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O O N O O HN HN N N O O S S 21 22 pioglitazone rosiglitazone

OH N O O O O O HN O HN N O O S S 23 24 troglitazone rivoglitazone 647'674)52*6,)0256326)166,-%<2/-(-1)(-21)-157/-15)15-6-<)45 EDL;HI;BO J>;79J?L7J?EDE;I;H;9;FJEHI?DDED J7H=;JJ?IIK;I>7I8;;DIK==;IJ;:JE8;J>; C7?D C;9>7D?IJ?9 H;7IED ; DKC;HEKI 7:L;HI; ;<<;9JI J>;I; -3I >7L; "D JHE=B?J7PED;M7IM?J>:H7MD;C7HA;J:K;JE?JI>;F7JEN?9?JO KHJ>;HCEH; J>;KI;E< HEI?=B?J7PED;M7I:?I9EDJ?DK;:EHH;IJH?9J;:?DL7H?EKI9EKDJH?;I:K;JE?JID;=7J?L;;<<;9JIED 97H:?EL7I9KB7H;L;DJI )?E=B?J7PED;?IIJ?BB7L7?B78B;EDC7DOC7HA;JI8KJIEC;7:L;HI; ;<<;9JI>7L;8;;DH;FEHJ;:IK9>7I8ED;7J>7L;B;:JEJ>;

M?J>:H7M7BE;:HK=8OIEC;9EKDJH?;I .* H7D9;7D: ;HC7DO ,EC;=;D;H7BC?DEH 7:L;HI;;<<;9JIE<-3I7H;M;?=>J=7?D ; CEIJ FHEC?I?D= 7D: H;9;DJ -3 :;H?L7J?L; ?D J>; JOF; :?78;J;I H;I;7H9> ?I H?LE=B?J7PED; ?= +?LE=B?J7PED;?I9EDI?:;H;:JE8;CEH;FEJ;DJ7D:>7I7BED=;H >7B< B?<;J>7DF?E=B?J7PED; !EM;L;H EDBO<;MI>EHJ J;HC9B?D?97BJH?7BIM?J>IC7BBI7CFB;I?P;I >7L;8;;DC7:; )EI?J?L;I?=DIH;=7H:?D=;<7L;8;;DFHEFEI;:8KJCEH; IJK:?;I 7H; D;;:;: JE ; FEJ;DJ?7B E< H?LE=B?J7PED; 7I 7 97D:?:7J; ; JH;7JC;DJEE:IJEFH;F7H;F?E=B?J7PED;7D:EJ>;HJ>?7PEB?:?D;:?ED;:;H?L7J?L;I>7L;8;;D H;FEHJ;: "DJ>;E: 7BAENO7D?B?D;?DJ;HC;:?7J;I 7H;FH;F7H;:8OH;:K9?D=J>; 7BAENOD?JHE8;DP;D;I E8J7?D;:;7B9E>EBFH;9KHIEH 7D: ; :?7PED?KC8HEC?:; :;H?L7J?L;E; 7BAENO7D?B?D;I C;J>OB79HOB7J;?DJ>; FH;I;D9;E<9KFHEKIEN?:;=7L;J>; 8HECEFHEF?ED7J;IK8IJH7J;I O9B?P7J?EDM?J>J>?EKH;7 O:HEBOI?IFHEL?:;:F?E=B?J7PED;EHEJ>;HJ>?7PEB?:?D;:?ED;I 7IJ>;E: ,9>;C; "DJ>;I;9ED:C;J>E: FOH?:OB7BAENO8;DP7B:;>O:; :;H?L7J?L;IM;H;;HEE:I ->;I;8;DP7B:;>O:;I M;H; E8J7?D;: 8O 9EKFB?D= FOH?:OB;J>7DEBI M?J> ;JH;7JC;DJE+7D;O'??D;FH;F7H7J?EDE;I;8;DP7B:;>O:;I?DLEBL;:J>;JEIOB7J?ED E< J>; FOH?:OB;J>7DEBI 7D: IK8I;GK;DJ 9EKFB?D= M?J> >O:HENO8;DP7B:;>O:; ?D J>; FH;I;D9; E< 7 F>7I; JH7DI<;H 97J7BOIJ ->; 8;DP7B:;>O:; ?DJ;HC;:?7J;I KD:;HM;DJ 7 $DE;L;D7=;B 9ED:;DI7J?ED M?J> J>?7PEB?:?D;:?ED; KD:;H 87I?9 9ED:?J?EDI JE ; 7BAOB?:;D;:;H?L7J?L;I O:HE=;D7J?EDE;:;H?L7J?L;I F?E=B?J7PED; EH EJ>;H J>?7PEB?:?D;:?ED;I M;H; E8J7?D;: C;J>E: ,9>;C; ->?I C;J>E: ?I 7BIE 7FFB?978B;;I?IE

