Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].C(O)C.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]#[N:25])[CH2:20][CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.Cl.C(N1N=NC(C2CCN([C@@H]3CN[C@H](C(N4CCSC4)=O)C3)CC2)=N1)(C)(C)C>C(Cl)(Cl)Cl>[ClH:4].[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:3][CH2:1][CH3:2])=[NH:25])[CH2:20][CH2:19]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)Cl
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)(C)n1nnc(C2CCN([C@@H]3CN[C@H](C(=O)N4CCSC4)C3)CC2)n1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=N)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
Acetyl chloride (180 mL) was dropwise added to a mixture of ethanol (160 mL) and chloroform (180 mL) under ice-cooling. After the mixture was stirred for 30 min, a solution of 1-benzyloxycarbonyl-4-cyanopiperidine [product of Example 298 (2), 20.6 g] in chloroform (180 mL) was added thereto under ice-cooling. The mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure to give 1-benzyloxycarbonyl-4-(ethoxycarbonimidoyl)piperidine hydrochloride (28.7 g) as a white solid.
Reaction SMILES: B(F)(F)F.CCOCC.CSC.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30]CC2C=CC=CC=2)=[CH:26][CH:25]=1)=[O:23]>C(Cl)Cl>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)=[O:23]
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1nc2ccccc2s1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CSC
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a 1 L round bottom flask was charged in a solution of boron trifluride diethyl etherate (101.2 g, 312 mmol) and dimethylsulfide (112 g, 809 mmol) in dry methylenedichloride (300 ml). Benzo[d]thiazol-2-yl(4-(benzyloxy)phenyl)methanone (30 g, 86.9 mmol) was added slowly to the mixture and the resulting solution was stirred at room temperature for 72 h. The reaction mixture was then quenched with water and diluted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by silica gel column chromatography with hexane and ethyl acetate to give benzo[d]thiazol-2-yl(4-hydroxyphenyl)methanone. [M+H]=256.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.O.[OH-].[Li+].CO>C1COCC1>[CH3:21][C:19]1[CH:18]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cc(C)cc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(C)cc(CC2CCc3[nH]c(C(=O)O)cc32)c1

Procedure:
The title compound was synthesized from methyl 4-(3,5-dimethylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.066 g, 0.23 mmol) and lithium hydroxide monohydrate (0.049 g, 1.16 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF was used. The resulting product was purified by chromatography over silica gel (gradient 0 to 100% EtOAc in heptane over 20 min) to afford the title compound. 30 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.06 (ddt, J=12.47, 8.52, 6.03, 6.03 Hz, 1H), 2.26 (s, 6H), 2.44-2.70 (m, 5H), 3.17-3.26 (m, 1H), 6.31 (s, 1H), 6.79 (s, 2H), 6.82 (s, 1H). LCMS m/e 270 (M+H) and 97% pure by HPLC.
Reaction SMILES: CO[C:3](=[O:26])[CH:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[S:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([N:8]3[C:3](=[O:26])[CH:4]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:5][C:6]3=[S:7])[S:10][C:11]=2[CH:17]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=S)Nc1nc2ccc(F)cc2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C(Cc2ccccc2)NC(=S)N1c1nc2ccc(F)cc2s1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
A solution of N-[[(6-fluoro-2-benzothiazolyl)amino]thioxomethyl]-DL-phenylalanine methyl ester (0.90 g, 2.31 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 48 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl ether-hexanes to provide 251 mg (31%) of the titled product:
