Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:45][CH:46]([C:50]1[CH:60]=[CH:59][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:52][CH:51]=1)[CH:47]([CH3:49])[CH3:48]>CN(C=O)C>[C:1]12([C:11]([NH:45][CH:46]([C:50]3[CH:60]=[CH:59][C:53]([C:54]([O:56][CH2:57][CH3:58])=[O:55])=[CH:52][CH:51]=3)[CH:47]([CH3:48])[CH3:49])=[O:13])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)c1ccc(C(N)C(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C(NC(=O)C23CC4CC(CC(C4)C2)C3)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a vial charged with 1-adamantylcarboxylic acid (0.031 g, 0.17 mmol) was added HATU (64.6 mg, 0.17 mmol), triethylamine (0.14 mL, 1.02 mmol) and DMF (1 mL). The solution was shaken at rt for 1 h then ethyl 4-(1-amino-2-methylpropyl)benzoate (0.038 g, 0.17 mmol) in DMF (1 mL) was added. The resulting mixture was shaken at rt for 16 h. Solvent was then evaporated. To the residue was added DCE (3 mL) and sat. NaHCO3 solution (1.5 mL). After separation, the aqueous layer was extracted with DCE twice. Combined organic layers were concentrated to give crude ethyl 4-{1-[(adamantan-1-ylcarbonyl)amino]-2-methylpropyl}benzoate as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([F:38])[CH:37]=1)[CH2:33]Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([CH2:33][C:32]2[CH:31]=[C:30]([F:29])[CH:37]=[C:36]([F:38])[CH:35]=2)[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: Fc1cc(F)cc(CCl)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(Cc4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 3,5-difluorobenzyl chloride gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH3:12].ClC1C=CC(O[CH2:19][C:20]#[N:21])=CC=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([CH2:19][C:20]#[N:21])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])cc1C
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC#N)c([N+](=O)[O-])cc1C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a solution of 1-methoxy-2-methyl-4-nitrobenzene (0.4 g) and (4-chlorophenoxy)acetonitrile (0.4 g) in N,N-dimethylformamide (10 mL) was added potassium tert-butoxide (0.3 g) under ice cooling and this mixture was stirred at the same temperature for 1 hours. This mixture was poured into water and the resulting mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.2 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH2:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)[CH2:19][CH3:20]>CN1CCCC1=O.O>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccc(CCC)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 8.6 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.5 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.14 g, 2.5 mmol) and allowed to stir for 10 min at RT. 2-Propyl-5-vinyl-pyridine (0.18 g, 0.5 mol) was added and stirred for further 15 h. at 100 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.015 g, 9% yield). 2,8-Dimethyl-5-[2-(6-propyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.015 g, 0.043 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.006 g, 0.043 mmol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.008 g, 42% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]2[CH2:14][CH2:15][CH2:16][C:4]=2[N:3]=1.[CH3:17][O:18][C:19]([C:21]1([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20]>C(O)(C)C>[CH3:17][O:18][C:19]([C:21]1([C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:2]3[N:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[C:5]4[CH2:14][CH2:15][CH2:16][C:4]=4[N:3]=3)=[CH:29][CH:30]=2)[CH2:22][CH2:23][CH2:24]1)=[O:20]
Reactant: COC(=O)C1(c2ccc(N)cc2)CCC1
Reactant: Clc1nc2c(c(N3CCOCC3)n1)CCC2
Solvent: CC(C)O
Product: COC(=O)C1(c2ccc(Nc3nc4c(c(N5CCOCC5)n3)CCC4)cc2)CCC1
Yield: 21 %