Method A

O2N

F O2N H2N 26 H2/Pd-C i) NaNO2, aq. HBr R-(CH2)n-OH NaH 25 O(CH2)n-R O(CH2)n-R ii) CH2CHCO2Me, CuO 27 28

O O

MeO2C (H2N)2CS, NaOAc aq. HCl HN HN Br S S O(CH ) -R O(CH2)n-R O(CH2)n-R 2 n HN O 29 30 21: n = 2, R = 5-ethyl-2-pyridyl

Method B

CN CN R R F N (CH2)nOH N (CH2)nO 31 NaH 32

Raney Ni, aq. HCO H i) TsCl, PhCH2NBu3Cl, 2 aq. NaOH ii) 4-hydroxybenzaldehyde, PhCH2NBu3Cl, aq. NaOH CHO 2,4-thiazolidinedione, piperidine R N (CH2)nO 33 O O

R NH H2/Pd-C R NH S S N (CH2)nO N (CH2)nO O O 34 21: n = 2, R = 5-ethyl !92%/6)41%6-8)0)6,2(5*246,)5;16,)5-52*3-2+/-6%<21)%1(26,)4!$5 %7J;HC7DOIODJ>;J?97FFHE79>;I;HCE:??7PEB?:?D;:?ED;I>7L;8;;D FH;I;DJ;:?D9BK:?D=C7DOCE:?;7BAENO879A8ED; BIE IEC;H;FEHJIE< IK8IJ?JKJ?EDEDJ>;D?JHE=;D7JEC?DJ>;J>?7PEB?:?D;:?ED;H?D=>7L;8;;DFH;I;DJ;: α BK9EI?:7I;?D>?8?JEHI "I )EIJFH7D:?7B>OF;H=BO9;C?7>7I8;;DH;FEHJ;:JE8;IJHED=BO7IIE9?7J;:M?J>J>;97H8E>O:H7J; 9EDJ;DJE;:?;J α BK9EI?:7I;?I7D;DPOC;?DJ>;IC7BB?DJ;IJ?D;H;IFEDI?8B;; 8H;7A:EMD E< 9ECFB;N 97H8E>O:H7J;I ?DJE IC7BB;H I799>7H?:; KD?JI α BK9EI?:7I; ?D>?8?JEHI 79J C7?DBO 8O 9ECF;J?D= M?J> EB?=EI799>7H?:;I ; 79J?L; I?J; E< α =BK9EI?:7I; 7D: J>;H;8O IBEMI J>; ?D=;IJ;: 97H8E>O:H7J; :?=;IJ?ED H7J; ->?I B;7:I JE 8;JJ;H=BO9;C?99EDJHEB8OBEM;H?D=J>;8BEE:=BK9EI;7D:?DIKB?DB;L;BI7; J>H;; "I9KHH;DJBO7L7?B78B;EDJ>;C7HA;J7H;797H8EI; C?=B?JEB 7D:LE=B?8EI; ?= 97H8EI; 9ECF;J;I M?J> FEBO 7D: EB?=EI799>7H?:;I M>;H;7I C?=B?JEB 7D: LE=B?8EI;9ECF;J;M?J>:?I799>7H?:;I ?=

CH2OH

HOH C OH 2 H3C O HO HO HN HOH2C HO HO N OH HOH2C HO OH OH OH O HO HN O OH HO OH HOH2C 35 36 37 OH O miglitol voglibose acarbose O OH HO OH OH !,4))5'744)16/;%8%-/%&/)216,)0%4.)6