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][CH2:13][C@:14]4([CH3:25])[C:18]([C:19]5[CH:20]=[CH:21][CH:22]=[N:23][CH:24]=5)=[CH:17][CH2:16][C@H:15]4[C@@H:10]3[CH2:9][CH:8]=[C:7]1[CH2:6][C@@H:5]([OH:26])[CH2:4][CH2:3]2.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:28][C:27]([O:26][C@@H:5]1[CH2:6][C:7]2[C@@:2]([CH3:1])([C@@H:11]3[C@@H:10]([CH2:9][CH:8]=2)[C@@H:15]2[CH2:16][CH:17]=[C:18]([C:19]4[CH:20]=[CH:21][CH:22]=[N:23][CH:24]=4)[C@@:14]2([CH3:25])[CH2:13][CH2:12]3)[CH2:3][CH2:4]1)=[O:29]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Temperature: -2.5 °C
Reaction time: 25 h

Procedure:
The crude abiraterone thus obtained (about 64 g) is taken up in methylene chloride (350 mL), and the resulting mixture, cooled to a temperature of −5 to 0° C., is added with acetic anhydride (130 mL) and then with triethylamine (190 mL), maintaining the temperature at −5 to 0° C. The mixture is stirred at room temperature for about 25 h, then washed with water and concentrated under vacuum, taking up the residue in acetone (250 mL). The resulting solid is isolated by filtration (at 0-5° C.) and dried under vacuum at 40° C. for 16 h (about 46 g; purity: 82.5%; assay: about 73%). A second fraction of crude abiraterone acetate, as an oil, is obtained by concentration of the mother liquor under vacuum (54 g, purity: 74%, assay: about 45%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH3:15])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[P:16](Cl)([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17]>N1C=CC=CC=1>[CH2:19]([O:18][P:16]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)([O:21][CH2:22][CH3:23])=[O:17])[CH3:20]
Reactant: CCOC(=O)/C(=N\OC)c1csc(N)n1
Reactant: CCOP(=O)(Cl)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(=NOC)c1csc(NP(=O)(OCC)OCC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirred solution of 4.6 g (0.02 mol) of ethyl 2-(aminothiazol-4-yl)-Z-2-methoxyiminoacetate in 40 ml pyridine at 10°-20° was added 9.0 ml (0.6 mol) diethyl chlorophosphate. The solution was stirred at room temperature for 2 hours. Pyridine was evaporated and the residue was codistilled with benzene and partitioned between water and methylene chloride. The methylene chloride layer was washed with excess 10% aqueous HCl, water, aqueous bicarbonate, saturated sodium chloride, and dried over sodium sulfate. Upon evaporation, 5.5 g brown oil was obtained which was purified on Biosil A using hexane/ethyl acetate (1:4) to afford 2.8 g of yellow crystals, m.p. 96.5-98.0; NMR (300MH2, DCCl3) δ 1.35 (3t, 9, CH2CH3), 3.97 (S, 3, OCH3), 4.17 (q, 4, OCH2), 4.39 (q, 2, OCH2), 6.93 (s, 1, thiazole H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7])=[O:2].[C:24](O)([C:26](F)(F)F)=[O:25].C1OC1C>C(Cl)Cl>[OH:25][CH:24]([CH3:26])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]([C:5]2[CH:4]=[C:3]([CH:23]=[CH:22][CH:21]=2)[CH:1]=[O:2])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C=O)c2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: CC1CO1
Solvent: ClCCl
Product: CC(O)CN1CCN(C(=O)c2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.5 %

Procedure:
To a solution of tert-butyl 4-(3-formylbenzoyl)piperazine-1-carboxylate 21 (700 mg, 2. 2 mmol) in DCM (5 mL) was added TFA (1.75 mL, 1.54 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3 h. After 3 h, RM was washed with 10% sodium bicarbonate solution and concentrated. The crude material was dissolved in methanol (4 mL) and propylene oxide (892 mg, 15.3 mmol) was added. The reaction was heated at 55° C. for 15 h. TLC analysis indicated complete consumption of starting material. The reaction mixture was concentrated and purification of crude material by column chromatography (3% MeOH/DCM, Silica (230-400)) afforded product as white sticky solid (100 mg, 16.4%).