Procedure:
A solution of 2-chloro-4-morpholin-4-yl-6,7-dihydro-5H-cyclopentapyrimidine (0.53 g, 2.8 mmol) and 1-(4-amino-phenyl)-cyclobutanecarboxylic acid methyl ester (0.57 g, 2.8 mmol) in anhydrous isopropanol (10 mL) was stirred under reflux for 18 hours. After cooling to a temperature in the range of 25° C. to 40° C., the mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel) to afford the title compound as a white solid (0.24 g, 27% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[C:30]([C:32]1[CH:46]=[CH:45][C:35]([CH2:36][O:37][CH2:38][C@@H:39]([NH:41][CH:42]([CH3:44])[CH3:43])[CH3:40])=[CH:34][CH:33]=1)#[N:31]>>[C:30]([C:32]1[CH:46]=[CH:45][C:35]([CH2:36][O:37][CH2:38][C@@H:39]([N:41]([CH:42]([CH3:43])[CH3:44])[C:21](=[O:22])[C:20]2[CH:19]=[CH:18][C:17]([C:8]3[C:7]4[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=4[C@@H:15]4[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]4)[N:9]=3)=[CH:25][CH:24]=2)[CH3:40])=[CH:34][CH:33]=1)#[N:31]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Reactant: CC(C)N[C@@H](C)COCc1ccc(C#N)cc1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COCc3ccc(C#N)cc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N—[(S)-2-(4-cyano-benzyloxy)-1-methyl-ethyl]-N-isopropyl-amine as described for example 1
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:4][CH:3]=1.Br.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(O)cc1)c1ccc(OCC(F)(F)F)cn1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1c1ccc(OCc2ccccn2)cc1)c1ccc(OCC(F)(F)F)cn1
Reaction time: 48 h
Yield: 27.2 %

Procedure:
A mixture of (1S*,2S*)-2-(4-hydroxyphenyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cyclopropanecarboxamide (15 mg, 0.039 mmol), 2-(Bromomethyl)pyridine hydrobromide (100 mg, 0.394 mmol) and potassium carbonate (27 mg, 0.197 mmol) in DMF (2 mL) was heated at 70 oC with stirring for 2 days. The mixture was poured into water, and the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 5 mg (27% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:35]=[C:34]([C:41](O)=[O:42])[C:33]2=[O:44])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:41]([C:34]5[C:33](=[O:44])[N:32]([C:29]6[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=6)[C:37]([CH:38]([CH3:40])[CH3:39])=[CH:36][CH:35]=5)=[O:42])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: CC(C)c1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 58.6 %

Procedure:
A mixture of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.459 mmol), 1-(4-fluorophenyl)-6-(1-methylethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (151 mg, 0.551 mmol), HATU (262 mg, 0.689 mmol), N,N-diisopropylethylamine (240 μL, 1.37 mmol) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 4 days. After dilution with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 30 g, ethyl acetate/hexane=2/98-+80/20) to give the title compound (157 mg, 58%) as a white powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][CH3:29])[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=1)[CH3:11].[OH-].[Na+].CO>O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:28][CH3:29])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=1)[CH3:11]
Reactant: CCOC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of ethyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino)ethoxy]-phenyl]-2-methoxypropanoate (1.5 g), 10% aqueous sodium hydroxide solution (7.5 mL) and methanol (23 mL) was stirred for 1.5 hrs at room temperature and then diluted with water (600 mL), washed with dichloromethane (300 mL) and acidified to pH2 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (3×300 mL) and the combined ethyl acetate solutions washed with water (2×200 mL) and brine (200 mL), dried (MgSO4) and evaporated. The residue was crystallised from ethyl acetate-dichloromethane-hexane to afford the title compound, mp 150°-153° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:23]1>COCCO.C(N(CC)CC)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=[C:9]1[N:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]([NH:29][S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=[O:31])=[O:32])[CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Reactant: Cc1ccc(S(=O)(=O)NC2CCCCNC2)cc1
Solvent: COCCO
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC2CCCCN(c3nc4c(c(=O)n(C)c(=O)n4C)n3Cc3ccccc3)C2)cc1

Procedure:
7-Benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (2A) (1.03 g, 3.40 mmol) and N-(azepan-3-yl)-4-methylbenzenesulfonamide (6B) (1.00 g, 3.73 mmol) were dissolved in 2-methoxyethanol (30 ml) and triethylamine (2.4 ml), and the mixture was heated to 120° C. for 2 days. The solvents were evaporated and the crude product was dissolved in 100 ml of EtOAc and 100 ml of water. The aqueous phase was acidified with 1M potassium hydrogen sulphate until pH=2. The organic layer was separated and extracted with 50 ml of 1M aqueous potassium hydrogen sulphate, and 50 ml of brine, and dried over sodium sulphate. The solvent was evaporated and the crude product was purified by column chromatography on silica gel using EtOAc:heptane (1:1) as the eluent. Evaporation of the solvent gave compound (6C) as a white foam.
Reaction SMILES: P(Br)(Br)[Br:2].N1C=CC=CC=1.[CH3:11][C:12]1([CH3:29])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16](/[C:24](/[CH3:28])=[CH:25]/[CH2:26]O)[CH:15]=[CH:14][C:13]1=2>C(OCC)C>[CH3:11][C:12]1([CH3:29])[CH2:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]2[CH:17]=[C:16](/[C:24](/[CH3:28])=[CH:25]/[CH2:26][Br:2])[CH:15]=[CH:14][C:13]1=2
Reactant: C/C(=C\CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: c1ccncc1
Product: C/C(=C\CBr)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 268.3 %

