Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N+:9]([O-])([O-:11])=[O:10].[Na+]>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:8]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1ccccc1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
2-Bromophenol (50.0 g, 0.29 mol) was added slowly to a cold (10° C.) solution of sodium nitrate (36.9 g, 0.43 mol) in conc. sulfuric acid (79 g) and water (100 mL) and the resulting mixture was allowed to stir at room temperature for 2 h. Water (400 mL) was added and the resulting mixture was extracted with diethyl ether and the extract was dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 5% ethyl acetate/hexane). The partly purified product was triturated with hexane to afford the title compound (19.2 g, 30%) as a bright, yellow solid. 1H NMR (300 MHz, CDCl) δ 11.10 (S, 1h), 8.13 (d, J=7.9 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 6.90 (t,J=7.9 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH2:40]([NH2:45])[CH2:41][CH2:42][CH2:43][CH3:44]>O1CCCC1>[CH2:40]([NH:45][C:18](=[O:20])[C@@H:17]1[CH2:21][CH2:22][CH2:23][N:16]1[C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCN
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: CCCCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
2 g (0.06 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 20 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 0.76 ml (0.06 mol) of N-ethylmorpholine and 0.79 ml (0.006 mol) of isobutyl chloroformate were added and the resulting mixture was stirred at -10° C. for 20 minutes. 0.69 ml (0.006 mol) of n-pentylamine was then added and the resulting solution was stirred at -20° C. for 1 hour and then left to stand at room temperature overnight. The solution was then evaporated to an oil which was dissolved in ethyl acetate. The ethyl acetate solution was washed twice with water, twice with 5% citric acid solution, once with water, twice with 5% sodium bicarbonate solution and twice with water, dried and evaporated to an oil. The desired N-benzyloxycarbonyl-L-alanyl-L-proline n-pentylamide was crystallised from ethyl acetate/petroleum ether in a yield of 1 g (42.8%) and with a melting point of 102°-104° C.
Reaction SMILES: Cl.[C:2]12([NH2:12])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.Cl[C:21](OC(Cl)(Cl)Cl)=[O:22].[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][NH2:43])[CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[CH2:36][CH2:37][N:38]([CH2:41][CH2:42][NH:43][C:21]([NH:12][C:2]34[CH2:9][CH:8]5[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]5)[CH2:3]3)[CH2:11]4)=[O:22])[CH2:39][CH2:40]2)[CH:32]=[CH:33][CH:34]=1
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NCCN1CCN(c2cccc(Cl)c2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCN1CCN(c2cccc(Cl)c2)CC1)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 1-adamantanamine hydrochloride (1.0 gm, 0.0053 mol) and triethylamine (2.2 gm, 0.021 mol) in 25 ml of dry methylene chloride under a dry nitrogen atmosphere was added, dropwise, trichloromethyl chloroformate (1.15 gm, 0.0027 mol). The resulting suspension was refluxed for three hours, and then a solution of 2-[4-(3-chlorophenyl)-1-piperazinyl]ethylamine (1.28 gm, 0.0053 mol) in 15 ml of dry methylene chloride was added. The resulting mixture was allowed to stir at room temperature overnight. The reaction mixture was then diluted to 200 ml with methylene chloride, washed with 3% aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator. The title compound (TLC on silica gel using a 5% methanol in ethyl acetate solvent system, Rf=0.43) was isolated by preparatory high pressure liquid chromatography (HPLC) on silica gel (using a gradient consisting of from 10% ethyl acetate in hexane to 20% methanol in ethyl acetate) and recrystallized from methylene chloride/hexane (1.51 gm, 68% of theory), mp.=136°-137° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][NH2:13].[Cl:14][C:15]1[C:16](=[O:36])[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:18]=[C:19]([CH2:25]Cl)[C:20]=1[C:21](OC)=[O:22]>CCO>[Cl:14][C:15]1[C:16](=[O:36])[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:18]=[C:19]2[CH2:25][N:13]([CH2:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[C:21](=[O:22])[C:20]=12
Reactant: COC(=O)c1c(CCl)cn(Cc2ccc(OC)cc2)c(=O)c1Cl
Reactant: NCCc1ccc2ccccc2n1
Solvent: CCO
Product: COc1ccc(Cn2cc3c(c(Cl)c2=O)C(=O)N(CCc2ccc4ccccc4n2)C3)cc1
Temperature: 100 °C
Yield: 53.4 %