Reaction SMILES: C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.N[CH:16]1[C:34](=[O:35])[N:18]2[C:19]([C:31]([OH:33])=[O:32])=[C:20]([CH2:23][S:24][C:25]3[S:26][C:27]([CH3:30])=[N:28][N:29]=3)[CH2:21][S:22][C@H:17]12.O>CC(C)=O>[CH3:30][C:27]1[S:26][C:25]([S:24][CH2:23][C:20]2[CH2:21][S:22][C@@H:17]3[CH2:16][C:34](=[O:35])[N:18]3[C:19]=2[C:31]([OH:33])=[O:32])=[N:29][N:28]=1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.7 %

Procedure:
3-(N-tert-butoxycarbonylamino)-3-(2-thienyl)-DL-propionic acid (10.8 g.) and triethylamine (4.04 g.) were dissolved in dry acetone (200 ml.) with stirring at room temperature. On cooling the solution at -10° to -15° C, pivaloyl chloride (4.82 g.) was added to the solution all at once with stirring. The mixture was stirred at -10° to -15° C for an hour and then cooled to -40° to -50° C. To the mixture was added a mixture of 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (13.76 g.), triethylamine (12.0 g.), water (40 ml.) and acetone (160 ml.) all at once. The resultant mixture was stirred at -40° to -50° C for 1.5 hours and then at room temperature for 2 hours. The acetone was removed from the reaction mixture under reduced pressure and the residue was washed with ethyl acetate. The aqueous layer was separated, adjusted with 10% hydrochloric acid to pH 1 and extracted with ethyl acetate. The extract was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal and then concentrated under reduced pressure. Ether was added to the concentrate and the mixture was stirred for 3 hours. The precipitate was filtered to give 7-[3-(N-tert-butoxycarbonylamino)-3-(2-thienyl)-DL-propionamido[-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (15.1 g.), m.p. 130° to 135° C (dec.).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=2)[NH:16][C:15]([C:27]2[S:28][CH:29]([CH2:32][C:33]([OH:35])=O)[CH2:30][N:31]=2)=[CH:14]3)=[CH:6][CH:5]=1.Cl.C[N:38](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>CCCCCC.C(OCC)(=O)C.CO.O.CN(C)C=O>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:19]=2)[NH:16][C:15]([C:27]2[S:28][CH:29]([CH2:32][C:33]([NH2:38])=[O:35])[CH2:30][N:31]=2)=[CH:14]3)=[CH:6][CH:5]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(N)=O)S4)cc3c2)cn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A mixture of {2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (400 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (308 mg), 1-hydroxybenzotriazole (135 mg), and N,N-dimethylformamide (15 mL) was stirred at 50° C. for 30 min. The reaction solution was cooled to room temperature, 10% aqueous ammonia solution (1.5 mL) was added, and the mixture was stirred at room temperature for 2.5 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (methanol:ethyl acetate:hexane=0:50:50 to 15:85:0, volume ratio) to give an orange oil. The obtained orange oil was purified by preparative HPLC to give the title compound (180 mg, yield 45%) as a white amorphous solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:43])=[N:14][C:15]([CH3:42])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CCO.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:43])=[N:14][C:15]([CH3:42])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccccc3OC)cc2)c1N1CCC(C)(C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccccc1COc1ccc(-c2c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c2N2CCC(C)(C)CC2)cc1
Yield: 72.1 %

Procedure:
A mixture of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((2-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.036 g, 0.061 mmol) and LiOH (0.015 g, 0.611 mmol) in 9:1 EtOH/H2O (2 mL0 was refluxed for 3 h. Then, cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((2-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid (0.0247 g, 0.044 mmol, 72.0% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.50 (dd, J=1.5, 7.5 Hz, 1H), 7.34 (dt, J=1.7, 7.8 Hz, 1H), 7.14-7.17 (m, 1H), 7.06-7.10 (m, 3H), 7.01 (dt, J=1.0, 7.5 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 5.94 (br. s., 1H), 5.17-5.24 (m, 2H), 3.91 (s, 3H), 3.61 (br. s., 1H), 2.90 (br. s., 1H), 2.66 (s, 3H), 2.24 (s, 3H), 1.24 (s, 9H), 0.88 (br.s., 3H), 0.68 (br.s., 3H). 6H of piperidine were not resolved. LCMS (M+H)=561.4.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[N:23][N:24]([CH3:42])[C:25]=1[C:26]1[CH:27]=[C:28]([NH:33][C:34]([C:36]2[CH:40]=[C:39]([CH3:41])[O:38][N:37]=2)=[O:35])[CH:29]=[CH:30][C:31]=1[OH:32].CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH2:58][C@@H:59]([NH:61]C(=O)OC(C)(C)C)[CH3:60]>C1COCC1>[NH2:61][C@@H:59]([CH3:60])[CH2:58][O:32][C:31]1[CH:30]=[CH:29][C:28]([NH:33][C:34]([C:36]2[CH:40]=[C:39]([CH3:41])[O:38][N:37]=2)=[O:35])=[CH:27][C:26]=1[C:25]1[N:24]([CH3:42])[N:23]=[CH:22][C:21]=1[Cl:20]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: Cc1cc(C(=O)Nc2ccc(O)c(-c3c(Cl)cnn3C)c2)no1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(OC[C@H](C)N)c(-c3c(Cl)cnn3C)c2)no1
