill ( 200 mL ) . The reaction mixture was diluted with

60 water ( 500 mL ) and extracted with ethyl acetate . The organic Isolated as an orange oil ( 2 . 254 g , 80 % ) : ' H NMR ( 400 layer was washed with brine , dried over sodium sulfate ,

MHz , CDC12 ) 07 . 20 ( d , J = 0 . 5 Hz , 2H ) , 4 . 58 ( d , J = 6 . 2 Hz , filtered , and concentrated to afford ( E ) - 3 - ( 3 . 5 - dichlorophe 1H ) , 3 . 90 ( s , 3H ) , 3 . 67 ( m , 4H ) , 2 . 74 ( d , J = 8 . 5 Hz , 1H ) , 2 . 22 nyl ) acrylaldehyde as a light yellow solid ( 115 g ) which was ( dd , J = 8 . 5 , 6 . 2 Hz , 1H ) , 1 . 31 ( m , 3H ) , 1 . 21 ( m , 3H ) ; 13C used directly without further purification : ' H NMR ( 300 NMR ( 101 MHz , CDC12 ) 8 151 . 87 , 131 . 55 , 129 . 27 , 129 . 20 , 65 MHz , CDC12 ) 8 9 . 72 ( dd , J = 7 . 4 , 0 . 5 Hz , 1H ) , 7 . 43 ( q , J = 1 . 8 127 . 21 , 101 . 21 , 62 . 39 , 61 . 88 , 61 . 68 , 60 . 70 , 37 . 67 , 36 . 96 , Hz , 3H ) , 7 . 35 ( d , J = 16 . 0 Hz , 1H ) , 6 . 69 ( dd , J = 16 . 0 , 7 . 4 Hz , 15 . 34 , 15 . 25 ; EIMS m / z 387 . 1H ) .

6

CH3 H3C ???

US 9 , 795 , 140 B2 135 136

Step 2 : Triethoxymethane ( 31 . 4 g , 208 mmol ) and pyri ( E ) - 1 , 3 - Dichloro - 5 - ( 3 , 3 - diethoxyprop - 1 - en - 1 - yl ) - 2 din - 1 - ium 4 - methylbenzenesulfonate ( 0 . 528 g , 2 . 079 mmol ) methoxybenzene ( C153 ) were added to a stirred solution of ( E ) - 3 - ( 3 , 5 - dichlorophe nyl ) acrylaldehyde ( 44 g , 208 mmol ) in ethanol ( 416 mL ) . The resulting mixture was stirred at 20° C . for 20 hours . A solution of saturated aqueous sodium carbonate ( 50 mL ) was 0 CH3 added to the reaction mixture . The resulting mixture was concentrated at 45° C . to remove the ethanol . The concen trate was diluted with water and extracted with hexane . The organic layer was washed with brine , dried over sodium 10 sulfate , filtered and concentrated to afford the title product as a light yellow oil ( 56 . 13 g , 93 % ) : ' H NMR ( 400 MHz , CDC1z ) 87 . 25 ( dt , J = 10 . 6 , 1 . 9 Hz , 3H ) , 6 . 61 ( dd , J = 16 . 1 , 1 . 1 Hz , 1H ) , 6 . 22 ( dd , J = 16 . 1 , 4 . 7 Hz , 1H ) , 5 . 17 ( s , 1H ) , Jy 15 5 . 14 - 5 . 00 ( m , 1H ) , 3 . 78 - 3 . 49 ( m , 4H ) , 1 . 24 ( q , J = 7 . 2 Hz , 6H ) ; 13C NMR ( 101 MHz , CDC1z ) 139 . 34 , 135 . 14 , 130 . 27 , 129 . 88 , 127 . 71 , 125 . 08 , 100 . 60 , 61 . 20 , 15 . 25 . Isolated as a yellow oil ( 2 . 305 g , 56 % ) : ' H NMR ( 400

The following compounds were prepared in like manner MHz , CDC13 ) 87 . 32 ( s , 2H ) , 6 . 56 ( d , J = 16 . 0 Hz , 1H ) , 6 . 14 to the procedure outlined in Example 30 : 20 ( dd , J = 16 . 1 , 4 . 8 Hz , 1H ) , 5 . 05 ( dd , J = 4 . 8 , 1 . 0 Hz , 1H ) , 3 . 89

( s , 3H ) , 3 . 69 ( m , 2H ) , 3 . 55 ( m , 2H ) , 1 . 25 ( t , J = 7 . 1 Hz , 6H ) ; 13C NMR ( 101 MHz , CDC1z ) 151 . 75 , 133 . 87 , 129 . 87 , ( E ) - 1 , 2 - Dichloro - 4 - ( 3 , 3 - diethoxyprop - 1 - en - 1 - yl ) 129 . 45 , 128 . 85 , 126 . 91 , 100 . 68 , 61 . 14 , 60 . 73 , 15 . 24 ; EIMS benzene ( C151 ) m / z 304 .

25

( E ) - 2 - Chloro - 4 - ( 3 , 3 - diethoxyprop - 1 - en - 1 - yl ) - 1 - fluo robenzene ( C154 ) O CH3

30

CH3 0 CH2 H2

- CH3 ü 35

40

Isolated as an orange oil ( 142 g , 91 % ) : ' H NMR ( 300 MHz , CDC13 ) 8 7 . 48 ( d , J = 2 . 0 Hz , 1H ) , 7 . 39 ( dd , J = 8 . 3 , 0 . 8 10 Hz , 1H ) , 6 . 62 ( d , J = 16 . 1 Hz , 1H ) , 6 . 20 ( ddd , J = 16 . 1 , 4 . 9 , 0 . 8 Hz , 1H ) , 5 . 06 ( dt , J = 4 . 9 , 1 . 0 Hz , 1H ) , 3 . 78 - 3 . 48 ( m , 4H ) , Isolated as an orange oil ( 283 g , 84 % ) : ' H NMR ( 400 1 . 25 ( td , J = 7 . 1 , 0 . 8 Hz , 6H ) .

MHz , CDC13 ) 8 7 . 44 ( dd , J = 7 . 0 , 2 . 2 Hz , 1H ) , 7 . 29 - 7 . 22 ( m , ( E ) - 1 , 2 , 3 - Trichloro - 5 - ( 3 , 3 - diethoxyprop - 1 - en - 1 - yl ) 451H ) , 7 . 09 ( t , J = 8 . 7 Hz , 1H ) , 6 . 62 ( dd , J = 16 . 1 , 1 . 2 Hz , 1H ) ,

benzene ( C152 ) 6 . 14 ( dd , J = 16 . 1 , 5 . 0 Hz , 1H ) , 5 . 05 ( dd , v = 4 . 9 , 1 . 2 Hz , 1H ) , 3 . 70 ( dq , J = 9 . 3 , 7 . 0 Hz , 2H ) , 3 . 56 ( dq , J = 9 . 4 , 7 . 1 Hz , 2H ) , 1 . 25 ( t , J = 7 . 1 Hz , 6H ) ; 13C NMR ( 101 MHz , CDC13 ) S

50 158 . 91 , 156 . 42 , 133 . 65 , 133 . 62 , 130 . 47 , 128 . 65 , 128 . 07 , CH3 128 . 05 , 126 . 39 , 126 . 32 , 121 . 26 , 121 . 08 , 116 . 72 , 116 . 51 ,

100 . 93 , 61 . 17 , 15 . 24 ; 19F NMR ( 376 MHz , CDC12 ) 8 O CH3 - 116 . 36 .

55 In another preparation , isolated as a colorless oil ( 16 . 75 g , 64 % ) : ' H NMR ( 400 MHz , CDC1z ) 8 7 . 43 ( dd , J = 7 . 0 , 2 . 2 Hz , 1H ) , 7 . 25 ( m , 1H ) , 7 . 07 ( t , J = 8 . 7 Hz , 1H ) , 6 . 62 ( d , J = 16 . 1 Hz , 1H ) , 6 . 13 ( dd , J = 16 . 1 , 4 . 9 Hz , 1H ) , 5 . 05 ( dd , J = 4 . 9 , 1 . 0 Hz , 1H ) , 3 . 70 ( dq , J = 9 . 4 , 7 . 1 Hz , 2H ) , 3 . 56 ( dq ,

60 J = 9 . 4 , 7 . 0 Hz , 2H ) , 1 . 25 ( t , J = 7 . 1 Hz , 5H ) ; 13C NMR ( 101 MHz , CDC12 ) 8 158 . 91 , 156 . 42 , 133 . 65 , 133 . 62 , 130 . 47 ,

Isolated as an orange oil ( 40 g 91 % ) : 1H NMR ( 400 MHz 128 . 65 , 128 . 07 , 128 . 05 , 126 . 39 , 126 . 32 , 121 . 26 , 121 . 08 . CDC1 . ) 8 7 . 41 ( s . 21 ) . 6 . 58 ( dd . J = 161 . 1 . 2 Hz 11 ) . 6 . 21 116 . 72 , 116 . 51 , 100 . 93 , 61 . 17 , 15 . 24 ; 1°F NMR ( 376 MHz , ( dd , J = 16 . 1 , 4 . 6 Hz , 1H ) , 5 . 06 ( dd , J = 4 . 7 , 1 . 2 Hz , 1H ) , 3 . 69 65 . CDC13 ) 0 - 116 . 36 ; EIMS m / z 258 . ( dq , J = 9 . 3 , 7 . 1 Hz , 2H ) , 3 . 55 ( dq , J = 9 . 5 , 7 . 0 Hz , 2H ) , 1 . 25 The following compounds were prepared in like manner ( t , J = 7 . 1 Hz , 6H ) . to the procedures outlined in Examples 27 through 30 :

manner

US 9 , 795 , 140 B2 137 138

trans - 2 , 2 - dichloro - 3 - ( 3 , 4 - difluorophenyl ) cyclopro trans - 2 , 2 - Dichloro - 3 - ( 3 - fluoro - 4 - ( trifluoromethyl ) pane - 1 - carboxylic acid ( C124 ) phenyl ) cyclopropane - 1 - carboxylic acid ( C127 )

