Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:17])=[O:7]
Reactant: O=C(O)c1ccc(Br)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1O
Yield: 52 %

Procedure:
4-Bromosalicylic acid (15.5 g, 71 mmol) was dissolved in methanol (500 ml), and concentrated sulfuric acid (9.7 g, 99 mmol) was added thereto. The reaction mixture was refluxed for 24 hrs, and the solvent was evaporated. The residue was neutralized with 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:20, v/v) were collected and concentrated to give methyl 4-bromosalicylate (8.7 g, 52%). Methyl 4-bromosalicylate (8.7 g, 37 mmol) and N,N-dimethylthiocarbamoyl chloride (6.0 g, 48 mmol) were dissolved in DMF (80 ml), and 1,4-diazabicyclo[2.2.2]octane (5.5 g, 49 mmol) was added thereto. The reaction mixture was stirred at room temperature for 24 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:4, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (10.6 g, 88%) as white crystals.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20](OC)=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=3)[CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>O>[C:28]1([CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([NH:38][CH2:37][CH2:36][O:35][CH3:34])=[C:19]([N+:25]([O-:27])=[O:26])[CH:18]=3)[CH2:14][CH2:15]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1[N+](=O)[O-]
Reactant: COCCN
Agent: Cl
Solvent: O
Product: COCCNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1[N+](=O)[O-]
Yield: 51 %

Procedure:
A solution of 20.8 parts of 1-(diphenylmethyl)-4-(4-methoxy-3-nitrophenylmethyl)piperazine dihydrochloride in 50 parts of 2-methoxyethanamine is stirred and refluxed overnight. Water is added and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified twice by columnchromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 11.6 parts (51%) of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N-(2-methoxyethyl)-2-nitrobenzenamine; mp. 97.2° C.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:12]([CH3:17])=[N:13][O:14][C:15]=1[CH3:16])=[O:10])[NH:2]2.[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[C:22]([C:24](O)=[O:25])[N:23]=1>>[NH2:18][C:19]1[S:20][C:21]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[C:22]([C:24]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:25])[N:23]=1
Reactant: Cc1noc(C)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Cc1noc(C)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 3,5-dimethyl-isoxazole-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.23 min; [M+H]+=456.1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[NH:17][C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.Br[CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[I:36]>C1COCC1>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[N:17]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=[CH:28][C:27]=3[I:36])[C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.4 %

Procedure:
To a stirred suspension of sodium hydride (60% dispersion in mineral oil; 1.3 g; 0.0325 mol) in THF (60 mL) at 0° C. under N2 was added dropwise a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Example 17) (4.077 g; 0.013 mol) in THF (50 mL). Gas evolution was observed. The resultant mixture stirred at 0° C. for 30 min prior to addition of a solution of 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (4.754 g; 0.013 mol) in THF (20 mL). The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was carefully quenched with H2O (15 mL) and partitioned between EtOAc (250 mL) and H2O (75 mL). The aqueous layer was extracted with EtOAc (3×100 mL). Combined organic layers were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc/hexanes gradient) to afford 6.4 g (82.5%) of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS=598.1 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.03 (d, J=8.2 Hz, 1H), 7.90 (s, 1H), 7.79 (s, 2H), 7.58 (s, 1H), 7.30 (dd, J=8.2 Hz, J=2.0 Hz, 1H), 5.76 (d, J=8 Hz, 1H), 4.88 (d, J=15.8 Hz, 1H), 4.37 (d, J=15.8 Hz, 1H), 4.09-4.02 (m, 1H), 0.8 (d, J=6.6 Hz, 3H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH2:7][C:8]([N:10]2[CH:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][O:12][C:11]2=[O:22])=[O:9])[C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]1=2.C([N-]C(C)C)(C)C.[Li+].Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>O1CCCC1>[C:40]([O:39][C:37](=[O:38])[CH2:36][C@H:7]([CH2:6][C:4]1[C:3]2[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=2[S:1][CH:5]=1)[C:8]([N:10]1[CH:14]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:13][O:12][C:11]1=[O:22])=[O:9])([CH3:43])([CH3:42])[CH3:41]
Reactant: O=C(CCc1csc2ccccc12)N1C(=O)OCC1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](Cc1csc2ccccc12)C(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-benzo[b]thiophen-3-yl-propionyl)-4-benzyl-oxazolidin-2-one (3.35 g, 9.18 mmol) in 100 mL anhydrous tetrahydrofuran at −78° C. was added lithium diisopropyl amide in tetrahydrofuran (6.1 mL, 11.01 mmol) and the reaction mixture was stirred for 30 min Following addition of t-butyl bromoacetate (1.62 mL, 11.01 mmol) at −78° C., the mixture was stirred overnight while it was allowed to warm to room temperature. The solvent was evaporated and the residue diluted with ethyl acetate. The organic layer was washed with water (3×100 mL), dried, filtered, and concentrated to give the crude product. The title product was obtained by filtration through a pad of silica, eluting with methylene chloride (49%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)C>[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(N)nc2)cn1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A degassed mixture of 2-amino-5-bromopyridine (3.5 g, 20.23 mmol), 6-methoxypyridin-3-ylboronic acid (3.71 g, 24.28 mmol) and bis[3-(diphenylphosphanyl)-cyclopenta-2,4-dien-1-yl]iron-dichloropalladium-dichloromethane complex (413 mg, 0.51 mmol) in 1,4-dioxane (36 mL) and a 2M aqueous potassium carbonate solution (36.4 mL) was heated at 90° C. under a nitrogen atmosphere for approximately 16 h. The reaction mixture was allowed to cool to room temperature and diluted with diethyl ether (100 mL). The organic phase was separated off, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was triturated with DCM (10 mL) and filtered, to afford the title compound (3.36 g, 83%) as a light brown solid. Method C LCMS: MH+ m/z 202, RT 0.60 minutes.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]3=[N:12][CH2:13][CH2:14][CH2:15][N:9]3[C:8]=2[CH:16]=1)([O-])=O.N.[H][H]>[Pd].CO>[N:12]1[CH2:13][CH2:14][CH2:15][N:9]2[C:8]3[CH:16]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=3[S:11][C:10]=12
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)N1CCCN=C1S2
Agent: [Pd]
Agent: N
Solvent: CO
Product: Nc1ccc2c(c1)N1CCCN=C1S2