Temperature: 65 °C
Yield: 21.34 %

Procedure:
Weighed polymer supported Triphenylphosphine (181 mg, 271 μmol, 3 eq; 1.5 mmol/gm) into a 20 mL scintillation vial; capped and flushed with nitrogen. The resin was then suspended in 2.0 mL dry THF and mixed in a rotary shaker for 2 minutes. N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-5-methylisoxazole-3-carboxamide (30.00 mg, 90.20 μmol) was added. The suspension was mixed briefly then DIAD (diisopropyl azodicarboxylate, 27.94 μl, 144 μmol) was added. After 30 minutes in a rotary shaker a solution of (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (19.75 mg. 112.7 μmol) in 0.5 mL of dry THF was added. The resulting suspension was heated to 65° C. and mixed overnight. LCMS showed that the reaction did not go to completion. A fresh batch of DIAD (27.94 μl, 144.3 μmol) and (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (19.75 mg. 112.7 μmol) were added to the reaction mixture and the suspension was heated to 65° C. and mixed overnight. The suspension was filtered and the resin washed with THF (3×3 mL). The filtrate and washings were combined and concentrated under vacuum. The resulting residue was dissolved in 20% TFA in DCM (2.0 mL), heated to 65° C. and mixed in a rotary shaker for 1.0 hour. The organic solvent was removed under vacuum and the crude residue was dissolved in acetonitrile (0.8 mL), neutralized with saturated NaHCO3 and subjected to purification by preparative LCMS. The desired fractions were pooled, frozen and lyophilized to afford the title compound as an off-white solid (21.34% yield). LCMS m/z=390.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.82 Hz, 3 H), 2.54 (s, 3 H), 3.46-3.57 (m, 1 H), 3.66 (bs, 3 H), 3.95-4.16 (m, 2 H), 6.66 (s, 1 H), 7.35 (dd, J=9.09, 2.53 Hz, 1 H), 7.66 (s, 1 H), 7.74 (d, J=2.53 Hz, 1 H), 7.95 (dd, J=9.09, 2.53 Hz, 1 H), 7.97-8.04 (bs, 2 H), 10.76 (s, 1 H).
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.C([Li])(C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[F:18])[NH2:14].C([Li])CCC.C1([Li])CC1.CCOCC.O=O.[OH-].[NH4+].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([NH:14][C:13]2[CH:15]=[CH:16][C:17]([F:18])=[C:11]([Br:10])[CH:12]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(F)c(Br)c1
Reactant: BrC1CC1
Agent: O=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: Fc1ccc(NC2CC2)cc1Br
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 28.9 %

Procedure:
To a flame dried flask containing 60 ml of anhydrous ethyl ether was added 5.63 g (46.5 mmoles) of cyclopropylbromide, and then the mixture was cooled to -78° C. under a nitrogen atmosphere. Then, 27.4 ml (46.5 mmoles) of 1.7M t-butyllithium was added slowly. The mixture was then warmed to -40° C. Into another flame dried flask was placed 2.95 g (15.5 mmoles) of 3-bromo-4-fluoroaniline and 50 ml of anhydrous tetrahydrofuran. This mixture was also cooled to -78° C. under nitrogen atmosphere. Then, 9.7 ml (15.5 mmoles) of 1.6M n-butyllithium was added to the second mixture which was stirred at -78° C. for 25 minutes followed by the addition of 1.39 g (15.5 mmoles) of cuprous cyanide. The mixture was then warmed to -40° C., stirred for 30 minutes at -40° C. and then cooled to -78° C. Then, the anilinocuprate was added via inverse addition by a cannula to the cyclopropyllithium/ether solution at -78° C. The reaction mixture was warmed to room temperature and maintained at room temperature overnight followed by heating to 35° C. in an oil bath for about 9 hours. The mixture was cooled to -78° C., oxygen was added for 5 minutes and then 100 ml of 1:1 concentrated ammonium hydroxide/saturated ammonium chloride was added. The mixture was warmed to room temperature, and the organic layer was washed three times with 1:1 ammonium hydroxide/ammonium chloride and twice with saturated brine. The resulting solution was dried over anhydrous sodium sulfate, suction filtered, concentrated in vacuo and column chromatographed on silica gel (20% ethyl acetate/hexanes, 1% triethylamine) to give the title compound as two components [1.03 g (28.9% yield) and 1.30 g (44.1%) yield].