!,)0)',%1-502*%'6-212*5 ->; C7?D 7:L7DJ7=; E< "I ?I J>;?H =EE: I7<;JO FHE;O H7H;BO 9EDJH?8KJ; JE >OFE=BO9;C?7M>;DKI;:7ICEDEJ>;H7FOEHKI;:?D9EC8?D7J?EDM?J>? ; IKBJ=7?D?I7IIE9?7J;:M?J> "I8KJ?DIEC;F;EFB;M?J>:?78;J;I7IC7BBM;?=>JBEII>7I 8;;DE8I;HL;: ;D;;H?IAE<97H:?EL7I9KB7H;L;DJI>7L;7BIE 8;;DH;FEHJ;:7L;8;;D I>EMD JE IBEM :EMD J>; ; C7?D 7:L;HI; ;<<;9JI E< "I 7H; =7IJHE?DJ;IJ?D7B IOCFJECI IK9> 7I ;7 IE; KI; E< "I ?I H;9ECC;D:;: 7J >7L; 7 >?=> 97H8E>O:H7J; :?;J "D 7::?J?ED E8;I;7D:;B:;HBOF;EFB;97D=;J8;D;;?H97H:?E FHEJ;9J?L;7D:M;?=>JD;KJH7B?JO<;7JKH;I BJ>EK=> "IFEII;II7M?:;I7<;JOFHE;O7H; KD:EK8J;:BOKD:;HKJ?B?P;:?DJ>;JH;7JC;DJE

?F;FJ?:OBF;FJ?:7I; ?D>?8?JEHI)) ?D>?8?JEHI "D9H;J?DI7H;7=HEKFEEHCED;IJ>7J7H;H;IFEDI?8B;;8BEE: =BK9EI;B;L;BI "D9H;J?DIH;B;7I;:7;I;9H;J?EDE;C7?D?D9H;J?D>EHCED;I =BK9EI; :;F;D:;DJ?DIKB?DEJHEF?9 FEBOF;FJ?:; ")7D:=BK97=ED B?A;F;FJ?:; %) 7D::?I9EL;HOE;?HFEJ;DJ?7B 7IJ7H=;JI;JH;7JC;DJE;:?I9EL;HOE<)) ?D>?8?JEHI "DJ>;;7HBO IJ>;KI;E< %) 7I7:?H;9JJ7H=;JM7IIJ?BBB?C?J;::K;JE?JIL;HO<7IJ ?D79J?L7J?ED ->;8H;7AJ>HEK=>?DM7IJ>;7J)) ?IH;IFEDI?8B;;H7F?: ?D79J?L7J?EDE< %) O?D>?8?J?D=)) J>;?D79J?L7J?EDE< %) ?IFH;L;DJ;:M>?9>M7I 9ED;I7C;J?C;J>;HEB;E< )) ?DJ>;?D79J?L7J?EDE;EJ>;H?D9H;J?D>EHCED; ")M7IH;FEHJ;: ->?IC7O>7L; 7::;:L7BK;?DJ>;=BK9EI;BEM;H?D=;<<;9JIE<)) ?D>?8?J?ED (L;H7BB )) ?D>?8?J?ED H;IKBJI?D?D9H;7I;:B;L;BIE< ")7D: %) 8O8BE9A?D=J>;?D79J?L7J?EDE;I;?D9H;J?D >EHCED;IM>?9>?DJKHDBEM;HI8BEE:9?H9KB7J?D==BK9EI;8OJ>;IJ?CKB7J?EDE?8?J?D==BK97=EDI;9H;J?ED ?=

!,)*71'6-212* -1,-&-6245-1/29)4-1+6,)&/22(+/7'25)/)8)/5 ->; :;L;BEFC;DJ E< )) ?D>?8?JEHI 8;=7D M?J> J>; :?I9EL;HO E< L7B?D; FOHHEB?:?D; ,9>;C; "DB7J; IEJ>;HFEJ;DJ?7B)) ?D>?8?JEHIM;H;?DJHE:K9;:8KJ?JJEEA KDJ?B 8;;;JH;7JC;DJE;.,7D:KHEF;7DC7HA;JI ,?J7=B?FJ?D?I7β 7C?DE79?::;H?L7J?L;7D:?JI;I?I M7I FH;I;DJ;: ?D %7J;H ?CFHEL;: I;9ED: 7D: J>?H: =;D;H7J?ED ,9>;C;IODJ>;I;IM;H;FH;I;DJ;: BBC;J>E:IKJ?B?P;7JH?7PEBEF?F;H7P?D;:;H?L7J?L; 7IJ>;A;O?DJ;HC;:?7J;

O + i-Pr2N HEt F F F F F F O O OH O O O O TFA F O F OH t-BuCOCl, DIPEA F O DMAP, MeCN O O O O

HN N xHCl N F F F F N O O NH2 O N CF3 F N N F N N N 39 N NH4OAc N

CF3 MeCN/MeOH CF3 82 % yield over four steps (one-pot)