Ciclo Ci Ci

OH " ?? L

10 L

F 15

Isolated as a white solid ( 1 . 44 g , 67 % ) : ‘ H NMR ( 400 MHz , CDC12 ) 8 8 . 69 ( s , 1H ) , 7 . 18 ( dt , J = 9 . 9 , 8 . 3 Hz , 1H ) , Isolated as a waxy tan solid ( 4 . 09 g , 69 % ) : ' H NMR ( 400 7 . 10 ( ddd , J = 10 . 8 , 7 . 3 , 2 . 3 Hz , 1H ) , 7 . 01 ( ddt , J = 8 . 1 , 3 . 8 , 1 . 7 MHz , CDC1z ) 7 . 83 ( s , 1H ) , 7 . 63 ( t , J = 7 . 7 Hz , 1H ) , Hz , 1H ) , 3 . 44 ( dd , J = 8 . 4 , 1 . 0 Hz , 1H ) , 2 . 83 ( d , J = 8 . 3 Hz , 1H ) ; 19F NMR ( 376 MHz , CDC1z ) - 136 . 40 , - 136 . 46 , 20 20 7 . 23 - 7 . 04 ( m , 2H ) , 3 . 51 ( d , J = 8 . 3 Hz , 1H ) , 2 . 92 ( d , J = 8 . 3 Hz ,

1H ) ; 19F NMR ( 376 MHz , CDC13 ) 8 - 61 . 40 , - 61 . 43 , - 137 . 42 , - 137 . 48 ; ESIMS m / z 266 ( [ M - H ] ; ) . - 113 . 24 , - 113 . 27 ; ESIMS m / z 316 ( [ M - H ] ) .

trans - 3 - ( 3 - Bromo - 4 - chlorophenyl ) - 2 , 2 - dichlorocy clopropane - 1 - carboxylic acid ( C125 ) 25 trans - 3 - ( 4 - Bromo - 3 - fluorophenyl ) - 2 , 2 - dichlorocy

clopropane - 1 - carboxylic acid ( C128 )

30

??? ??? ??

35 Br

Isolated as a white solid ( 1 . 05 g , 63 % ) : ' H NMR ( 400 MHz , CDC13 ) 8 8 . 07 - 7 . 63 ( m , 1H ) , 7 . 58 - 7 . 42 ( m , 2H ) , 7 . 17 40 o Isolated as a white solid ( 0 . 41 g , 42 % ) : ' H NMR ( 400

MHz , CDC1z ) 8 8 . 04 ( s , 1H ) , 7 . 57 ( dd , J = 8 . 2 , 7 . 1 Hz , 1H ) , ( dd , J = 8 . 3 , 2 . 1 Hz , 1H ) , 3 . 43 ( d , J = 8 . 3 Hz , 1H ) , 2 . 86 ( d , J = 8 . 3 Hz , 1H ) ; 13C NMR ( 101 MHz , CDC13 ) 171 . 46 , 7 . 00 ( ddd , J = 33 . 6 , 8 . 7 , 2 . 1 Hz , 2H ) , 3 . 43 ( d , J = 8 . 3 Hz , 1H ) ,

2 . 85 ( d , J = 8 . 3 Hz , 1H ) ; 19F NMR ( 376 MHZ , CDC13 ) 8 134 . 71 , 133 . 88 , 132 . 43 , 130 . 42 , 128 . 70 , 122 . 73 , 77 . 33 , . - 106 . 06 ; ESIMS m / z 327 ( [ M - H ] ) ) . 77 . 22 , 77 . 01 , 76 . 69 , 61 . 51 , 39 . 50 , 37 . 21 ; ESIMS m / z 343 ( [ M - H ] ) .

trans - 3 - ( 3 - Bromo - 4 - ( trifluoromethyl ) phenyl ) - 2 , 2 trans - 2 , 2 - Dichloro - 3 - ( 3 , 4 - dibromophenyl ) cyclopro dichlorocyclopropane - 1 - carboxylic acid ( C129 )

pane - 1 - carboxylic acid ( C126 ) 50

Ciclo

OH 55

OH

Br

60

Isolated as a white solid ( 0 . 488 g , 57 % ) : ' H NMR ( 400 MHz , CDC13 ) 8 8 . 85 ( s , 1H ) , 7 . 77 - 7 . 47 ( m , 2H ) , 7 . 08 ( ddd , Isolated as a white solid ( 0 . 55 g , 54 % ) : 1H NMR ( 400 J = 8 . 3 , 2 . 1 , 0 . 7 Hz , 1H ) , 3 . 57 - 3 . 25 ( m , 1H ) , 2 . 86 ( d , J = 8 . 3 MHz , CDC1z ) 8 7 . 78 - 7 . 57 ( m , 2H ) , 7 . 42 - 7 . 29 ( m , 1H ) , 3 . 50 Hz , 1H ) ; 13C NMR ( 101 MHz , CDC13 ) d 171 . 54 , 133 . 82 , 65 ( d , J = 8 . 3 Hz , 1H ) , 2 . 93 ( d , J = 8 . 3 Hz , 1H ) ; 19F NMR ( 376 133 . 78 , 133 . 08 , 128 . 78 , 125 . 13 , 124 . 98 , 77 . 33 , 77 . 22 , 77 . 01 , MHz , CDC12 ) 8 - 62 . 66 , - 62 . 67 , - 62 . 81 ; ESIMS m / z 377 76 . 70 , 61 . 41 , 39 . 59 , 37 . 14 , 0 . 01 ; ESIMS m / z 387 ( [ M - H ] ) . ( [ M - H ] ) .

( IM - PCI , ) ) , 2 . 93 )

US 9 , 795 , 140 B2 139 140

trans - 3 - ( 4 - Bromo - 3 - ( trifluoromethyl ) phenyl ) - 2 , 2 trans - 3 - ( 3 - Bromo - 4 - fluorophenyl ) - 2 , 2 - dichlorocy dichlorocyclopropane - 1 - carboxylic acid ( C130 ) clopropane - 1 - carboxylic acid ( C133 ) hogy te is engenvon 23

Clo Ciclo F

OH OH 10

Ty

15

20

Isolated as a white solid ( 1 . 21 g , 51 % ) : ' H NMR ( 400 MHz , CDC13 ) 8 10 . 87 ( s , 1H ) , 7 . 74 ( d , J = 8 . 3 Hz , 1H ) , 7 . 58 Isolated as a white solid ( 0 . 850 g , 44 % ) : ' H NMR ( 400 ( d , J = 2 . 2 Hz , 1H ) , 7 . 30 ( dd , J = 8 . 3 , 2 . 2 Hz , 1H ) , 3 . 49 ( d , MHz , CDC1 _ ) 8 8 . 47 ( s , 1H ) , 7 . 47 ( ddd , J = 6 . 3 , 2 . 3 , 0 . 7 Hz , J = 8 . 3 Hz , 1H ) , 2 . 91 ( d , J = 8 . 3 Hz , 1H ) ; 19F NMR ( 376 MHz , 1H ) , 7 . 32 - 7 . 08 ( m , 2H ) , 3 . 44 ( dd , J = 8 . 3 , 1 . 0 Hz , 1H ) , 2 . 84 CDC1z ) 8 - 62 . 77 , - 62 . 78 ; ESIMS m / z 377 ( [ M - H ] ; ) . 40 ( d , J = 8 . 3 Hz , 1H ) ; 19F NMR ( 376 MHz , CDC13 ) 8 - 107 . 16 ;

ESIMS m / z 327 ( [ M - H ] ) ) . trans - 2 , 2 - Dichloro - 3 - ( 3 - chloro - 4 - ( trifluoromethyl ) phenyl ) cyclopropane - 1 - carboxylic acid ( C131 ) trans - 2 , 2 - Dichloro - 3 - ( 4 - fluoro - 3 - ( trifluoromethyl )

phenyl ) cyclopropane - 1 - carboxylic acid ( C134 ) 25

Ciclo Ciclo

30

OH poleksi OH

F

35 F

Isolated as a white solid ( 0 . 778 g , 43 % ) : ' H NMR ( 400 40 Isolated as a white solid ( 3 . 08 g , 67 % ) : ' H NMR ( 400 MHz , CDC1z ) 9 . 72 ( s , 1H ) , 7 . 71 ( d , J = 8 . 2 Hz , 1H ) , MHz , CDC1z ) 8 8 . 18 ( s , 1H ) , 7 . 64 - 7 . 39 ( m , 2H ) , 7 . 24 ( t , 7 . 53 - 7 . 39 ( m , 1H ) , 7 . 35 - 7 . 19 ( m , 1H ) , 3 . 50 ( d , J = 8 . 3 Hz , J = 9 . 3 Hz , 1H ) , 3 . 50 ( dd , J = 8 . 4 , 1 . 0 Hz , 1H ) , 2 . 89 ( d , J = 8 . 3 1H ) , 2 . 93 ( d , J = 8 . 3 Hz , 1H ) ; 19F NMR ( 376 MHz , CDC13 ) Hz , 1H ) ; 19F NMR ( 376 MHz , CDC13 ) 8 - 61 . 48 , - 61 . 51 , 8 - 62 . 63 ; ESIMS m / z 332 ( [ M - H ] ) ) . - 114 . 23 , - 114 . 26 , - 114 . 29 ; ESIMS m / z 316 ( [ M - H ] ; ) . 714 . 23 45 trans - 2 , 2 - Dichloro - 3 - ( 4 - chloro - 3 - ( trifluoromethyl ) phenyl ) cyclopropane - 1 - carboxylic acid ( C132 ) trans - 2 , 2 - Dichloro - 3 - ( 4 - chloro - 3 - fluorophenyl ) cy

clopropane - 1 - carboxylic acid ( C135 )

50

CICLO Ciclo F

F tish . Tot ?? H

F 55

60

Isolated as a white solid ( 2 . 02 g , 43 % ) : ' H NMR ( 400 Isolated as a white solid ( 0 . 96 g , 36 % ) : 1H NMR ( 400 MHz , CDC13 ) 8 7 . 96 - 7 . 51 ( m , 3H ) , 7 . 39 ( dd , J = 8 . 3 , 2 . 2 Hz , MHz , CDC13 ) 8 11 . 57 ( s , 1H ) , 7 . 42 ( dd , J = 8 . 2 , 7 . 6 Hz , 1H ) , 1H ) , 3 . 50 ( d , J = 8 . 3 Hz , 1H ) , 2 . 90 ( d , J = 8 . 3 Hz , 1H ) ; 19F 65 7 . 11 - 6 . 98 ( m , 2H ) , 3 . 46 ( d , J = 8 . 2 Hz , 1H ) , 2 . 85 ( d , J = 8 . 3 Hz , NMR ( 376 MHz , CDC13 ) 8 - 62 . 75 , - 62 . 75 ; ESIMS m / z 332 1H ) ; 19F NMR ( 376 MHz , CDC1z ) - 114 . 07 ; ESIMS m / z ( [ M - H ] ) . 282 ( [ M - H ] ) .