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([NH:14][S:15]([C:18]([Cl:22])=[C:19]([Cl:21])[Cl:20])(=[O:17])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl:23][C:24]([Cl:30])([S:28]Cl)[CH:25]([Cl:27])[Cl:26]>ClCCl>[CH:8]1([N:14]([S:28][C:24]([Cl:30])([Cl:23])[CH:25]([Cl:27])[Cl:26])[S:15]([C:18]([Cl:22])=[C:19]([Cl:20])[Cl:21])(=[O:17])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=S(=O)(NC1CCCCC1)C(Cl)=C(Cl)Cl
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C(Cl)=C(Cl)Cl)N(SC(Cl)(Cl)C(Cl)Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A 4.0 g (0.04 mol) sample of triethylamine was added dropwise to a cooled (-10° to 0° C.) solution of 9.5 g (0.0324 mol) N-(cyclohexyl)trichlorovinylsulfonamide, m.p. 152°-153° C., and 7.6 g (0.0324 mol) 1,1,2,2-tetrachloroethylsulfenyl chloride in 200 ml dichloromethane. The reaction mixture was then stirred at about 25° C. for 3 hours, washed with water, dried over magnesium sulfate and evaporated to give an oil. The oil was chromatographed on silica gel. The N-cyclohexyl-N-(1,1,2,2-tetrachloroethylthio)trichlorovinylsulfonamide product, 11 g (72% yield), was eluted from the silica gel with 30% ether/20% hexane. The infrared spectrum of the product showed strong absorption bands at 1385 cm-1 and 1160 cm-1. The elemental analysis for the product is tabulated in Table I under Compound No. 6.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:12])[CH2:7][C:8]([CH2:10][Cl:11])=[O:9])[CH2:2][CH2:3][CH3:4]>C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6](=[O:12])[CH2:7][C@@H:8]([OH:9])[CH2:10][Cl:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)CC(=O)CCl
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)C[C@@H](O)CCl

Procedure:
The procedure of example 375 was repeated using n-butyl-4-chloroacetoacetate as the substrate to afford n-butyl-4-chloro-3(R)-hydroxybutyrate, [α]D23 +20.1° (c, 3.1, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1.[H-].[Na+].O>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:8])[CH2:15][S:12](=[O:14])(=[O:13])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CS(=O)(=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of methyl 4-bromo-2-(methylsulfonyl)benzoate (774 mg, 2.64 mmol) in anhydrous THF (10 mL) was added NaH (60% in mineral, 111 mg, 2.77 mmol). The mixture was stirred at room temperature for 5 hr. The reaction was monitored by LCMS for completion. H2O (1 mL) was added to quench the reaction followed by the addition of aqueous hydrochloric acid (1N, 50 mL) and EtOAc (50 mL). The organic layer was separated, and the water layer was extracted with 2×EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (689 mg, 100%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([C:11]#[N:12])=[C:9]([OH:10])[C:4]=2[C:3]=1[C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21]([OH:23])=O)=[CH:17][CH:16]=1.C[CH2:27][N:28]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CN>CN(C=O)C.ClCCl>[Cl:1][C:2]1[S:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([C:11]#[N:12])=[C:9]([OH:10])[C:4]=2[C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]([NH:28][CH3:27])=[O:23])=[CH:24][CH:25]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: N#Cc1c(O)c2c(-c3ccc(OCC(=O)O)cc3)c(Cl)sc2[nH]c1=O
Agent: CN
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)COc1ccc(-c2c(Cl)sc3[nH]c(=O)c(C#N)c(O)c23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of [4-(2-chloro-5-cyano-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridin-3-yl)-phenoxy]-acetic acid (20 mg, 0.053 mmol, Example 184A)), EDCI (10.2 mg, 0.053 mmol), HOBT (7.2 mg, 0.053 mmol), and NMM (0.0146 mL, 0.133 mmol), in DMF (0.4 mL) was added methylamine (0.0265 mL, 0.053 mmol, 2M in THF). The solution was stirred at room temperature overnight. The solution was diluted with dichloromethane, washed with water, concentrated to dryness and purified by RP-HPLC to give the title compound. MS (ESI) m/e 387.9 (M−H)+; 1H NMR (300 MHz, MeOD-d4) δ 2.9 (s, 3H), 4.55 (s, 2H), 4.8 (m, 2H), 6.95 (d, 2H), 7.30 (d, 2H).