Procedure:
A stirred solution of phosphorous tribromide (0.31 g, 1.16 mmol) and pyridine (0.057 g, 0.72 mmol) in petroleum ether (18 mL) was cooled to -10° C. under argon. The mixture was treated with a solution of 35 (0.94 g, 3.62 mmol) in anhydrous diethyl ether (18 mL). The reaction mixture was allowed to warm to room temperature over 2.5 h. The solution was then diluted with diethyl ether and washed twice with water. The aqueous layers were combined and back-extracted with another portion of diethyl ether. The organic layers were combined, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1.00 g (86%) of 36 as an off-white solid. The bromide was used without purification in the next reaction. 1H NMR (300 MHz, CDCl3) δ7.33 (d, 1H, ArH), 7.28 (d, 1H, ArH), 7.18 (dd, J=12 Hz, 1H, ArH), 6.05 (t, J=9 Hz, 1H, C=CH), 4.12 (d, J=9 Hz, 2H, CH2Br), 2.13 (s, 3H, CH=CCH3), 1.68 (s, 4H, CH2CH2), 1.26 (s, 6H, 2'CH3), and 1.24 (s, 6H, 2×CH3).
Reaction SMILES: C[O:2][C:3](=[S:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=1.[OH-].[Na+]>O.CO>[C:11]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([OH:2])=[S:14])(=[O:13])[CH3:12]
Reactant: COC(=S)c1ccc(C)c(C(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)c1cc(C(O)=S)ccc1C
Reaction time: 6 h
Yield: 79.8 %

Procedure:
3-acetyl4-methylthiobenzoic acid methyl ester (0.43 g) in water:methanol (1:3, 290 ml) containing sodium hydroxide (0.2 g) was stirred for 6 h. Methanol was removed at reduced pressure and the solution acidified with conc. hydrochloric acid to give 3-acetyl-4-methylthiobenzoic acid (0.32 g) after filtration. m/z (API+): 211 (MH+).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[Li+].[Br-:22].[BH4-].[Na+]>C(OCC)(=O)C.C1C=CC=CC=1>[CH3:1][C@@:2]12[C:18](=[O:19])[C@H:17]([Br:22])[CH2:16][C@H:15]1[C@@H:14]1[CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([OH:20])[CH:8]=[CH:7][C:6]=3[C@H:5]1[CH2:4][CH2:3]2
Reactant: [Br-]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](Br)C2=O

Procedure:
16α-Bromoestrone was prepared by bromination of the enol acetate of estrone and then epimerized with LiBr (as described by Fishman et al., J. Org. Chem. 23, 1190 (1958) and Mueller et al., supra, which are hereby incorporated by reference). The resulting mixture of 16α- and 16β-bromoestrone was reduced with NaBH4. All four of the possible bromohydrins were isolated from the reaction mixture by chromatography on silica gel in 5 percent ethyl acetate in benzene. The second compound eluted from the column (60 percent of the reaction mixture) melted at 176° to 178° C., where-upon a new crystalline structure formed (melting point, 255° to 256° C.). It was identified as 16β-bromoestradiol by reaction with KOH to form estrone (cis-bromohydrin); epimerization with LiBr to form 16α-bromoestradiol (compared to an authentic sample); and its mass spectrum. 16α-Iodoestradiol (melting point, 190° to 191° C.) was synthesized from 16β-bromoestradiol by exchange with NaI. Its nuclear magnetic resonance (NMR) and mass spectra were consistent with the predicted structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:13])[C:9](=O)[CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:20]#[C:21][NH2:22].[OH-].[Na+]>O1CCCC1.O>[NH2:22][C:21]1[O:11][CH:10]=[C:9]([CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:2]([F:1])[CH:7]=2)[CH3:13])[N:20]=1
Reactant: CC(C(=O)CO)c1ccc(-c2ccccc2)c(F)c1
Reactant: N#CN
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1coc(N)n1
Reaction time: 8 h