US 9 , 795 , 140 B2 141 142

trans - 2 , 2 - Dichloro - 3 - ( 3 , 5 - difluorophenyl ) cyclopro trans - 3 - ( 3 - Bromo - 5 - ( trifluoromethyl ) phenyl ) - 2 , 2 pane - 1 - carboxylic acid ( C136 ) dichlorocyclopropane - 1 - carboxylic acid ( C139 )

u

CI Clo Ciclo

F OH Br ?

TV F ?

Isolated as a clear colorless oil ( 1 . 55 g , 29 % ) : ' H NMR ( 400 MHz , CDC13 ) d 10 . 44 ( s , 1H ) , 6 . 82 ( qd , J = 6 . 4 , 2 . 3 Hz , 3H ) , 3 . 44 ( d , J = 8 . 3 Hz , 1H ) , 2 . 86 ( d , J = 8 . 3 Hz , 1H ) ; 1°F 20 Isolated as a tan solid ( 0 . 375 g , 31 % ) : ' H NMR ( 400 NMR ( 376 MHz , CDC1z ) - 108 . 49 , - 108 . 69 , - 108 . 82 , MHz , CDC13 ) 8 10 . 52 ( s , 1H ) , 7 . 77 ( s , 1H ) , 7 . 62 ( d , J = 1 . 8 - 109 . 85 ; ESIMS m / z 266 ( [ M - H ] ) . Hz , 1H ) , 7 . 46 ( s , 1H ) , 3 . 52 ( d , J = 8 . 2 Hz , 1H ) , 2 . 93 ( d , J = 8 . 3

Hz , 1H ) ; 1°F NMR ( 376 MHz , CDC1z ) 8 - 62 . 84 ; ESIMS m / z 377 ( [ M - H ] ; ) . trans - 2 , 2 - Dichloro - 3 - ( 3 - fluoro - 5 - ( trifluoromethyl )

phenyl ) cyclopropane - 1 - carboxylic acid ( C137 ) Example 31

25

C1 Clo 30 Preparation of trans - 2 , 2 - dibromo - 3 - ( 3 , 5 - dichloro phenyl ) cyclopropane - 1 - carboxylic acid ( C155 )

OH

Br Bro 35

OH

F F 40

Isolated as a white solid ( 3 . 7 g , 55 % ) : ' H NMR ( 400 MHz , CDC13 ) 11 . 40 ( s , 1H ) , 7 . 42 - 7 . 27 ( m , 2H ) , 7 . 20 ( dt , J = 8 . 9 , 2 . 0 Hz , 1H ) , 3 . 53 ( d , J = 8 . 3 Hz , 1H ) , 2 . 93 ( d , J = 8 . 3 Hz , 1H ) ; 19F NMR ( 376 MHz , CDC1z ) 8 - 62 . 86 , - 109 . 49 ; ESIMS m / z 316 ( [ M - H ] ) . 45

OH 55

trans - 3 - ( 3 - Bromo - 5 - fluorophenyl ) - 2 , 2 - dichlorocy To a solution of trans - 2 , 2 - dibromo - 3 - ( 3 , 5 - dichlorophe nyl ) cyclopropane - 1 - carbaldehyde ( C156 ) ( 1 . 67 g , 4 . 48 clopropane - 1 - carboxylic acid ( C138 ) mmol ) in acetonitrile ( 15 . 36 mL ) and water ( 2 . 5 mL ) was

50 added sodium hydrogen sulfite ( 3 . 26 g , 31 . 36 mmol ) . The resultant solution was cooled to 0° C . , sodium chlorite ( 3 . 54

ciclo g , 17 . 92 mmol ) was added slowly , and the solution was stirred for overnight while slowly warming to room tem perature . The mixture was then diluted with aqueous hydro chloric acid solution ( 1 N ) until the pH was equal to or less than 3 . The mixture was then repeatedly extracted with ethyl acetate . The combined organic extracts were dried over sodium sulfate , filtered and concentrated under vacuum . Purification of the crude solid by flash column chromatog raphy with 0 - 100 % ethyl acetate / hexanes as eluent provided the title compound as a light brown solid ( 0 . 91 g , 52 % ) : ' H

Isolated as a white solid ( 0 . 76 g , 47 % ) : ' H NMR ( 400 NMR ( 400 MHz , CDC12 ) 87 . 36 ( t , J = 1 . 9 Hz , 1H ) , 7 . 17 ( dd , MHz , CDC1z ) 8 11 . 06 ( s , 1H ) , 7 . 36 - 7 . 14 ( m , 2H ) , 7 . 03 - 6 . 87 J = 1 . 9 , 0 . 8 Hz , 2H ) , 3 . 39 ( d , J = 8 . 2 Hz , 1H ) , 2 . 91 ( d , J = 8 . 2 ( m , 1H ) , 3 . 45 ( d , J = 8 . 3 Hz , 1H ) , 2 . 87 ( d , J = 8 . 3 Hz , 1H ) ; 1°F 65 Hz , 1H ) ; 13C NMR ( 101 MHz , CDC1 ) 8 172 . 15 , 136 . 91 , NMR ( 376 MHz , CDC1z ) 8 - 109 . 73 , - 109 . 73 ; ESIMS m / z 135 . 25 , 128 . 64 , 127 . 29 , 40 . 29 , 37 . 32 , 26 . 57 ; ESIMS m / z 327 ( [ M - H ] ) . 386 ( M - H ] ) ) .

Br

US 9 , 795 , 140 B2 143 144

Example 32 ( 100 mL ) and washed with aqueous hydrochloric acid ( 1 N , 10 mL ) and brine ( 30 mL ) . The organic layer was dried over

Preparation of trans - 2 , 2 - dibromo - 3 - ( 3 , 5 - dichloro sodium sulfate , filtered and concentrated to afford the title phenyl ) cyclopropane - 1 - carbaldehyde ( C156 ) product as a white solid ( 10 . 33 g , 88 % enantiomeric excess

5 “ ee ” ) . 2nd resolution : ( R ) - 1 - Phenylethanamine ( 3 . 4 g , 28 mmol )

Br . Bro . was slowly added to a stirred solution of rac - 2 , 2 - dichloro 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - carboxylic acid )

10 ( 10 . 33 g , 88 % ee ) in acetone ( 100 mL ) . After 2 hours , a solid was collected , washed with minimal cold acetone and dried . The solid was treated with aqueous hydrochloric acid to afford the title compound as a white solid ( 7 . 84 g , 97 % ee , 24 . 2 % ) : Specific Rotation : + 47 . 4 ( 10 mg / mL in acetonitrile ,

15 589 nm , 25 . 2° C . ) ; ' H NMR ( 300 MHz , CDC1z ) 8 7 . 36 ( t , J = 1 . 9 Hz , 1H ) , 7 . 17 ( dd , J = 1 . 9 , 0 . 7 Hz , 2H ) , 3 . 48 - 3 . 37 ( m , 1H ) , 2 . 87 ( d , J = 8 . 3 Hz , 1H ) ; 13C NMR ( 400 MHz , DMSO

To a solution of ( E ) - 1 , 3 - dichloro - 5 - ( 3 , 3 - diethoxyprop - 1 do ) d 166 . 28 , 136 . 40 , 133 . 39 , 127 . 27 , 127 . 04 , 61 . 36 , 37 . 10 , en - 1 - yl ) benzene ( C150 ) ( 0 . 500 g , 1 . 817 mmol ) in bromo form ( 12 . 1 mL ) were added tetrabutylammonium hexafluo - 20 ee was determined by Chiral HPLC method as follows : rophosphate ( V ) ( 70 . 4 mg , 0 . 182 mmol ) followed by the Column : CHIRALPAK© ZWIX ( + ) , particle size 3 um , careful addition of solid sodium hydroxide ( 1454 mg , 36 . 3 dimension 3 mmx150 mm , DAIC 511584 ; Mobile phase : mmol ) . The mixture was heated to 90° C . while stirring 49 % acetonitrile / 49 % methanol / water with 50 mM formic overnight . The mixture was diluted with dichloromethane acid and diethylamine ; Flow rate : 0 . 5 mL / min ; Time : 9 min ; and water and was extracted with additional dichlorometh - 25 Temperature : 25° C . ane . The organic layer was then dried over sodium sulfate , filtered , and concentrated . Purification by flash column The following compounds were prepared in like manner chromatography using 0 - 100 % ethyl acetate / hexanes as elu - to the procedure outlined in Example 33 : ent provided an elutant which was then dissolved in acetone ( 4 mL ) and aqueous hydrochloric acid ( 2 N ) ( 1 mL , 2 mmol ) . 30 ( 1R , 3R ) - 2 , 2 - Dichloro - 3 - ( 3 , 4 - dichlorophenyl ) cyclo The mixture was stirred overnight . The mixture was diluted propane - 1 - carboxylic acid ( C158 ) with saturated sodium bicarbonate solution until the pH was greater than 7 . The mixture was then extracted with diethyl ether and ethyl acetate , and the combined organic layers were dried over sodium sulfate and concentrated providing 35 Ci Cic the dark brown product ( 0 . 03 g , 4 % ) : ' H NMR ( 400 MHz , CDC13 ) 89 . 48 ( d , J = 4 . 0 Hz , 1H ) , 7 . 37 ( t , J = 1 . 9 Hz , 1H ) , 7 . 17 ( dd , J = 1 . 9 , 0 . 7 Hz , 2H ) , 3 . 60 - 3 . 36 ( m , 1H ) , 2 . 90 ( dd , J = 7 . 9 , L UR ( R ) ( R ) 4 . 0 Hz , 1H ) ; 13C NMR ( 101 MHz , CDC12 ) 8 194 . 74 , 136 . 55 , 135 . 31 , 128 . 76 , 127 . 34 , 42 . 34 , 39 . 84 , 26 . 05 ; ESIMS m / z 40 343 ( [ M - CHO ] ) .

OH

Example 33

45 Preparation of ( 1R , 3R ) - 2 , 2 - dichloro - 3 - ( 3 , 5 - dichlo rophenyl ) - cyclopropane - 1 - carboxylic acid ( C157 ) Isolated as a white solid ( 6 . 7 g , 30 % , 96 % ee ) . Analytical

data are consistent with racemic acid C3 .