Procedure:
A solution of 2-(quinolin-2-yl)ethanamine (48.4 mg, 0.281 mmol, see Example a1)), methyl 3-chloro-5-(chloromethyl)-1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridine-4-carboxylate (100 mg, 0.281 mmol) and TEA (0.117 ml, 0.842 mmol) were dissolved in EtOH (3.0 ml) in a 5 ml microwave reaction vial. The suspension was heated in a Biotage microwave at about 100° C. for about 20 min. After cooling, it was verified by LC-MS that the reaction was almost completed. The solution was concentrated to dryness and recrystallized from EtOH to give the title compound (69 mg, 0.150 mmol, 53.4% yield) as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH2:12][CH2:13][CH2:14][O:15][CH3:16])[N:4]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH:29]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[C:32](=[O:37])[CH2:31][C:30]2=O>ClCCl.C(N(CC)CC)C>[O:37]=[C:32]1[CH:33]2[CH2:36][CH:29]([CH2:35][CH2:34]2)[C:30]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:3]([CH:2]([F:1])[F:17])=[N:4][C:5]=2[CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:31]1
Reactant: O=C1CC(=O)C2CCC1C2
Reactant: COCCCc1nc(C(F)F)ccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCc1nc(C(F)F)ccc1C(=O)OC1=CC(=O)C2CCC1C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of 181 g of 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid methyl ester in 750 ml of a 2:1 methanol/water mixture is treated with 43.9 g of lithium-hydroxide monohydrate, and the mixture stirred at ambient temperature for 1 hour. Then the methanol is removed by distillation in vacuo, and the reaction mixture then diluted with crushed ice and acidified with aqueous 6N hydrochloric acid. The product is filtered and washed thoroughly with water. Crystallisation from n-hexane:methylene chloride gives 138.3 g of 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid as white crystals (melting point 86-87° C.). A solution of 101.2 g of 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid in 1250 ml of dichloromethane is charged initially, 1 ml of dimethylformamide are added and the mixture is subsequently treated with 38.4 ml of oxalyl chloride. After the intensive evolution of gas has ceased, the mixture is stirred at room temperature for 1 hour and then cooled to 0° C. and treated with 57 g of bicyclo[3.2.1]octane-2,4-dione and 87 ml of triethylamine and the mixture then stirred for 2 hours at ambient temperature. The mixture is then diluted with methylene chloride, and washed with cold 1N hydrochloric acid, dried over magnesium sulphate and concentrated in vacuo to give 150.9 g of 6-Difluoromethyl-2-(3-methoxy-propyl)-nicotinic acid 4-oxo-bicyclo[3.2.1]oct-2-en-2-yl ester as an oil which is used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][CH2:9]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:11]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(#N)C>[Br:11][CH2:9][CH2:8][CH2:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCC1CCCC1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: BrCCCCC1CCCC1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of 4-cyclopentyl-butan-1-ol (3.1 g, 22 mmol) in acetonitrile (200 mL) was treated with dibromotriphenylphosphorane (10.1 g, 23.9 mmol). The reaction was stirred for two hours and quenched with water (10 mL). The reaction was diluted with dichloromethane (300 mL) and washed with water (3×100 mL). The organic phase was dried (MgSO4), filtered, and concentrated to yield an oil. The product was passed through a pad of silica to yield (4-bromo-butyl)-cyclopentane as a colorless oil (3.37 g, 76%). 1H NMR (CDCl3, 300 MHz) δ 3.42 (t, 7.0 Hz, 2 H), 1.9-1.7 (m, 4 H), 1.6-1.3 (m, 9 H), 1.07 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:7].C([N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[ClH:7].[ClH:7].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: O=CN1CCCNCC1
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(CN2CCCNCC2)cc(OC)c1OC
Product: Cl
Temperature: 55 °C
Yield: 31.5 %