Procedure:
To 3-(2-Fluoro-4-biphenylyl)-2-oxo-1-butanol (3.57 g, 13.8 mmol) in tetrahydrofuran (35 ml) was added cyanamide (3.65 g, 77.6 mmol) in water and 2N-sodium hydroxide to pH 10. After the addition, the mixture was stirred overnight, then cyanamide (3.65 g, 77.6 mmol) was added to the reaction mixture to pH 10, the mixture was stirred overnight. The reaction mixture was extracted with ether and the extracts were washed with water, dried over and evaporated under reduced pressure to a residue, which was chromatographed to afford 2-Amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)oxazole as crystalline material (1.05 g, 27% yield): mp 150.5°-151.5° C.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:18][CH:17]=1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Reactant: Cc1ccc(B(O)O)cc1
Product: CSc1ccc(C2=C(c3ccc(C)cc3)CCC2)cc1
Yield: 92 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 250 mg (0.93 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio)benzene (Example 1, Step 2) was reacted with 260 mg (1.9 mmol) of 4-methylphenylboronic acid (Lancaster) . Purification by silica gel chromatography (MPLC) with hexane gave 240 mg (92%) of 1-[2-(4-methyl phenyl)cyclopenten-1-yl]-4-(methylthio)benzene as a colorless solid: mp 64.5°-66.5° C.; NMR (CDCl3) d 2.03 (m, J=7 Hz, 2H), 2.30 (s, 3H), 2.45 (s, 3H), 2.86 (t, J=7 Hz, 4H) , 6.99-7.15 (m, 8H) . Step 2: Preparation of 1-[2-(4-Methylphenyl)Cyclopenten-1-yl]-4-(Methylsulfonyl)Benzene
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([C:19]([OH:21])=[O:20])[C:17]=1[OH:18])[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].S(=O)(=O)(O)O.[OH-].[Na+].[CH2:29](O)[CH2:30][CH3:31]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([C:19]([O:21][CH2:29][CH2:30][CH3:31])=[O:20])[C:17]=1[OH:18])[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13]
Reactant: O=C(Nc1cc(Br)c(O)c(C(=O)O)c1)c1ccccc1O
Reactant: CCCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCOC(=O)c1cc(NC(=O)c2ccccc2O)cc(Br)c1O
Yield: 54.5 %

Procedure:
3'-Bromo-5'-carboxy-2,4'-dihydroxybenzanilide (1.0 g.) described in Example 4 was dissolved in n-propanol (50 ml.), and after adding conc. sulfuric acid (1 ml.) the solution was refluxed for 8 hours. After neutralizing with sodium hydroxide solution, the reaction solution was evaporated to dryness and the residue was washed with 5% sodium bicarbonate solution and recrystallized from aqueous acetone to give 3'-bromo-2,4'-dihydroxy-5'-n-propyloxycarbonylbenzanilide (0.61 g.). Yield: 54.5% Melting point 198°-200° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][C:11](O)=[O:12])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:10][C:11]([NH:28][C:27]2[CH:29]=[CH:30][C:24]([F:23])=[CH:25][CH:26]=2)=[O:12])=[CH:5][C:4]=1[C:19]([F:20])([F:22])[F:21])#[N:2]
Reactant: Nc1ccc(F)cc1
Reactant: N#Cc1ccc(N(CC(=O)O)CC(F)(F)F)cc1C(F)(F)F
Product: N#Cc1ccc(N(CC(=O)Nc2ccc(F)cc2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2,2,2-trifluoroethyl)glycine and 4-fluoroaniline: MS (APCI) m/z 420 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[C:13]([OH:20])=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:26]O>>[CH3:26][O:18][C:17]([C:16]1[C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:12][C:11]=2[C:13]([OH:20])=[CH:14][CH:15]=1)=[O:19]
Reactant: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3)nc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3)nc12
Temperature: 25 °C
Yield: 80 %

Procedure:
2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (200 mg, 0.69 mmol) obtained in step 3 was dissolved in 5 ml of methanol, H2SO4 (0.18 ml, 3.45 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with 1M NaHCO3. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel column chromatography (eluent—MeOH/CDCl3=5/95, Merck, Silicagel 60) to obtain the title compound (166 mg, 0.55 mmol) in a yield of 80%.