CI cl 50 50 ( 1R , 3R ) - 2 , 2 - Dichloro - 3 - ( 3 - chloro - 4 - fluorophenyl ) cyclopropane - 1 - carboxylic acid ( C159 )

OH VIDEO ( R ) ( R )

55

CI OH DURO " ( R ) ( R )

1st resolution : ( R ) - 1 - Phenylethanamine ( 6 . 49 g , 53 . 0 60 mmol ) was slowly added to a stirred solution of rac - 2 , 2 dichloro - 3 - ( 3 , 5 - dichlorophenyl ) cyclopropane - carboxylic acid ) ( 32 . 45 g , 106 mmol ) in acetone ( 106 mL ) . The resulting solution was stirred at 45° C . After a solid began to deposit , the mixture was placed at 5° C . for 4 hours . The 65 solid was collected , washed with minimal cold acetone and dried . The white solid salt was diluted with ethyl acetate

Isolated as a white solid ( 0 . 5 g , 13 % , 99 % ee ) . Analytical data are consistent with racemic acid C16 .

US 9 , 795 , 140 B2 145 146

( 1R , 3R ) - 2 , 2 - Dichloro - 3 - ( 3 , 4 , 5 - trichlorophenyl ) cy ( 1S , 3S ) - 2 , 2 - Dichloro - 3 - ( 3 , 4 - dichlorophenyl ) cyclo clopropane - 1 - carboxylic acid ( C160 ) propane - 1 - carboxylic acid ( C162 )

ciclo CI Clo

?? ?? * 111 ( R ) ( R ) ( S ) ( 5 ) 10

Isolated as a as a white solid ( 7 g , 35 % , 98 % ee ) . 15 Analytical data are consistent with racemic acid C3 .

Both the bulsaras en gran nombor teleserye non se renginiai gali

( 18 , 3S ) - 2 , 2 - Dichloro - 3 - ( 3 - chloro - 4 - fluorophenyl ) cyclopropane - 1 - carboxylic acid ( C163 ) Isolated as a white solid ( 2 g , 29 % , 99 % ee ) . Analytical

data are consistent with racemic acid C2 . 20

CI Clo Example 34

25 OH ( 1S , 3S ) - 2 , 2 - Dichloro - 3 - ( 3 , 5 - dichlorophenyl ) - cyclo - propane - 1 - carboxylic acid ( C161 )

F

?? ?? 30 Isolated as a white solid ( 0 . 64 g , 27 % , 98 % ee ) . Analytical data are consistent with racemic acid C16 .

?? ( 1S , 3S ) - 2 , 2 - Dichloro - 3 - ( 3 , 4 , 5 - trichlorophenyl ) cyclo propane - 1 - carboxylic acid ( C164 )

?? ??

OH

The mother liquor from the 1st R , R - acid resolution ( from Example 33 ) was concentrated and dissolved in acetone ( ~ 100 mL ) and warmed to 45° C . With swirling , ( S ) - 1 - 45 phenylethanamine ( 5 . 0 g , 41 . 2 mmol , 0 . 8 eq ) was added . The resulting solution was stirred at 45° C . After a solid began to deposit , the mixture was placed at 5° C . for 2 hours . Isolated as a white solid ( 0 . 75 g , 41 % , 99 % ee ) . Analytical A solid was collected , washed with minimal cold acetone data are consistent with racemic acid C2 . and vacuum - dried at 35° C . The solid was treated with 50 It is recognized that some reagents and reaction condi aqueous hydrochloric acid to provide the free 5 , 5 - acid as a tions may not be compatible with certain functionalities that white solid ( 9 . 87 g , 59 % , 85 % ee ) . A second resolution of may be present in certain molecules of Formula One or the 85 % ee combined 5 , 5 - acid ( 13 . 45 g , 41 . 7 mmol , 85 % ee ) certain molecules used in the preparation of certain mol using the same procedure with ( S ) - 1 - phenylethanamine ( 3 . 8 ecules of Formula One . In such cases , it may be necessary g , 31 . 3 mmol , 0 . 75 eq ) provided the 5 , 5 - acid as a white solid 55 to employ standard protection and deprotection protocols ( 8 . 53 g , 26 % , 99 % ee ) . Specific Rotation : - 51 . 9 ( 10 mg / mL comprehensively reported in the literature and well known in acetonitrile , 589 nm , 25 . 2° C . ) . Analytical data are con to a person skilled in the art . In addition , in some cases it sistent with racemic acid Ci may be necessary to perform further routine synthetic steps

not described herein to complete the synthesis of desired ee was determined by Chiral HPLC method as follows : 60 molecules . A person skilled in the art will also recognize that

Column : CHIRALPAK© ZWIX ( + ) , particle size 3 um , it may be possible to achieve the synthesis of desired dimension 3 mmx150 mm , DAIC 511584 ; Mobile phase : molecules by performing some of the steps of the synthetic 49 % acetonitrile / 49 % methanol / water with 50 mM formic routes in a different order to that described . A person skilled acid and diethylamine ; Flow rate : 0 . 5 mL / min ; Time : 9 min ; in the art will also recognize that it may be possible to Temperature : 25° C . 65 perform standard functional group interconversions or sub

The following compounds were prepared in like manner stitution reactions on desired molecules to introduce or to the procedure outlined in Example 34 : modify substituents .

15 15

US 9 , 795 , 140 B2 147 148

Biological Assays in each well ( 3 mL ) of the diet tray that had been previously The following bioassays against Beet Armyworm filled with 1 mL of artificial diet to which 50 ug / cm² of the

( Spodoptera exigua ) , Cabbage Looper ( Trichoplusia ni ) , test molecule ( dissolved in 50 uL of 90 : 10 acetone - water Green Peach Aphid ( Myzus persicae ) , and Yellow Fever mixture ) had been applied ( to each of eight wells ) and then Mosquito ( Aedes aegypti ) , are included herein due to the 5 allowed to dry . Trays were covered with a clear self damage they inflict . Furthermore , the Beet Armyworm and adhesive cover , vented to allow gas exchange , and held at Cabbage Looper are two good indicator species for a broad 25° C . , 14 : 10 light - dark for five to seven days . Percent range of chewing pests . Additionally , the Green Peach Aphid itionally , the Green Peach Aphid mortality was recorded for the larvae in each well ; activity is a good indicator species for a broad range of sap - feeding in the eight wells was then averaged . The results are indi pests . The results with these three indicator species along 10 cated in the table entitled " Table ABC : Biological Results " with the Yellow Fever Mosquito show the broad usefulness ness ( See Table Section ) . of the molecules of Formula One in controlling pests in Phyla Arthropoda , Mollusca , and Nematoda ( Drewes et al . ) Example B

Example A Bioassays on Green Peach Aphid ( Myzus persicae , Bioassays on Beet Armyworm ( Spodoptera exigua , MYZUPE ) ( “ GPA " )

LAPHEG ) ( “ BAW ” ) , and Cabbage Looper ( Trichoplusia ni , TRIPNI ) ( “ CL ” ) GPA is the most significant aphid pest of peach trees ,

20 causing decreased growth , shriveling of the leaves , and the Beet armyworm is a serious pest of economic concern for death of various tissues . It is also hazardous because it acts

alfalfa , asparagus , beets , citrus , corn , cotton , onions , peas , as a vector for the transport of plant viruses , such as potato peppers , potatoes , soybeans , sugar beets , sunflowers , virus Y and potato leafroll virus to members of the night tobacco , and tomatoes , among other crops . It is native to shade / potato family Solanaceae , and various mosaic viruses Southeast Asia but is now found in Africa , Australia , Japan , 25 to many other food crops . GPA attacks such plants as North America , and Southern Europe . The larvae may feed broccoli , burdock , cabbage , carrot , cauliflower , daikon , egg in large swarms causing devastating crop losses . It is known plant , green beans , lettuce , macadamia , papaya , peppers , to be resistant to several pesticides . sweet potatoes , tomatoes , watercress , and zucchini , among

Cabbage looper is a serious pest found throughout the other crops . GPA also attacks many ornamental crops such world . It attacks alfalfa , beans , beets , broccoli , Brussel 30 as carnation , chrysanthemum , flowering white cabbage , sprouts , cabbage , cantaloupe , cauliflower , celery , collards , poinsettia , and roses . GPA has developed resistance to many cotton , cucumbers , eggplant , kale , lettuce , melons , mustard , pesticides . Currently , it is a pest that has the third largest parsley , peas , peppers , potatoes , soybeans , spinach , squash , number of reported cases of insect resistance ( Sparks et al . ) . tomatoes , turnips , and watermelons , among other crops . Consequently , because of the above factors control of this This species is very destructive to plants due to its voracious 35 appetite . The larvae consume three times their weight in pest is important . Furthermore , molecules that control this

pest ( GPA ) , which is known as a sap - feeding pest , are useful food daily . The feeding sites are marked by large accumu lations of sticky , wet , fecal material , which may contribute in controlling other pests that feed on the sap from plants .