F F NH2 O [Rh(COD) OTf], O 2 N t-Bu JOSIPHOS F N H2N N N N MeOH, 50 oC 90 psi H2 40 CF3 82 % 38 !,)*-456 -1,-&-6248%/-1)3;442/-(-1) %1(6,)6,-4(+)1)4%6-215;16,)5-52*6,) β%0-12%'-( -1,-&-6245-6%+/-36-1 ;H=B?FJ?DIL?B:7=B?FJ?D I7N7=B?FJ?D 7BE=B?FJ?D 7D: B?D7=B?FJ?D ;DJ;H;: J>; C7HA;J /?B:7=B?FJ?D 7D: I7N7=B?FJ?D 8;BED= JE J>; 9O7DEFOHHEB?:?D; )) <7C?BO ->; ?D?J?7B J>H;; IJ;F IODJ>;I?I HEKJ; ;C;'EL7HJ?I7K;H*7&0 %7J;H 7D 7BJ;HD7J?L;IJ7HJ?D=

HO NH2 N NH ClCOCH2Cl N TFAA 2 Cl Cl N CN N O K CO O NH O N CN H 2 3 O 2 THF K CO THF, THF, rt. 2 3, H O rt., 1 h 52 % yield over rt. 41 two steps 42 30 - 50 % -4565;16,)5-52*6,)';%123;442/-(-1) -1,-&-6248-/(%+/-36-1 ->;;I?IE;9O7DEFOHHEB?:?D;I7N7=B?FJ?D H?IJEB &O;HI,GK?88 ?DLEBL;: J>; IODJ>;I?I E< JME A;O ?DJ;HC;:?7J;I C;J>7DEFHEB?D7C?:; O:HENO7:7C7DJOB=BO9?D;OB;IJ;H ->?IB78EH?EKI 7FFHE79>;B78EH7J;:IJ;FI?DJEJ7B &EH;H;9;DJBO 7D?CFHEL;:7IOCC;JH?97FFHE79>; FH;F7H7J?EDE;C;>7I8;;DF7J;DJ;:8O$EL?*7&0

(i) (S)-(+)-p-toluenesulfinamide/ H CH3COOH, H Ti(OEt) 4 N S HCl NH2 O O (ii) NaCN, NaHSO3, MeOH, CN 91 % COOH KMnO 43 4 62 %

HO HO O O HN O phthalic anhydride KMnO CN N 4 N 45 N K2CO3, DMF O NaOH O O COOH COOH EDC, HOBt, DIPEA O 52 % 44 % N 44 CN HO xHCl

NH2 (i) methyl amine O (ii) HCl N

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i) O CN Br NH2 O CN O CN H3C O NaHCO3, MeOH, NN 48 NaH, CH I H C o xTFA HN N 3 3 NN 100 C HN NH O N O Cl NaH, LiBr, O Cl THF/DMF O Cl (ii) TFA DMF, DMSO 47 49 50 NH2 54 % 72 % 70 - 76 % %6)16)(342')55*246,)34)3%4%6-212*6,)3;4-0-(-1)(-21) -1,-&-624%/2+/-36-1 EHJ>;CEIJH;9;DJ&7D: 7FFHEL;:)) ?D>?8?JEHN7DJ>?D;87I;:B?D7=B?FJ?D E;>H?D=;H "D=;B>;?C JME IODJ>;J?9 7FFHE79>;I >7L; 8;;D H;FEHJ;: ->; H;; IJ;F IODJ>;I?I E< B?D7=B?FJ?D ,9>;C; M7I FH;I;DJ;: 8O 9A>7H:J *7 &0 %7J;H IEC; 7BJ;HD7J?L;7FFHE79>;IM;H;?DJHE:K9;:

O O O N Br N H Br N N HN N HN N N Br Br Br N O N N O N N DIPEA, DMF, rt. O N N K2CO3, DMF, rt. 86 % 77 - 98 %

HN O (i) N NHBoc N N o N K2CO3, DMF, 75 C N O N N (ii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f C;9>7D?ICE<79J?ED?IDED ?DIKB?D:;F;D:;DJM>?9>=?L;IIEC;7:L7DJ7=;I7I7JH;7JC;DJ :?78;J;I , %-I7H;BE97J;:?DJ>;FHEN?C7BJK8KB;?DJ>;A?:D;O7D: 7H; H;IFEDI?8B; ; =BK9EI; H;78IEHFJ?ED "D>?8?J?D= , %- ?D:K9;I =BO9EIKH?7 ;N9H;J?EDE<=BK9EI;?DKH?D; M>?9>B;7:IJEH;C7HA78B;=BK9EI; BEM;H?D=;<<;9JI ?= ->;J>H;I>EB:KC7DI?I7HEKD: C= :% EH F;EFB; M?J> :?78;J;I J>; J>H;I>EB: ?I ?D9H;7I;: JE C= :% M>?9> ?D:K9;I >OF;H=BO9;C?7 !EM;L;H J>;C;9>7D?IC8;>?D:J>?IH;IFEDI;?IIJ?BB;BKI?L;8KJ;L?:;D9;E< J>;HEB;E<, %-I8;?D=?D9H;7I?D=BO;NFH;II;:>7I8;;DI;;D