Procedure:
A mixture of 3,4,5-trimethoxybenzyl chloride (10.5 g), N-formyl homopiperazine (6.82 g), potassium carbonate (8 g) and ethyl acetate (40 ml) is heated at 50-60° C. for 4 hours. After addition of water the reaction mixture is shaken thoroughly. The organic layer is separated, washed with water, dried and evaporated under reduced pressure. To the residue is added 10% hydrochloric acid (20 ml), and the mixture is extracted with ethyl acetate. The aqueous layer is made alkaline (>pH 9) with a 20% aqueous solution of sodium hydroxide, and extracted with methylene chloride. The extract solution is evaporated under reduced pressure. To the residue is added 10% hydrochloric acid (15 ml), and the mixture is stirred at 100° C. for 3 hours. The reaction mixture is made alkaline with a 20% aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The extract solution is dried and evaporated under reduced pressure. The residue is converted to the hydrochloride in a mixture of ethyl acetate and ethanol to yield 1-(3,4,5-trimethoxybenzyl) homopiperazine dihydrochloride (2.7 g) as colorless powdery crystals, m.p. 216°-220° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[S:31][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[O:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]3[OH:30])[C:9]=2[C:8]=1[CH3:32])=[O:6].Cl>CO.C1COCC1.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:9]3[C:8]([CH3:32])=[C:7]([C:5]([OH:6])=[O:4])[S:31][C:10]=3[N:11]=[CH:12][N:13]=2)=[C:17]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[OH:30])[CH:18]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCC[C@@H]3O)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCC[C@@H]3O)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5 ml sodium hydroxide solution (4M) was added to a mixture of 2.960 g 4-[4-Fluoro-2-((1S,2S)-2-hydroxy-cyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (cpd. 51.1) in 60 ml methanol/THF (1:1). The reaction mixture was stirred at rt for 3 hours, then acidified with aq. HCl and diluted with water. The mixture was filtered and the filtercake was dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCOCC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)ccc1N1CCOCC1
Yield: 18.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-morpholinophenyl) methanesulfonamide (240 mg, 0.342 mmol) was hydrolyzed by lithium hydroxide (143 mg, 3.42 mmol), THF/Methanol/water (20/8/8 mL) to yield 34 mg (18%) of the titled compound. 1H NMR (DMSO-D6, 400 MHz): δ 11.8 (s, 1H), 8.618 (s, 1H), 8.469-8.464 (m, 1H), 8.421 (s, 1H), 8.317-8.313 (d, 1H), 7.963 (s, 1H), 7.782-7.777 (d, 1H), 7.649-7.645 (d, 1H), 7.58-7.52 (m, 1H), 7.44-7.366 (m, 2H), 7.16-7.08 (m, 3H), 5.402 (s, 2H), 3.80.3-3.791 (m, 4H), 3.197 (s, 3H), 2.898-2.887 (m, 4H). MS: m/z=546.8 (M+1); HPLC: 96.04% in method B.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].B1C2CCCC1CCC2.C(CN)O>O1CCCC1>[CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)COc2ccc(C(=O)OC)cc21
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: NCCO
Product: CCCCN1CCOc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 80.1 %

Procedure:
A solution of methyl 4-butyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (800 mg) and 9-BBN (1.6 g) in tetrahydrofuran (13 mL) was refluxed for 1.5 h. The mixture was cooled to room temperature, ethanolamine (0.4 mL) was added, and the resulting solution was concentrated under reduced pressure. The residue was washed with hexanes, filtered, and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (silica, 25% ethyl acetate/hexanes) afforded 607 mg of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 7.21, 7.16, 6.75, 4.24–4.21, 3.78, 3.34–3.24, 1.55–1.47, 1.38–1.30, 0.95–0.90.
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C@@H:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]([C:18]([OH:20])=O)[CH2:8][N:7]4[CH3:21])=[CH:3]1.P(Cl)(Cl)(Cl)=O.[NH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.[OH-].[NH4+]>CN(C)C=O>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][NH:27][C:18]([C@@H:9]2[CH2:10][C@H:11]3[C@@H:6]([CH2:5][C:4]4[C:17]5[C:16](=[CH:15][CH:14]=[CH:13][C:12]3=5)[N:2]([CH3:1])[CH:3]=4)[N:7]([CH3:21])[CH2:8]2)=[O:20])[CH:30]=1
Reactant: CN1CC(C(=O)O)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21
Reactant: NCc1cccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN1C[C@H](C(=O)NCc2cccnc2)C[C@@H]2c3cccc4c3c(cn4C)C[C@H]21
Reaction time: 0.5 h

Procedure:
One gram of 1,6-dimethylergoline-8-carboxylic acid was slurried with 40 ml of dimethylformamide under a nitrogen atmosphere. The mixture was cooled by means of an external ice/acetone bath. To the slurry were added 700 mcl of phosphorous oxychloride in dropwise fashion keeping the temperature below 0° C. After stirring for 30 minutes, 800 mcl of 3-(aminomethyl)pyridine were added. After stirring an additional two hours, the mixture was poured into approximately 200 ml of dilute ammonium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The residue was crystallized from ethyl acetate/hexane to provide 700 mg of the desired title product, m.p. 185°-187° C.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>>[CH3:17][C@:16]12[CH2:18][CH2:19][C@H:20]3[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH2:2][OH:1])[CH2:4][CH2:5][C@H:6]([OH:22])[CH:7]=4)[C@@H:12]1[CH2:13][CH2:14][C@@H:15]2[OH:21]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Product: C[C@]12CC[C@H]3[C@@H](CCC4=C[C@@H](O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O