Certain molecules disclosed in this document were tested to higher disease pressure thereby causing secondary prob lems on the plants in the site . It is known to be resistant to 40 against GPA using procedures described in the following several pesticides . example . In the reporting of the results , the “ GPA & YFM

Consequently , because of the above factors control of Rating Table ” was used ( See Table Section ) . these pests is important . Furthermore , molecules that control Cabbage seedlings grown in 3 - inch pots , with 2 - 3 small these pests ( BAW and CL ) , which are known as chewing ( 3 - 5 cm ) true leaves , were used as test substrate . The pests , will be useful in controlling other pests that chew on 45 seedlings were infested with 20 - 50 GPA ( wingless adult and plants . nymph stages ) one day prior to chemical application . Four

Certain molecules disclosed in this document were tested pots with individual seedlings were used for each treatment . against BAW and CL using procedures described in the Test molecules ( 2 mg ) were dissolved in 2 mL of acetone / following examples . In the reporting of the results , the methanol ( 1 : 1 ) solvent , forming stock solutions of 1000 ppm “ BAW & CL Rating Table ” was used ( See Table Section ) . 50 test molecule . The stock solutions were diluted 5x with Bioassays on BAW 0 . 025 % Tween 20 in water to obtain the solution at 200 ppm

Bioassays on BAW were conducted using a 128 - well diet test molecule . A hand - held aspirator - type sprayer was used tray assay . One to five second instar BAW larvae were for spraying a solution to both sides of cabbage leaves until placed in each well ( 3 mL ) of the diet tray that had been runoff . Reference plants ( solvent check ) were sprayed with previously filled with approximately 1 . 5 mL of artificial diet 55 the diluent only containing 20 % by volume of acetone / to which 50 ug / cm² of the test molecule ( dissolved in 50 uL methanol ( 1 : 1 ) solvent . Treated plants were held in a holding of 90 : 10 acetone - water mixture ) had been applied ( to each room for three days at approximately 25° C . and ambient of eight wells ) and then allowed to dry . Trays were covered relative humidity ( RH ) prior to grading . Evaluation was with a clear self - adhesive cover , vented to allow gas conducted by counting the number of live aphids per plant exchange , and held at 25° C . , 14 : 10 light - dark for five to 60 under a microscope . Percent control was measured using seven days . Percent mortality was recorded for the larvae in Abbott ' s correction formula ( W . S . Abbott , “ A Method of each well , activity in the eight wells was then averaged . The Computing the Effectiveness of an Insecticide ” J . Econ . results are indicated in the table entitled “ Table ABC : Entomol . 18 ( 1925 ) , pp . 265 - 267 ) as follows . Corrected % Biological Results ” ( See Table Section ) . Control = 100 * ( X - Y ) / X where X = No . of live aphids on Bioassays on CL 65 solvent check plants and Y = No . of live aphids on treated

Bioassays on CL were conducted using a 128 - well diet plants . The results are indicated in the table entitled “ Table tray assay , one to five second instar CL larvae were placed ABC : Biological Results ” ( See Table Section ) .

Pos

US 9 , 795 , 140 B2 149 150

Example C derivative may be prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt . A free

Bioassays on Yellow Fever Mosquito ( Aedes base may be regenerated by treating the salt with a suitable aegypti , AEDSAE ) ( “ YFM ” ) dilute aqueous base solution such as dilute aqueous sodium

5 hydroxide , potassium carbonate , ammonia , and sodium YFM prefers to feed on humans during the daytime and bicarbonate . As an example , in many cases , a pesticide , such

is most frequently found in or near human habitations . YFM as 2 , 4 - D , is made more water - soluble by converting it to its is a vector for transmitting several diseases . It is a mosquito dimethylamine salt . that can spread the dengue fever and yellow fever viruses . Molecules of Formula One may be formulated into stable Yellow fever is the second most dangerous mosquito - borne 10 complexes with a solvent , such that the complex remains disease after malaria . Yellow fever is an acute viral hemor - intact after the non - complexed solvent is removed . These rhagic disease and up to 50 % of severely affected persons complexes are often referred to as " solvates . ” However , it is without treatment will die from yellow fever . There are an particularly desirable to form stable hydrates with water as estimated 200 , 000 cases of yellow fever , causing 30 , 000 the solvent . deaths worldwide each year . Dengue fever is a nasty , viral 15 Molecules of Formula One containing an acid function disease ; it is sometimes called “ breakbone fever ” or “ break - ality may be made into ester derivatives . These ester deriva heart fever ” because of the intense pain it can produce . tives can then be applied in the same manner as the mol Dengue fever kills about 20 , 000 people annually . Conse - ecules disclosed in this document are applied . quently , because of the above factors control of this pest is Molecules of Formula One may be made as various important . Furthermore , molecules that control this pest 20 crystal polymorphs . Polymorphism is important in the ( YFM ) , which is known as a sucking pest , are useful in development of agrochemicals since different crystal poly controlling other pests that cause human and animal suffer morphs or structures of the same molecule can have vastly ing . different physical properties and biological performances .

Certain molecules disclosed in this document were tested Molecules of Formula One may be made with different against YFM using procedures described in the following 25 isotopes . Of particular importance are molecules having 2H paragraph . In the reporting of the results , the “ GPA & YFM ( also known as deuterium ) or H ( also known as tritium ) in Rating Table ” was used ( See Table Section ) . place of ' H . Molecules of Formula One may be made with Master plates containing 400 ug of a molecule dissolved different radionuclides . Of particular importance are mol

in 100 uL of dimethyl sulfoxide ( DMSO ) ( equivalent to a ecules having 14C ( also known as radiocarbon ) . Molecules 4000 ppm solution ) are used . A master plate of assembled 30 of Formula One having deuterium , tritium , or 14C may be molecules contains 15 uL per well . To this plate , 135 uL of used in biological studies allowing tracing in chemical and a 90 : 10 water / acetone mixture is added to each well . A robot physiological processes and half - life studies , as well as , is programmed to dispense 15 uL aspirations from the MoA studies . master plate into an empty 96 - well shallow plate ( “ daugh - Combinations ter ” plate ) . There are 6 reps ( “ daughter ” plates ) created per 35 In another embodiment of this invention , molecules of master . The created “ daughter ” plates are then immediately Formula One may be used in combination ( such as , in a infested with YFM larvae . compositional mixture , or a simultaneous or sequential

The day before plates are to be treated , mosquito eggs are application ) with one or more active ingredients . placed in Millipore water containing liver powder to begin In another embodiment of this invention , molecules of hatching ( 4 g . into 400 mL ) . After the “ daughter ” plates are 40 Formula One may be used in combination ( such as , in a created using the robot , they are infested with 220 uL of the compositional mixture , or a simultaneous or sequential liver powder / larval mosquito mixture ( about 1 day - old lar - application ) with one or more active ingredients each having vae ) . After plates are infested with mosquito larvae , a a MoA that is the same as , similar to , but more likely — non - evaporative lid is used to cover the plate to reduce different from , the MoA of the molecules of Formula One . drying . Plates are held at room temperature for 3 days prior 45 In another embodiment , molecules of Formula One may to grading . After 3 days , each well is observed and scored be used in combination ( such as , in a compositional mixture , based on mortality . The results are indicated in the table or a simultaneous or sequential application ) with one or entitled “ Table ABC : Biological Results ” ( See Table Sec - more molecules having acaricidal , algicidal , avicidal , bac tion ) . tericidal , fungicidal , herbicidal , insecticidal , molluscicidal , Agriculturally Acceptable Acid Addition Salts , Salt Deriva - 50 nematicidal , rodenticidal , and / or virucidal properties . tives , Solvates , Ester Derivatives , Polymorphs , Isotopes , and in another embodiment , the molecules of Formula One Radionuclides may be used in combination ( such as , in a compositional

Molecules of Formula One may be formulated into agri - mixture , or a simultaneous or sequential application ) with culturally acceptable acid addition salts . By way of a non - one or more molecules that are antifeedants , bird repellents , limiting example , an amine function can form salts with 55 chemosterilants , herbicide safeners , insect attractants , insect hydrochloric , hydrobromic , sulfuric , phosphoric , acetic , repellents , mammal repellents , mating disrupters , plant acti benzoic , citric , malonic , salicylic , malic , fumaric , oxalic , vators , plant growth regulators , and / or synergists , succinic , tartaric , lactic , gluconic , ascorbic , maleic , aspartic , In another embodiment , molecules of Formula One may benzenesulfonic , methanesulfonic , ethanesulfonic , also be used in combination ( such as in a compositional hydroxyl - methanesulfonic , and hydroxyethanesulfonic 60 mixture , or a simultaneous or sequential application ) with acids . Additionally , by way of a non - limiting example , an one or more biopesticides . acid function can form salts including those derived from In another embodiment , in a pesticidal composition com alkali or alkaline earth metals and those derived from binations of a molecule of Formula One and an active ammonia and amines . Examples of preferred cations include ingredient may be used in a wide variety of weight ratios . sodium , potassium , and magnesium . 65 For example , in a two - component mixture , the weight ratio

Molecules of Formula One may be formulated into salt of a molecule of Formula One to an active ingredient , the derivatives . By way of a non - limiting example , a salt weight ratios in Table B may be used . However , in general ,

151 US 9 , 795 , 140 B2

152 weight ratios less than about 10 : 1 to about 1 : 10 are pre water - immiscible organic solvent and emulsifiers . Useful ferred . It is also preferred sometimes to use a three , four , organic solvents include aromatics , especially xylenes and five , six , seven , or more , component mixture comprising a petroleum fractions , especially the high - boiling naphtha molecule of Formula One and an additional two or more lenic and olefinic portions of petroleum such as heavy active ingredients . 5 aromatic naphtha . Other organic solvents may also be used ,

Weight ratios of a molecule of Formula One to an active such as the terpenic solvents including rosin derivatives , ingredient may also be depicted as X : Y ; wherein X is the aliphatic ketones such as cyclohexanone , and complex alco parts by weight of a molecule of Formula One and Y is the hols such as 2 - ethoxyethanol . Suitable emulsifiers for emul parts by weight of active ingredient . The numerical range of sifiable concentrates are selected from conventional anionic the parts by weight for Xis ( < Xs100 and the parts by weight 10 and non - ionic surfactants . for Y is 0 < Ys100 and is shown graphically in TABLE C . By Aqueous suspensions comprise suspensions of water way of non - limiting example , the weight ratio of a molecule insoluble pesticides dispersed in an aqueous carrier at a of Formula One to an active ingredient may be 20 : 1 . concentration in the range from about 5 % to about 50 % by

Ranges of weight ratios of a molecule of Formula One to weight . Suspensions are prepared by finely grinding the an active ingredient may be depicted as X : Y , to X , Y , , 15 pesticide and vigorously mixing it into a carrier comprised wherein X and Y are defined as above . of water and surfactants . Ingredients , such as inorganic salts

In one embodiment , the range of weight ratios may be and synthetic or natural gums may , also be added to increase X? : Y1 to X2 : Y2 , wherein X , > Y1 and X _ < Y2 . By way of the density and viscosity of the aqueous carrier . It is often non - limiting example , the range of a weight ratio of a most effective to grind and mix the pesticide at the same molecule of Formula One to an active ingredient may be 20 time by preparing the aqueous mixture and homogenizing it between 3 : 1 and 1 : 3 , inclusive of the endpoints in an implement such as a sand mill , ball mill , or piston - type

In another embodiment , the range of weight ratios may be homogenizer . The pesticide in suspension might be micro X : Y , to X2 : Y2 , wherein X , > Y , and X2 > Y2 . By way of encapsulated in plastic polymer . non - limiting example , the range of weight ratio of a mol Oil dispersions ( OD ) comprise suspensions of organic ecule of Formula One to an active ingredient may be 25 solvent - insoluble pesticides finely dispersed in a mixture of between 15 : 1 and 3 : 1 , inclusive of the endpoints . organic solvent and emulsifiers at a concentration in the