Procedure:
A mixture of 18 parts of 3,4-dihydro-7-nitro-2H-pyrimido[2,1-b]benzothiazole and 240 parts of methanol, previously saturated with gaseous ammonia is hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 8.6 parts of 3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-amine; mp. 197° C.
Reaction SMILES: [S:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[S:4][CH2:3][CH2:2]1.[H-].[Na+].[C:14](=O)([O:17]C)[O:15][CH3:16]>C1COCC1>[CH3:16][O:15][C:14]([C:9]1[CH2:10][C:5]2([CH2:6][CH2:7][C:8]=1[OH:11])[S:4][CH2:3][CH2:2][S:1]2)=[O:17]
Reactant: O=C1CCC2(CC1)SCCS2
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1=C(O)CCC2(C1)SCCS2
Temperature: 25 °C

Procedure:
To 1,4-dithia-spiro[4.5]decan-8-one (2.35 g, 12.5 mmoL, 1.0 eq), in THF (10 mL) at 0° C. under nitrogen was added NaH (60%, 2.0 g, 50 mmoL, 4.0 eq) slowly. After gas releasing was completed, dimethy carbonate (11.3 g, 125 mmoL, 10.0 eq) was added via syringe. The reaction mixture was warmed to room temperature and further heated at 50° C. for 2 hours. The reaction was then cooled down to room temperature and quenched with saturated ammonia chloride solution. The solvent was removed in vacuo and the residue was partitioned between ethyl ether and water. The aqueous layer was extracted with ethyl ether twice. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a colorless oil. The crude material was then purified by column chromatography using 5:1 hexanes: ethyl acetate to give the title compound as a colorless solid.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH:9]1([C:13]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10]1.CO>S(=O)(=O)(O)O>[CH:9]1([C:13]2[CH:22]=[C:21]([CH3:23])[C:20]([I:1])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(C)cc1C1CCC1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(I)c(C)cc1C1CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-Iodosuccinimide (5.25 g, 23.3 mmol) was added portionwise to a solution of methyl 2-cyclobutyl-4-methylbenzoate (219.2, 4.77 g, 23.3 mmol) in concentrated sulfuric acid (100 ml) at 0° C. The mixture turned very thick after it was stirred at 0° C. for 30 min and at RT for 2 hours. The mixture was cooled to 0° C. again and MeOH (100 ml) was added. The mixture was heated at 60° C. for 2 hours. The methanol was removed under reduced pressure and the residue was poured into ice water (200 ml). The mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, then aq. 1N NaHCO3, dried (Na2SO4), and concentrated. The residue was purified using column (silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1). Yield: 5.0 g, clear oil, 65%. 1H NMR (400 MHz, Chloroform-d) δ 8.19 (s, 1H), 7.24 (s, 1H), 4.17-4.04 (m, 1H), 3.86 (s, 3H), 2.48-2.44 (s, 3H), 2.40-2.28 (m, 2H), 2.13-1.92 (m, 3H), 1.85-1.75 (m, 1H).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C@@H:11]1[C@@H:23]([OH:37])[C@@H:24]([N+:34]([O-])=O)[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O>CO.[Ni](Cl)Cl>[C:3]([O:7][C:8]([N:10]1[CH2:14][C@H:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C@@H:11]1[C@@H:23]([OH:37])[C@@H:24]([NH2:34])[CH2:25][C:26]1[CH:27]=[C:28]([F:33])[CH:29]=[C:30]([F:32])[CH:31]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@@H]1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reaction time: 0.33 h
Yield: 94.9 %