diabetic nephron diabetic nephron with SGLT2 inhibitor

Decreased glucose Increased glucose excretion in urine excretion in urine

SGLT2 SGLT2

Glucose Glucose SGLT2 inhibitor Increased glucose Reduced glucose reabsorption via reabsorption via SGLT2 SGLT2 inhibition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`=B?H;;=B?7L;8;;D7FFHEL;: 7D:IEC; EJ>;HI 7H; ?D 9B?D?97B JH?7BI ;D;H7BBO J>; IODJ>;I?I E< =B?H;; C7?D CE:?;7HOBCE?;JO 9EKFB?D=E;7HOBCE?;JOM?J>J>;=BO9ED 8O=BK9EIOB7J?ED7D:7IOCC;JH?9H;:K9J?ED7JJ>;7DEC;H?997H8ED;H;CEL7BE< J>;FHEJ;9J?D==HEKFI BB=B?OB;D; 8H?:=; ->H;;7BJ;HD7J?L;7FFHE79>;I>7L;8;;DFH;I;DJ;:?I8H?:=;DK9B;EF>?B?9 7::?J?EDKI?D=EH=7DEC;J7BB?9H;7=;DJI ;B;9JHEF>?B?97HEC7J?9IK8IJ?JKJ?ED8O H?;:;B H7; H;:K9J?ED E< J>; ?DJ;HC;:?7J;I ;DOB8EHED?979?:I "D7::?J?ED J>;; =BO9EIOB?98ED: ?IKIK7BBO:ED;8OJ>;DK9B;EF>?B?97JJ79AE<7D7HOBC;J7BED7D;B;9JHEF>?B?9IK=7H9ECFED;DJ KIK7BBO7B79JED;:;H?L7J?L; 7JJ>;7DEC;H?997H8ED (J>;H;B;9JHEF>?B?9IK=7H:;H?L7J?L;I IK9> 7I ;FEN?:;I >7B?:;I EF;D 9>7?D >;C?A;J7BI 7D: IEC; CEH; KD9ECCED IK=7HI >7L; 7BIE 8;;D KI;: ->; C;J>E:I KI;: J7A; 97H; E< E8J7?D?D= J>; 9EHH;9J IJ;H;E9>;C?IJHOE;=B?;;KHEF;7D7D:.,C7HA;JI7H;97D7=B?;F7J;DJ;:IODJ>;I?IE<97D7=B?E: OB8;DPE?9 79?: M7I FH;I;DJ;: 8O &;J?B *7 &0 7LE?:?D= 7DO FHEJ;9J?ED EH :;FHEJ;9J?EDIJ;FIEDJ>;=BO9EDF7HJ,9>;C;

O O S O F I SOCl AlCl I I S OH 2, 3 Cl F

DMF, AlCl3 chlorobenzene 52 chlorobenzene 65-70 oC, 4h 55-60 oC, 4h

O O TMSO S F TMSO OTMS TMSO TMDS, AlCl OTMS 3 I S F TMSO O chlorobenzene 1) n-BuLi, THF, 45-50 oC, 4h toluene, - 75 oC, 3 h OTMS OTMS 83 % over three steps 2) TFA, 5 oC, 3 h TMSO (one-pot) 84 %

S F S F

OH TES, BF .Et O MsOH, MeOH OH 3 2 OH O O 15 oC, 3 h DCM HO o HO 87 % crude OH -40 C, 3h OH yield OH 67 % OH 53 ;16,)5-52*6,) !-1,-&-624'%1%+/-*/2<-1 34)5)16)(&;)6-/)6%/ ->;;7HBOIODJ>;J?9MEHAEDJ>;I;9ED:7FFHEL;:=B??IFHE9;IIKDJ?B>?HK:*7&0 F7J;DJ;:7DEL;BFHE9;II,9>;C; O O TMSO

TMSO OTMS Cl O Cl O OTMS Et3SiH.BF3 Br DCM Br n-BuLi, THF O 74 %

Cl Cl

O O HO O OTMS MsOH OH Et3SiH.BF3 O O TMSO MeOH HO DCM/MeCN OTMS OH OTMS OH 46 % over two steps Cl