In another embodiment , the range of weight ratios may be range from about 2 % to about 50 % by weight . One or more X : Y , to X2 : Y2 , wherein X , < Y , and X _ < Y2 . By way of pesticide might be dissolved in the organic solvent . Useful non - limiting example , the range of weight ratios of a mol - organic solvents include aromatics , especially xylenes and ecule of Formula One to an active ingredient may be 30 petroleum fractions , especially the high - boiling naphtha between about 1 : 3 and about 1 : 20 , inclusive of the end - lenic and olefinic portions of petroleum such as heavy points . aromatic naphtha . Other solvents may include vegetable Formulations oils , seed oils , and esters of vegetable and seed oils . Suitable

A pesticide is many times not suitable for application in emulsifiers for oil dispersions are selected from conven its pure form . It is usually necessary to add other substances 35 tional anionic and non - ionic surfactants . Thickeners or gell so that the pesticide may be used at the required concentra - ing agents are added in the formulation of oil dispersions to tion and in an appropriate form , permitting ease of applica - modify the rheology or flow properties of the liquid and to tion , handling , transportation , storage , and maximum pesti - prevent separation and settling of the dispersed particles or cide activity . Thus , pesticides are formulated into , for droplets . example , baits , concentrated emulsions , dusts , emulsifiable 40 Pesticides may also be applied as granular compositions concentrates , fumigants , gels , granules , microencapsula - that are particularly useful for applications to the soil . tions , seed treatments , suspension concentrates , suspoemul - Granular compositions usually contain from about 0 . 5 % to sions , tablets , water soluble liquids , water dispersible gran about 10 % by weight of the pesticide , dispersed in a carrier ules or dry flowables , wettable powders , and ultra - low that comprises clay or a similar substance . Such composi volume solutions . 45 tions are usually prepared by dissolving the pesticide in a

Pesticides are applied most often as aqueous suspensions suitable solvent and applying it to a granular carrier , which or emulsions prepared from concentrated formulations of has been pre - formed to the appropriate particle size , in the such pesticides . Such water - soluble , water - suspendable , or range of from about 0 . 5 mm to about 3 mm . Such compo emulsifiable formulations are either solids , usually known as sitions may also be formulated by making a dough or paste wettable powders , water dispersible granules , liquids usu - 50 of the carrier and molecule , and then crushing and drying to ally known as emulsifiable concentrates , or aqueous suspen - obtain the desired granular particle size . Another form of sions . Wettable powders , which may be compacted to form granules is a water emulsifiable granule ( EG ) . It is a for water dispersible granules , comprise an intimate mixture of mulation consisting of granules to be applied as a conven the pesticide , a carrier , and surfactants . The concentration of tional oil - in - water emulsion of the active ingredient ( s ) , the pesticide is usually from about 10 % to about 90 % by 55 either solubilized or diluted in an organic solvent , after weight . The carrier is usually selected from among the disintegration and dissolution in water . Water emulsifiable attapulgite clays , the montmorillonite clays , the diatoma - granules comprise one or several active ingredient ( s ) , either ceous earths , or the purified silicates . Effective surfactants , solubilized or diluted in a suitable organic solvent that comprising from about 0 . 5 % to about 10 % of the wettable is ( are ) absorbed in a water soluble polymeric shell or some powder , are found among sulfonated lignins , condensed 60 other type of soluble or insoluble matrix . naphthalenesulfonates , naphthalenesulfonates , alkylbenze - Dusts containing a pesticide are prepared by intimately nesulfonates , alkyl sulfates , and non - ionic surfactants such mixing the pesticide in powdered form with a suitable dusty as ethylene oxide adducts of alkyl phenols . agricultural carrier , such as kaolin clay , ground volcanic

Emulsifiable concentrates of pesticides comprise a con - rock , and the like . Dusts can suitably contain from about 1 % venient concentration of a pesticide , such as from about 50 65 to about 10 % of the pesticide . Dusts may be applied as a to about 500 grams per liter of liquid dissolved in a carrier seed dressing or as a foliage application with a dust blower that is either a water miscible solvent or a mixture of machine .

US 9 , 795 , 140 B2 153 154

It is equally practical to apply a pesticide in the form of surface on which it is spreading . Wetting agents are used for a solution in an appropriate organic solvent , usually petro two main functions in agrochemical formulations : during leum oil , such as the spray oils , which are widely used in processing and manufacture to increase the rate of wetting of agricultural chemistry . powders in water to make concentrates for soluble liquids or

Pesticides can also be applied in the form of an aerosol 5 suspension concentrates ; and during mixing of a product composition . In such compositions , the pesticide is dis - with water in a spray tank to reduce the wetting time of solved or dispersed in a carrier , which is a pressure - gener - wettable powders and to improve the penetration of water ating propellant mixture . The aerosol composition is pack into water - dispersible granules . Examples of wetting agents aged in a container from which the mixture is dispensed used in wettable powder , suspension concentrate , and water through an atomizing valve . 10 dispersible granule formulations are : sodium lauryl sulfate ;

Pesticide baits are formed when the pesticide is mixed sodium dioctyl sulfosuccinate ; alkyl phenol ethoxylates ; and with food or an attractant or both . When the pests eat the aliphatic alcohol ethoxylates . bait , they also consume the pesticide . Baits may take the dispersing agent is a substance that adsorbs onto the form of granules , gels , flowable powders , liquids , or solids . surface of particles , helps to preserve the state of dispersion Baits may be used in pest harborages . 15 of the particles , and prevents them from reaggregating .

Fumigants are pesticides that have a relatively high vapor Dispersing agents are added to agrochemical formulations to pressure and hence can exist as a gas in sufficient concen - facilitate dispersion and suspension during manufacture , and trations to kill pests in soil or enclosed spaces . The toxicity to ensure the particles redisperse into water in a spray tank . of the fumigant is proportional to its concentration and the They are widely used in wettable powders , suspension exposure time . They are characterized by a good capacity for 20 concentrates , and water - dispersible granules . Surfactants diffusion and act by penetrating the pest ' s respiratory system that are used as dispersing agents have the ability to adsorb or being absorbed through the pest ' s cuticle . Fumigants are strongly onto a particle surface and provide a charged or applied to control stored product pests under gas proof steric barrier to reaggregation of particles . The most com sheets , in gas sealed rooms or buildings , or in special monly used surfactants are anionic , non - ionic , or mixtures of chambers . 25 the two types . For wettable powder formulations , the most

Pesticides may be microencapsulated by suspending the common dispersing agents are sodium lignosulfonates . For pesticide particles or droplets in plastic polymers of various suspension concentrates , very good adsorption and stabili types . By altering , the chemistry of the polymer or by z ation are obtained using polyelectrolytes , such as sodium changing factors in the processing , microcapsules may be naphthalene - sulfonate - formaldehyde - condensates . formed of various sizes , solubility , wall thicknesses , and 30 Tristyrylphenol ethoxylate phosphate esters are also used . degrees of penetrability . These factors govern the speed with Non - ionics such as alkylarylethylene oxide condensates and which the active ingredient within is released , which in turn , EO - PO block copolymers are sometimes combined with affects the residual performance , speed of action , and odor anionics as dispersing agents for suspension concentrates . In of the product . The microcapsules might be formulated as recent years , new types of very high molecular weight suspension concentrates or water dispersible granules . 35 polymeric surfactants have been developed as dispersing

Oil solution concentrates are made by dissolving pesticide agents . These have very long hydrophobic ‘ backbones ' and in a solvent that will hold the pesticide in solution . Oil a large number of ethylene oxide chains forming the " teeth ' solutions of a pesticide usually provide faster knockdown of a ' comb ' surfactant . These high molecular weight poly and kill of pests than other formulations due to the solvents mers can give very good long - term stability to suspension themselves having pesticidal action and the dissolution of 40 concentrates because the hydrophobic backbones have many the waxy covering of the integument increasing the speed of anchoring points onto the particle surfaces . Examples of uptake of the pesticide . Other advantages of oil solutions dispersing agents used in agrochemical formulations are : include better storage stability , better penetration of crev - sodium lignosulfonates ; sodium naphthalene sulfonate ices , and better adhesion to greasy surfaces . formaldehyde condensates ; tristyrylphenol - ethoxylate - phos

Another embodiment is an oil - in - water emulsion , wherein 45 phate - esters ; aliphatic alcohol ethoxylates ; alkyl ethoxy the emulsion comprises oily globules which are each pro - lates ; EO - PO block copolymers ; and graft copolymers . vided with a lamellar liquid crystal coating and are dispersed An emulsifying agent is a substance that stabilizes a in an aqueous phase , wherein each oily globule comprises at suspension of droplets of one liquid phase in another liquid least one molecule which is agriculturally active , and is phase . Without the emulsifying agent , the two liquids would individually coated with a monolamellar or oligolamellar 50 separate into two immiscible liquid phases . The most com layer comprising : ( 1 ) at least one non - ionic lipophilic sur monly used emulsifier blends contain an alkylphenol or an face - active agent , ( 2 ) at least one non - ionic hydrophilic aliphatic alcohol with twelve or more ethylene oxide units surface - active agent , and ( 3 ) at least one ionic surface - active and the oil - soluble calcium salt of dodecylbenzenesulfonic agent , wherein the globules having a mean particle diameter acid . A range of hydrophile - lipophile balance ( “ HLB ” ) val of less than 800 nanometers . 55 ues from about 8 to about 18 will normally provide good Other Formulation Components stable emulsions . Emulsion stability can sometimes be

Generally , when the molecules disclosed in Formula One improved by the addition of a small amount of an EO - PO are used in a formulation , such formulation can also contain block copolymer surfactant . other components . These components include , but are not A solubilizing agent is a surfactant that will form micelles limited to , this is a non - exhaustive and non - mutually exclu - 60 in water at concentrations above the critical micelle con sive list ) wetters , spreaders , stickers , penetrants , buffers , centration . The micelles are then able to dissolve or solu sequestering agents , drift reduction agents , compatibility bilize water - insoluble materials inside the hydrophobic part agents , anti - foam agents , cleaning agents , and emulsifiers . A of the micelle . The types of surfactants usually used for few components are described forthwith . solubilization are non - ionics , sorbitan monooleates , sorbitan

Awetting agent is a substance that when added to a liquid 65 monooleate ethoxylates , and methyl oleate esters . increases the spreading or penetration power of the liquid by Surfactants are sometimes used , either alone or with other reducing the interfacial tension between the liquid and the additives such as mineral or vegetable oils as adjuvants to

US 9 , 795 , 140 B2 155 156

spray - tank mixes to improve the biological performance of such as octanol and nonanol , or silica . In both cases , the the pesticide on the target . The types of surfactants used for function of the anti - foam agent is to displace the surfactant bioenhancement depend generally on the nature and mode of from the air - water interface . action of the pesticide . However , they are often non - ionics “ Green ” agents ( e . g . , adjuvants , surfactants , solvents ) can such as : alkyl ethoxylates ; linear aliphatic alcohol ethoxy - 5 reduce the overall environmental footprint of crop protection lates ; and aliphatic amine ethoxylates . formulations . Green agents are biodegradable and generally

A carrier or diluent in an agricultural formulation is a derived from natural and / or sustainable sources , e . g . plant material added to the pesticide to give a product of the and animal sources . Specific examples are : vegetable oils , required strength . Carriers are usually materials with high seed oils , and esters thereof , also alkoxylated alkyl polyg absorptive capacities , while diluents are usually materials 10 lucosides . with low absorptive capacities . Carriers and diluents are Applications used in the formulation of dusts , wettable powders , granules , Molecules of Formula One may be applied to any locus . and water - dispersible granules .