Procedure:
Add sodium borohydride (0.242 mg, 6.42 mmol) over 1 minute to a solution of (2R,4R)-4-benzyloxy-2-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-2-nitropropyl]pyrrolidine-1-carboxylic acid tert-butyl ester (0.696 g, 1.41 mmol) and nickel (II) chloride (0.29 g, 2.25 mmol) in methanol (30 mL) at room temperature. Stir 20 minutes, add water (3 mL) and evaporate the methanol. Partition the residue with ethyl acetate and water. Filter through a filtering agent, wash with ethyl acetate (300 mL), separate away the aqueous layer, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), filter and concentrate to give the title compound as a colorless oil (619 mg, 95%).
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH2:3][CH:4]=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:1][C:2]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]2[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)([CH3:6])[CH2:3][CH2:4][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CC=O)cn1
Reactant: C1COCCN1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CCN2CCOCC2)cn1

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid [1-(1,1-dimethyl-3-oxo-propyl)-1H-imidazol-4-yl]-amide was reacted with morpholine to afford the title compound: MS m/z 492.2 (M+1).
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6](=[O:8])[CH3:7])(=[O:4])=[O:3].[Br:9][C:10]1[CH:11]=C[C:13]2[N:18]=[C:17]([CH3:19])OC(=O)[C:14]=2[CH:21]=1.Cl>CN(C)C=O>[Br:9][C:10]1[CH:11]=[C:7]2[C:13](=[CH:14][CH:21]=1)[N:18]=[C:17]([CH3:19])[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[C:6]2[OH:8]
Reactant: CC(=O)CS(C)(=O)=O
Reactant: Cc1nc2ccc(Br)cc2c(=O)o1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1nc2ccc(Br)cc2c(O)c1S(C)(=O)=O
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
Methanesulfonylacetone (12.6 g, 92.9 mmol) was dissolved in N,N-dimethylformamide (200 mL) and cooled in ice under nitrogen. Then potassium tert.butylate (11.7 g, 102 mmol) was added (exothermic 20° C.) and stirring without cooling continued for 15 min. Cooled in ice again, then 6-bromo-2-methyl-4H-3,1-benzoxazin-4-one (example B.1) (22.3 g, 92.9 mmol) was added and then stirred without cooling for 4 h. Cooled in ice again, then potassium tert.butylate (11.7 g, 102 mmol) was added, and the resulting red solution was stirred at 20° C. for 15 min and then heated at 100° C. for 30 min. After cooling, 4 M HCl (30 mL) was added, and the mixture was evaporated thoroughly at 0.1 mbar/50° C. The residue was suspended in water (200 mL) and stirred vigorously for 30 min which led to the formation of a filterable precipitate. This solid was filtered off and washed with water (50 mL). One obtained 14.25 g (48.5%) of white crystals. MS: m/z=315/317 (M+H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[CH:12][CH:11]=1.[I:22]I>C1COCC1>[I:22][C:20]1[S:19][CH:18]=[C:17]([CH2:16][C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH:21]=1
Reactant: Fc1ccc(Cc2ccsc2)cc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(Cc2csc(I)c2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 87.6 %