O OH O HO OH OH 54 %6)16)(342')55*246,)34)3%4%6-212* !-1,-&-624(%3%+/-*/2<-1 07D=*7&0 H;FEHJ;:?D 7IODJ>;J?97FFHE79>;FH;F7H7J?EDE<;CF7=B?BEHE8;DP7B:;>O:; 7D:# 9>BEHEF>;DENOJ;JH7>O:HE?A*7&0 ,9>;C;

O Cl OH Cl OTMS Cl CHO O n-BuLi THF TMSCl + O O o - 80 to 70 C Br Et3N Br Br 1-2 h Cl 80 % 55 56 O O

Cl OTMS Cl O O O TMSO

TMSO OTMS O O HO O OTMS OTMS MsOH, MeOH OH O O THF, - 80 to - 60 oC TMSO O 20 to 40 oC HO O 1-2 h OTMS 12-16 h OH OTMS OH

n-BuLi, TES, THF O o OH - 80 to 70 C O 1-2 h HO O OH 23 % OH 57 ;16,)5-52*6,) !-1,-&-624)03%+/-*/2<-1 34)5)16)(&;%75,-.)6%/ ->;B7J;IJ7FFHEL;:C;C8;HE;=B?;I?I8O&7I9?JJ?*7&0 M7I7L;HOB78EH?EKIFHE9;IIM?J>IJ;FI7D: 7DEL;H7BBO?;B:E< IJ7HJ?D=;I7C;=HEKF97C;KFM?J>7D ?CFHEL;: IJ;H;EI;B;9J?L; IODJ>;I?I E< ;HJK=B?;O C7D7=;: JE :;9H;7I; J>; DKC8;HE;EL;H7BBO?;B:E;FHE:K9JJE 7H:MEHAJ>; I7C;=HEKF;I?IE<;HJK=B?;I?IE<;HJK=B??9> H;GK?H;:GK?J;>7HI>7D:J?C; 9EDIKC?D=H;79J?EDI +;9;DJBOB?*7&0 F7J;DJ;:7D?CFHEL;: IODJ>;I?I E< ;HJK=B?;C; I?C?B7H JE &7I9?JJ?fI )E: !;H; >?=>;H O?;B:I 9EKB: 8; E8J7?D;: C7?DBO EM?D= JE 8;JJ;H 7D: CEH; I;B;9J?L; FHEJ;9J?D==HEKFIJH7J;=O

Cl Cl

Br O TBDMSCl O HO O TBDMSO O Et3NNaH HO OH O HO OH O OH OH

Cl Cl

O O (COCl) DMSO TBDMSO O CH3COCl HO O 2, o 30 C, 1 h DCM, Et3N BnO OBn O BnO OBn O OBn OBn

Cl Cl

O O O O O O CH2O, KOH i) TFA, DCM o BnO OBn BnO OBn O DMF, 25 C O ii) H2, Pd/C OBn OBn MeOH/THF, 30 oC

O O HO

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O Cl O O S S O 1) 2 N NaOH, S OH N Cl NH2 H S O THF/MeOH (1:1.25), o K2CO3, MEK O 4 h, 50 C O O O reflux, a OH 2) HCl HOBt, EDC*HCl overnight, dry DMF, rt., overnight Cl Cl Cl 65 61 4)3%4%6-21 2* 6,) 4)*)4)1') '203271( 3-[(4-chlorophenyl)methoxy]-N-](S)-1- phenylethyl]-2-thiophenecarboxamide (61). aEDC*HCl = 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride

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

->;IKBH;;:?<<;H;DJ7D?B?D;I C;J>OB7D?B?D; 8HECE OB :?;IKBBEH?:;IM;9>EI;I?CFB; 7HOB 9ECFEKD:I 7D: >?=>BO ;J;HE7HOB:;H?L7J?L;I9ECFEKD:I 7D: ;16,)5-52**-456+)1)4%6-2157/*21%1-/-()5 R2 R2 3 3 4 NHR NR SO2R 4 pyridine + R SO2Cl Me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fI<7LEH78B;>7B< B?<; C?D -E =;J 7 8;JJ;H KD:;HIJ7D:?D= E< J>; ?CFEHJ7DJ FHEJ;?D B?=7D: ?DJ;H79J?EDI 8;JM;;D J>; IKB;79J?L;I?J;E<,!")F>EIF>7J7I;:EC7?D9HOIJ7BIJHK9JKH;) 7 :E9A?D= IJK:O M7I F;H; KDIK8IJ?JKJ;: 7D: 7BAOBIK8IJ?JKJ;: 7HOB IKBEM;: EDBO 7 <;M ?DJ;H79J?EDI M?J> J>; 79J?L; I?J; E< J>; FHEJ;?D M>;H;7I >;J;HE7HOB IKB7: IEC; 7::?J?ED7B <7LEH78B; >O:HE=;D 8ED: ?DJ;H79J?EDI &EH;EL;H 8O ?D9EHFEH7J?D=;IJHK9JKH;J>;DKC8;HE