Organic solvents are used mainly in the formulation of Particular loci to apply such molecules include loci where Par emulsifiable concentrates , oil - in - water emulsions . Suspoe - 15 alfalfa , almonds , apples , barley , beans , canola , corn , cotton , mulsions , oil dispersions , and ultra - low volume formula crucifers , flowers , fodder species ( Rye Grass , Sudan Grass , tions , and to a lesser extent , granular formulations . Some - Tall Fescue , Kentucky Blue Grass , and Clover ) , fruits , times mixtures of solvents are used . The first main groups of lettuce , oats , oil seed crops , oranges , peanuts , pears , pep solvents are aliphatic paraffinic oils such as kerosene or pers , potatoes , rice , sorghum , soybeans , strawberries , sug refined paraffins . The second main group ( and the most 20 arcane , sugarbeets , sunflowers , tobacco , tomatoes , wheat common ) comprises the aromatic solvents such as xylene ( for example , Hard Red Winter Wheat , Soft Red Winter and higher molecular weight fractions of C9 and C10 Wheat , White Winter Wheat , Hard Red Spring Wheat , and aromatic solvents . Chlorinated hydrocarbons are useful as Durum Spring Wheat ) , and other valuable crops are growing cosolvents to prevent crystallization of pesticides when the or the seeds thereof are going to be planted . formulation is emulsified into water . Alcohols are sometimes 25 Molecules of Formula One may also be applied where used as cosolvents to increase solvent power . Other solvents plants , such as crops , are growing and where there are low may include vegetable oils , seed oils , and esters of vegetable levels ( even no actual presence of pests that can commer and seed oils . cially damage such plants . Applying such molecules in such Thickeners or gelling agents are used mainly in the locus is to benefit the plants being grown in such locus . Such formulation of suspension concentrates , oil dispersions , 30 ben su benefits , may include , but are not limited to : helping the emulsions and suspoemulsions to modify the rheology or plant grow a better root system ; helping the plant better flow properties of the liquid and to prevent separation and withstand stressful growing conditions ; improving the settling of the dispersed particles or droplets . Thickening , gelling , and anti - settling agents generally fall into two health of a plant ; improving the yield of a plant ( e . g . categories , namely water - insoluble particulates and water - 35 increased biomass and / or increased content of valuable soluble polymers . It is possible to produce suspension con ingredients ) ; improving the vigor of a plant ( e . g . improved centrate and oil dispersion formulations using clays and plant growth and / or greener leaves ) ; improving the quality silicas . Examples of these types of materials , include , but are of a plant ( e . g . improved content or composition of certain not limited to , montmorillonite , bentonite , magnesium alu - ingredients ) ; and improving the tolerance to abiotic and / or minum silicate , and attapulgite . Water - soluble polysaccha - 40 biotic stress of the plant . rides in water based suspension concentrates have been used Molecules of Formula One may be applied with ammo as thickening - gelling agents for many years . The types of nium sulfate when growing various plants as this may polysaccharides most commonly used are natural extracts of provide additional benefits . seeds and seaweeds or are synthetic derivatives of cellulose . Molecules of Formula One may be applied on , in , or Examples of these types of materials include , but are not 45 around plants genetically modified to express specialized limited to , guar gum ; locust bean gum ; carrageenam ; alg - traits , such as Bacillus thuringiensis ( for example , Cry1 Ab , inates ; methyl cellulose ; sodium carboxymethyl cellulose Cry1Ac , Cry1Fa , Cry1A . 105 , Cry2Ab , Vip3A , mCry3A , ( SCMC ) ; and hydroxyethyl cellulose ( HEC ) . Other types of Cry3Ab , Cry3Bb , Cry34Abi / Cry35Abl ) , other insecticidal anti - settling agents are based on modified starches , poly - toxins , or those expressing herbicide tolerance , or those with acrylates , polyvinyl alcohol , and polyethylene oxide . 50 " stacked ” foreign genes expressing insecticidal toxins , her Another good anti - settling agent is xanthan gum . bicide tolerance , nutrition - enhancement , or any other ben Microorganisms can cause spoilage of formulated prod eficial traits .

ucts . Therefore , preservation agents are used to eliminate or Molecules of Formula One may be applied to the foliar reduce their effect . Examples of such agents include , but are and / or fruiting portions of plants to control pests . Either such not limited to : propionic acid and its sodium salt ; sorbic acid 55 molecules will come in direct contact with the pest , or the and its sodium or potassium salts ; benzoic acid and its pest will consume such molecules when eating the plant or sodium salt ; p - hydroxybenzoic acid sodium salt ; methyl while extracting sap or other nutrients from the plant . p - hydroxybenzoate ; and 1 , 2 - benzisothiazolin - 3 - one ( BIT ) . Molecules of Formula One may also be applied to the soil ,

The presence of surfactants often causes water - based and when applied in this manner , root and stem feeding pests formulations to foam during mixing operations in produc - 60 may be controlled . The roots may absorb such molecules tion and in application through a spray tank . In order to thereby taking it up into the foliar portions of the plant to reduce the tendency to foam , anti - foam agents are often control above ground chewing and sap feeding pests . added either during the production stage or before filling Systemic movement of pesticides in plants may be uti into bottles . Generally , there are two types of anti - foam lized to control pests on one portion of the plant by applying agents , namely silicones and non - silicones . Silicones are 65 ( for example by spraying a locus ) a molecule of Formula usually aqueous emulsions of dimethyl polysiloxane , while One to a different portion of the plant . For example , control the non - silicone anti - foam agents are water - insoluble oils , of foliar - feeding insects may be achieved by drip irrigation

US 9 , 795 , 140 B2 157 158

or furrow application , by treating the soil with for example ticks that are bothersome to such animals . Suitable formu pre - or post - planting soil drench , or by treating the seeds of lations are administered orally to the animals with the a plant before planting . drinking water or feed . The dosages and formulations that

are suitable depend on the species . Molecules of Formula One may be used with baits . Molecules of Formula One may also be used for control Generally , with baits , the baits are placed in the ground 3 ling parasitic worms , especially of the intestine , in the where , for example , termites can come into contact with , animals listed above . and / or be attracted to , the bait . Baits can also be applied to Molecules of Formula One may also be employed in a surface of a building , ( horizontal , vertical , or slant surface ) therapeutic methods for human health care . Such methods where , for example , ants , termites , cockroaches , and flies , include , but are limited to , oral administration in the form of , can come into contact with , and / or be attracted to , the bait . 10 for example , tablets , capsules , drinks , granules , and by

Molecules of Formula One may be encapsulated inside , or dermal application . placed on the surface of a capsule . The size of the capsules Molecules of Formula One may also be applied to inva can range from nanometer size ( about 100 - 900 nanometers sive pests . Pests around the world have been migrating to in diameter ) to micrometer size ( about 10 - 900 microns in new environments ( for such pest ) and thereafter becoming a diameter ) . new invasive species in such new environment . Such mol

Molecules of Formula One may be applied to eggs of - ecules may also be used on such new invasive species to pests . Because of the unique ability of the eggs of some pests control them in such new environments . to resist certain pesticides , repeated applications of such Before a pesticide may be used or sold commercially , molecules may be desirable to control newly emerged lar such pesticide undergoes lengthy evaluation processes by vae . various governmental authorities ( local , regional , state , Molecules of Formula One may be applied as seed 20 national , and international ) . Voluminous data requirements

treatments . Seed treatment may be applied to all types of are specified by regulatory authorities and must be addressed seeds , including those from which plants genetically modi through data generation and submission by the product fied to express specialized traits will germinate . Represen registrant or by a third party on the product registrant ' s tative examples include those expressing proteins toxic to invertebrate pests , such as Bacillus thuringiensis or other 25 behalf , often using a computer with a connection to the insecticidal toxins , those expressing herbicide tolerance , World Wide Web . These governmental authorities then such as “ Roundup Ready ” seed , or those with " stacked ” review such data and if a determination of safety is con foreign genes expressing insecticidal toxins , herbicide tol - cluded , provide the potential user or seller with product erance , nutrition - enhancement , drought tolerance , or any registration approval . Thereafter , in that locality where the other beneficial traits . Furthermore , such seed treatments product registration is granted and supported , such user or with molecules of Formula One may further enhance the 30 seller may use or sell such pesticide . ability of a plant to withstand stressful growing conditions Molecules according to Formula One may be tested to better . This results in a healthier , more vigorous plant , which determine its efficacy against pests . Furthermore , mode of can lead to higher yields at harvest time . Generally , about 1 action studies may be conducted to determine if said mol gram of such molecules to about 500 grams per 100 , 000 ecule has a different mode of action than other pesticides . seeds is expected to provide good benefits , amounts from 35 Thereafter such acquired data may be disseminated , such as Thereafter , such acquired data may be disseminated , such as about 10 grams to about 100 grams per 100 , 000 seeds is by the internet , to third parties . expected to provide better benefits , and amounts from about The Headings in this Document are for Convenience Only 25 grams to about 75 grams per 100 , 000 seeds is expected to provide even better benefits . Molecules of Formula One and Must not be Used to Interpret any Portion Hereof . may be applied with one or more active ingredients in a soil 40 lab Tables amendment . Molecules of Formula One may be used for controlling TABLE B

endoparasites and ectoparasites in the veterinary medicine sector or in the field of non - human - animal keeping . Such Weight Ratios