Procedure:
To a solution of LDA (3.67 mmol) in THF at -78° C. was added a solution of 3-(4-fluorophenylmethyl)thiophene (640 mg, 3.33 mmol), prepared as in Example 35, step 1, and the reaction mixture was stirred for 25 min. A solution of I2 (1.01 g, 4.00 mmol) in THF was added and the cold bath was removed. The reaction mixture was warmed to ambient temperature, quenched with saturated aqueous NH4Cl, and extracted with ether. The organic phase was washed with 1N aqueous H3PO4, saturated aqueous NaHCO3, saturated aqueous Na2S2O3, and brine, dried over MgSO4, filtered, and concentrated in vacuo to give 928 mg of 2-iodo-4-(4-fluorophenylmethyl)thiophene which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.S(Cl)(Cl)=O.[CH3:16]O>>[OH:1][CH2:2][CH:3]1[CH2:4][CH2:5][CH:6]([C:9]([O:11][CH3:16])=[O:10])[CH2:7][CH2:8]1
Reactant: CO
Reactant: O=C(O)C1CCC(CO)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.). solution of 4-(hydroxymethyl)cyclohexanecarboxylic acid (40 g) in methanol (632 mL) was added thionyl chloride (22.15 mL) dropwise via an addition funnel. The reaction was slowly warmed to room temperature, stirred for 1 hour, concentrated by rotary evaporation, and the residue was purified by regular phase flash column chromatography (Analogix, 0-100% hexanes/ethyl acetate).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[C:23]([O:1][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1)(=[O:25])[CH3:24]
Reactant: OCc1coc(SCCC(F)=C(F)F)n1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1coc(SCCC(F)=C(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
3 g of 4-hydroxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole and 1.5 g of triethylamine were dissolved in 50 ml of dichloromethane, to which a solution of 1 g of acetyl chloride in 20 ml of dichloromethane was added dropwise under ice cooling. After stirring at room temperature for 8 hours, the mixture was washed with water and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was treated by column chromatography to obtain 2.7 g of 4-acetoxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole (yield 76.5%). n20D=1.4752.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH3:14][S:15][C:16](=[O:29])[CH2:17][C@H:18]([NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:19]([OH:21])=[O:20].[Cl-].[NH4+]>CN(C=O)C>[CH3:14][S:15][C:16](=[O:29])[CH2:17][C@H:18]([NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH:26]=[CH2:27])[C:19]([O:21][CH2:2][C:3]#[N:4])=[O:20]
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SC)C(=O)O
Reactant: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCC(=O)N[C@@H](CC(=O)SC)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
2-Bromoacetonitrile (2.64 ml, 37.8 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.29 ml, 18.9 mmol) were added to a solution of (S)-4-(methylthio)-4-oxo-2-(pent-4-enamido)butanoic acid (Compound 1f-IA) (1.17 g, 3.78 mmol) in DMF (5 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (3 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→30/70) to afford (S)-cyanomethyl 4-(methylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1g-IA) (368 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.5 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then, under nitrogen atmosphere, pyrrolidine (1.99 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature over the weekend. The precipitate which had formed was filtered and the filtrate was evaporated to dryness. The solid residue was triturated with water and dried under high vacuum at 50° C. overnight. The solid was recrystallized from isopropyl alcohol with refrigeration. The precipitate was collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at room temperature overnight to give 2.84 g (60%) of title compound, mp 224°-225° C.
Reaction SMILES: [CH2:1]([C:3]([OH:32])([CH2:30][CH3:31])[C:4]#[C:5][CH2:6][O:7][CH2:8][C:9]1[C@:10]2([CH2:27][CH2:26][C@H:25]3[C:15](=[CH:16][CH:17]=[C:18]4[C@:23]3([CH3:24])[C@@H:22]([OH:28])[CH2:21][C@H:20]([OH:29])[CH2:19]4)[C@@H:12]2[CH2:13][CH:14]=1)[CH3:11])[CH3:2].N1C2C(=CC=CC=2)C=CC=1>[Pd].CO>[CH2:1]([C:3]([OH:32])([CH2:30][CH3:31])[CH2:4]/[CH:5]=[CH:6]\[O:7][CH2:8][C:9]1[C@:10]2([CH2:27][CH2:26][C@H:25]3[C:15](=[CH:16][CH:17]=[C:18]4[C@:23]3([CH3:24])[C@@H:22]([OH:28])[CH2:21][C@H:20]([OH:29])[CH2:19]4)[C@@H:12]2[CH2:13][CH:14]=1)[CH3:11])[CH3:2]
Reactant: CCC(O)(C#CCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)CC
Agent: [Pd]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: CCC(O)(CC)C/C=C\OCC1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The fraction (0.3 g) containing 17-(4-ethyl-4-hydroxy-2-hexynyloxymethyl)-1α,3β-dihydroxyandrosta-5,7,16-triene obtained in Example 11 (2), 5% palladium/barium sulfate (0.3 g), quinoline (0.03 ml, 0.2538 mmol) and methanol (6.8 ml) were subjected to reaction using a procedure similar to that of Example 29(1) (4 hours) and worked up to give a mixture (0.80 mg) containing the targeted compound.