7/*21%1-/-() &271(626,)%'6-8)5-6)2* 3,253,%6%5)(20%-1 ,KBJBO8;JM;;DJ>;;79J?L;I?J;E<,!") ->;?CFEHJ7D9;E;I;7C?DE79?:I;8?D:?D=>7I 8;;DFH;L?EKIBO:?I9KII;:8OB;EG*7&0FF7H;DJBO 8;D;;?D>?8?J?ED C7O8;E8J7?D;:8OJ>;I;7C?DE79?:I KHJ>;HCEH; J>;O:HE=;D8ED:;:JEJ>;7C?DE79?:IH=7D: BK7D:π IJ79A?D= ?IE8I;HL;:;F>;DOBH?D=JEJ>;H=KD?J ,;9ED: =;D;H7J?EDIKB?8?JEHI ->; ; :;I?=D E< J>; I;9ED: =;D;H7J?EDJ7?BEH C7:;IKB; ?CFEHJ7DJ ?DJ;H79J?EDI 8;JM;;D J>; FHEJ;?D ,!") 7D: J>; B?=7D: "DEH:;HJE;L7BK7J;J>;?CFEHJ7DJ?DJ;H79J?EDI?D:;J7?B M;CE:;B;:EKH9ECFB;NE< ,!") 7D::;I?=D;:7IC7BBI;JE<:;H?L7J?L;IE< 8O?DI;HJ?D=9>EI;D; IF;9?7J 9EKB: ?D9H;7I; J>; 8?D:?D= 7<;H;8O M; :;I?=D;: 7D: IODJ>;I?P;:ED;IKBCE:?;H 8?EBE=?97B;L7BK7J?ED""" "D?J?7BBOM;M;H;?DJ;H;IJ;:?D9>7D=?D=J>;IKB; ?CFEHJ7D9; E< J>; C;J>OB =HEKF "D 7::?J?ED 7B?F>7J?9 7D: FEB7H =HEKFIIK9>7I>O:HENOB 97H8ENOB7D:97H8EN7C?:;M;H;7::;:JEIF;9?9;HJ7?D7C?DE79?:I ::?D=FEB7H=HEKFI7BIE?CFHEL;I J>;:HK= B?A;FHEF;HJ?;IE;IKB;J7H=;J9ECFEKD:IIKB;I?P;:?DED;IJ;FBEH?:;I 7D: 7D?B?D; EH F>;DEB :;H?L7J?L;I KD:;H 87I?9 9ED:?J?EDI 7I EKJB?D;: ?D I9>;C;

F F O F O F O Cl F S F S Et3N O O + HO DCM F F F F 78 quantitative yield F O O F O Cl pyridine S S + N O N Me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

F F F O Cl F + - F S F NH2 37 % HCl N2 Cl SOCl H O 2, 2 O HO HO CuCl HO 0 oC O O O 80 81 72 %

F F F O Cl O NH2 + - SOCl2, H2O O S 37 % HCl O N2 Cl O CuCl 0 oC 82 83 84 66)03656234)3%4)'200)4'-%//;71%8%-/%&/)57/*21;/',/24-()5 %1( >BEHEIKB;DFHEJ;9J;:7IJ>;C;J>OB;IJ;H :?OB7D?B?D; ?DFOH?:?D;=?L?D=

?D7BBO >O:HEBOP?D=J>;C;J>OB;IJ;HM?J>B?J>?KC>O:HEN?:;%?(!?D-! &;(!!( H;IKBJ;:?DJ>;J7H=;JIKB;C;