Molecule of the Formula One : active ingredient molecules may be applied by oral administration in the form of , for example , tablets , capsules , drinks , granules , by der - 45 100 : 1 to 1 : 100 mal application in the form of , for example , dipping , spray 50 : 1 to 1 : 50 ing , pouring on , spotting on , and dusting , and by parenteral 20 : 1 to 1 : 20 administration in the form of , for example , an injection . 10 : 1 to 1 : 10

Molecules of Formula One may also be employed advan 5 : 1 to 1 : 5 3 : 1 to 1 : 3 tageously in livestock keeping , for example , cattle , chickens , 50 2 : 1 to 1 : 2 geese , goats , pigs , sheep , and turkeys . They may also be 1 : 1

employed advantageously in pets such as , horses , dogs , and cats . Particular pests to control would be flies , fleas , and

TABLE C 100 50 X , Y

active ingredient ( Y ) Parts by weight

X , Y X , Y X , Y

X , Y X , Y X , Y

X , Y 20 15

X , Y X , Y X , Y

X , Y X , Y X , Y

Nwao X , Y X , Y X , Y X , Y X , Y X , Y X , Y X , Y X , Y

1

X , Y X , Y X , Y 3

2 1

X , Y X , Y

X , Y X , Y X , Y X , Y X , Y X , Y X , Y X , Y X , Y

3 5 10 15 molecule of Formula One

( X ) Parts by weight

X , Y X

X , Y 20

X , Y , Y

X , Y 50

X , Y 2

X , Y 100

US 9 , 795 , 140 B2 ? 15 159 160

TABLE 2

Structure and preparation method for F and PF Series molecules - No . No . Structure Prep . * Prep . * F1 Cl . Cl ?

F )

CH3

F3 13 F ?????

F4 13 C1 C1 ???

F5 13

???? ??? ??

F

F6 13 Cl . Cl (

US 9 , 795 , 140 B2 161 162

TABLE 2 - continued Structure and preparation method for F and PF Series molecules

No . Structure Prep . * |

F7 Cl . 13 Cl 0

Z

F8 Cl Cl 0

F9 ? C1 Cl ?

LZ

F10 ) Cl . Cl 0

?? ????? ?? ??? ?????? ???

CH2

?? F11 Cl . Cl 0

CH ,

F12 Cl . Cl ?

US 9 , 795 , 140 B2 | 163 163 164

TABLE 2 - continued

Structure and preparation method for F and PF Series molecules

No . Structure Prep . *

F13 13 Cl Cl 0

?? ?????? F14 13 C1 C1

F15 13 Cl . Cl ?

F16 Cl . Cl

F17 1 C1

????? ??? ?????

F18 ? Cl Cl

US 9 , 795 , 140 B2 165 166

TABLE 2 - continued 1

Structure and preparation method for F and PF Series molecules

No . Structure Prep . *

F19 13 CI Clo

M ina F20

CICIO

F21 13 ci Clo

IZ

F22 13 Ci Clo

NH

F23 CICI

N play F24

?????? N

US 9 , 795 , 140 B2 | 167 167 168

TABLE 2 - continued

Structure and preparation method for F and PF Series molecules

No . Structure Prep . *

F25 13 Cl Cl 0

F26 13 Cl . Cl (

F27 14 Cl . Cl

F28 F 14 Cl Cl ,

F29

??? - ??? 15 Cl . Cl o

LZ

F30 ) 16 Cl . Cl o CH ,

CH ,

US 9 , 795 , 140 B2 169 170

TABLE 2 - continued Structure and preparation method for F and PF Series molecules

No . Structure Prep . *

F31 16 Cl . Cl o

= o

F32 ?? 16 Cl . Cl ?

??

F33

??? - ????

16 C1 C1

- CH3

F34 16 ? Cl Cl 16

* CH

H , C ??? ????? F35 16 Cl . Cl o

F36 H3C 16

CH , ? Cl Cl CH3 ?

Z ????

US 9 , 795 , 140 B2 US 9 , 293 , 140 ? 17 171 172 TABLE 2 - continued

Structure and preparation method for F and PF Series molecules

No . Structure Prep . *

F37 16 ? Cl Cl

F38 16 C1 C1 ??? .

?? ? ??? F39 16 Cl . Cl ?

- HT

F40 ) 16 ? Cl Cl |

11 ??? |

F41 16

Cl Clo ????? F42 CH3 16

? Cl Cl 0 = $ = 0 ???? CH?

US 9 , 795 , 140 B2 173 174

TABLE 2 - continued |

Structure and preparation method for F and PF Series molecules |

No . Structure Prep . * |

F43 Ci Clo 16

F4A 16 Cl . Cl 6

F

F45 16 Cl . Cl 0

CH ,

LZ

F46 16 Cl . Cl 0

CH3

????? ??? ????

???? ???? ??????

F47 16 Cl Clo

CA

F48 16 ? C1 C1

Z F

US 9 , 795 , 140 B2 175 176 " TABLE 2 - continued " Structure and preparation method for F and PF Series molecules

No . Structure Prep . *

? F4 16 Cl Cl , F F 1

1 ??? F50 ) 16 C1 Clo

CH ?

CH ,

F51 16 Cl . Cl ?

??? ????? ???? ????? ????

??? ???

F52 16 Cl . Cl

CH3

F53 16 Cl Clo

, CH ?

F54 16 ? Cl Cl

CH3

US 9 , 795 , 140 B2 177 178

TABLE 2 - continued Structure and preparation method for F and PF Series molecules

No . Structure Prep . *

F55 ? Cl Cl 16 ?

N CH ,

E56 16 ? C1 C1

LZ CH ?

F57 16 Cl . Cl 0

F58 16 Cl . Cl 0

CH3 LZ

- ???? ???? ????

??? ?????

F59 16 ? Cl Cl CH : F

F60 ) 16 Cl Clo

1

1

F F

US 9 , 795 , 140 B2 179 180

TABLE 2 - continued Structure and preparation method for F and PF Series molecules

No . Structure Prep . *

F61 Cl . 16 Cl o F F F 1

1

FF

F62 16 ? C1 C1 CH3

Z

LZ CH3

F63 16 Cl . Cl 0 CH3 , N CH ?

F64 16 ? C1 C1 CH :

1

???? 1

F65 16 Cl ? CH

CR

??? ??? ?????

F66 16 Cl . Cl o CH : N

US 9 , 795 , 140 B2 181 181 182

TABLE 2 - continued |

Structure and preparation method for F and PF Series molecules |

No . Structure Prep . * |

F67 ? Cl Cl 16 Cl

CH ? * 0 LZ

F68 Cl 16 C1 Cl 0 ( CH3

CM ??

??? ???? ??? F69 16 Cl . Cl ? CH

F70 ) 16 Cl . Cl ? ???

H

F1 16

1

???? ????

?? ?????? F72 16 Cl . Cl 0

1

1

US 9 , 795 , 140 B2 183 184

TABLE 2 - continued Structure and preparation method for F and PF Series molecules on ???????

No . Structure Prep . *

F73 Cl 16 Cl . Cl o CH : ???

F4 Cl Cl o

CH ,

F5 ? C1 Cl

?? - CH ,

F78 16 0H

CH3

?????? ??? ??? ???? ????

F79 16

NH

F84 16 C1 C1

11 - 0

US 9 , 795 , 140 B2 185 186

TABLE 2 - continued Structure and preparation method for F and PF Series molecules

| | | No . Structure Prep . * F85 16 ? Cl Cl

LZ

H3C

F86 16 ? C1 C1

LZ

????

F8 16 ??? ? ????? Cl . Cl , T F -

1

F88 16 CT

1

1

-

F ? H3 . F91 16

Cl . Cl 0 CH3

LZ ???? F92 16

Cl . Cl ? ???

US 9 , 795 , 140 B2 187 187 188

TABLE 2 - continued

Structure and preparation method for F and PF Series molecules

No . Structure Prep . *

F93 16

Cl . Cl , ???????? F94 16

Cl Cl , ???? LZ

F95 16

Cl Clo

CH3

F96 23 Cl . Cl 6

CH3

F97 15 ? C1 C1

?

8 H?c CH ,

US 9 , 795 , 140 B2 189 190

TABLE 2 - continued | | Structure and preparation method for F and PF Series molecules

No . Structure Prep . * | F98 Cl C ] 16 ? Cl Cl

CH ,

LZ

F99 16 C1 C1 ???? ? ??? ??? F100 ) 16 Cl . Cl ,

F101 16 ?? C1 C1

LZ CH ,

F102 CI 16 Cl . Cl 0

1

????? - ??? ????

1 -

F103 16 Cl . Cl ,

H

F

US 9 , 795 , 140 B2 191 192

TABLE 2 - continued

Structure and preparation method for F and PF Series molecules

No . Structure Prep . *

F104 16 Cl Cl ??? F

F105 16 Cl Cl ????? ???

F106 16 Cl . Cl ?

CH3

F

F107 16 Cl 0

IT ??? IT

F108 24 ?? Cl Cl

F " F ???? ? ??? F109 24 Cl . Cl ?

Br

US 9 , 795 , 140 B2 193 193 194

TABLE 2 - continued Structure and preparation method for F and PF Series molecules

No . Structure Prep . *

F111 24 Cl . Cl 0 F

3r ,

F112 24 ? C1 C1

\

LZ

F LT .

F113 24 Cl . Cl ? HT

F114 C ] ? a Cl 24

????? ???? F

Br

F F

F115 24 ? Cl C1

??

?

F116 24 C1 C1 ??

C ,

?? ?????? ??????

F

F

F117 24 Cl Clo

US 9 , 795 , 140 B2 195 195 196

TABLE 2 - continued

Structure and preparation method for F and PF Series molecules

No . Structure Prep . *

F118 24 C ]

F ?

F119 24 Cl 0

F

????? ?????

?????? ???

F120 24 ? C1 C1

LZ

F121 24 Cl . Cl ?

H

=

F122 Cl ( 244

FF F

F123 24 ? Cl Cl

F ?? Br