F F F O F F O F O N O F O Cl Cl O F S H F S F S F N F S 1. SOCl2, DCM N O O 2. MeOH 86 F LiOH HO O O O F pyridine, MeCN THF:MeOH:H O O 2 O 81 O 85 87 1:3:1 OH 88 49 % 75 % quantitative yield 4)3%4%6-212*6%4+)657/*21%1-/-() ,?D9;J>; ENO8;DP;D;IKBBEH?:; ,9>;C;?DJ;HC;:?7J;I;;C;: L;HOFHED;JEM7H:I>O:HEBOI?IM;:;9?:;:JEKI;J>;ED; FEJI;GK;DJ?7B ,7D:, '9EKFB?D= ;FH;F7H7J?EDE;C;IJ7HJ?D= ?DLEBL;: J>; ENOF>;DOBC7=D;I?KC 8HEC?:;?DJ;HC;:?7J;BEH?D7J?ED7D: :??I9EKFB?D=H;79J?ED<7?B;:CEIJB?A;BO:K;JEJ>;FEEH

=;D;H7J?EDE<,(?DJ>;9KIJEC?P;:H;79J?EDI;JKF "DEKH7BJ;HD7J?L;7FFHE79>M;CE:?;: C;J>E: M>;H; 7 I;GK;DJ?7B , 7D: , ' 9EKFB?D= 8;JM;;D 7 ENOF>;DOB8EHED?979?: 7D: :?

J>;,( IEKH9;JEEAFB79; ,9>;C; ->?I=7L;KIIKB

->;IKBOB7J;:KI?D=?E:EC;J>7D;&;"?DJ>;FH;I;D9;E<$( O?;B:?D= OB7J?ED7JJ>;C;J>ENO=HEKFM?J>&8EHEDJH?8HEC?:;H?D &KD:;H7H=ED7JCEIF>;H;7J °J>;J7H=;J9ECFEKD: M7IE8J7?D;:?D7EL;H7BB O?;B: A) F F F O 1. Mg, I2, dry THF O O Br 2. SO -source O S 2 N H 3. chlorination F F 4. 2,4-difluoroaniline

O2N 89 90

B) F F OH 92 F F F F O F O F O O O O B DABSO, K CO O 2 3 O S MeI, K2CO3 O S BBr3 in DCM HO S OH N N N a H o PTC , dry MeCN F acetone F -75 C- rt F

91 90 93 94 26 % 89 % 66 % !,) -1-6-%/ %66)036 62 34)3%4) 57/*21%1-/-() %1( 6,) 34)3%4%6-21 2* 6,) 6%4+)6 57/*21%1-/-() !3,%5)64%15*)4'%6%/;560)6,;/64-2'6;/%0021-70',/24-() -E E8J7?D J>; ;C; 7D: ,9>;C; 9EDL;DJ?ED7B IODJ>;J?9 C;J>E:I M;H; KJ?B?P;: C?DE

M7I;IJ;H?,(B &;(!H;IKBJ?D=?DJ>;C;J>OB;IJ;H ->;IKB;C;M7I JH?BEH?:;

->;D C;J>OB7J?ED E< M?J> ?E:EC;J>7D; &;" ?D J>; FH;I;D9; E< $( =7L; J>; IKBO:HEBOP;J>;C;J>OB;IJ;H KD:;H87I?99ED:?J?EDIM?J>

%?(!EH7 K($?D:?<<;H;DJIEBL;DJ9EC8?D7J?EDI&;(!-! !(45 -! !(45

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&;(!-! !( M7I KI;: 7 C?NJKH; E< 3 C;J>ENO 7D: 3 >O:HENO M7I E8I;HL;: !EM;L;H M?J>EKJJ>;C;J>7DEBEDBO3 >O:HENO M7IE8J7?D;: KHJ>;HCEH; KI?D=7 K($

7I 87I; ?D -! !( EH J(!( EDBO 3 7*57 8KJENO M7I E8J7?D;: ->;H;

;N7C?D;:J>;;IJ;H9B;7L7=;E< L?77D, JOF;:;7BAOB7J?EDM?J>B?J>?KC?E:?:;%?"?D & M>?9>=7L;J>;97H8ENOB?979?:IK99;II;97H8ENOB?979?:M7I9EDL;HJ;:

JEJ>;79?:9>BEH?:;KI?D=,(B7D:IK8I;GK;DJBOJEJ>;J7H=;JFH?C7HO7C?:;8OJH;7JC;DJ M?J>7GK;EKI7CCED?7 ->;EL;H7BBO?;B:E?I

F O F O F O O O O F S 1. SOCl2, CHCl3 F S N F F S LiI N F 2. NH3 (aq.) N F

F O O DMF F HO O F H2N O

99 100 101 92 % 75 % 92 %

B) R F O O O O O F S F S N F X+ -OR N F

F O O Solvent mix F O O

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