Procedure:
The 3,17-dihydroxy-4-androsten-19-ones and the diether derivatives are available from the corresponding 19-hydroxy-4-androstene-3,17-dione acylates. Reduction of these compounds with lithium tri-t-butoxyaluminum hydride reduces the 3 and 17-ketones to the β-alcohols without loss of the 19-acylate to furnish 4-androstene-3β,17β,19-triol 19-acylate.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([OH:36])=O)=[O:30])[CH:11]=1)=[O:9].[N:45]1([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:51][CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1.C(N(CC)CCN(C)C(=O)C1C=CC=C(C(NC2C=CC(N3CCCCC3)=CC=2C2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=CN=2)=O)C=1)C>>[N:22]1([C:20]2[CH:19]=[CH:18][C:17]([NH:28][C:29]([C:31]3[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=3)[C:34]([N:48]3[CH2:49][CH2:50][CH2:51][N:45]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:46][CH2:47]3)=[O:36])=[O:30])=[C:16]([C:12]3[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]4[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:43])([F:1])[F:44])[CH:4]=4)[CH:15]=[CH:14][N:13]=3)[CH:21]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CCN(CC)CCN(C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid 4.1e and tert-butyl 1,4-diazepane-1-carboxylate using the procedure used to prepare N1-(2-(diethylamino)ethyl)-N1-methyl-N3-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-isophthalamide 4.1.
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]([CH:8]([F:10])[F:9])([OH:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[C:16]1([S:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[C:16]1([S:22]([C:25]2[CH:26]=[CH:27][C:28]([NH:29][C:4](=[O:5])[C:3]([OH:7])([CH:8]([F:10])[F:9])[CH:2]([F:11])[F:1])=[CH:30][CH:31]=2)(=[O:23])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C(O)(C(F)F)C(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccc2)cc1)C(O)(C(F)F)C(F)F
Temperature: -10 °C
Yield: 57.2 %

Procedure:
To a solution of 2,2-bis-difluoromethyl-2-hydroxyacetic acid (0.5 g, 2.84 mmoles) in dimethylacetamide (10 ml) at -10° C. was added thionyl chloride (0.34 g, 2.84 mmoles) dropwise. The resulting solution vas stirred at -10° C. for approximately 30 mina. 4-(Phenylsulfonyl) aniline (0.58 g, 2.5 mmoles) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water, sodium bicarbonate solution added to give a pH of 7 and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed with water, brine, dried (Na2SO4), decolorized (charcoal), and evaporated. The crude solid was dissolved in ether, clarified by filtration, and evaporated. Crystallization from methanol/water gave the title compound (0.56 g, 57%) as white, silky needles; mp 105°-108° C. 1H-NMR (300 MHz, d6 -DMSO) 6.44 (t, J=53.94 Hz, 2H, HCF2), 7.58-7.68(m, 3H, ArH), 7.92-8.01 (m, 7H, ArH, OH), 10.51 (s, 1H, NH). MS(CI,CH4): 392 (M+1, 100%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1([C@@H:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>C(#N)C>[C:13]1([C@@H:19]([NH:21][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)C1CCCCC1=O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1

Procedure:
In another embodiment, the present invention may utilize ethyl 2-oxocyclohexane carboxylate (6) to prepare (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) as described in FIG. 4 by modification of methods of synthesis using an aprotic solvent to produce an amine [See Xu D et al., Tetrahedron Asymmetry, Vol. 8, No. 9, pp/1445-51, 1997]. The current embodiment may comprise reacting ethyl 2-oxocyclohexane carboxylate (6) with (S)-(−)-1-phenylethylamine (7) in the presence of an aprotic solvent including, but not limited to, toluene and acetonitrile, to produce (S)-Ethyl 241-phenylethylamino)cyclohex-1-enecarboxylate (8). The ratio of compound (6) to compound (7) generally ranges from approximately 10:1 to approximately 1:10. In one embodiment, the ratio of compound (6) to compound (7) ranges from approximately 5:1 to approximately 1:5. In another embodiment, the ratio of compound (6) to compound (7) ranges from approximately 2:1 to approximately 1:2. In an additional embodiment, the ratio of compound (6) to compound (7) comprises approximately 1:1.05.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]2[C:18](=[O:39])[CH2:19][NH:20][C:21](=[O:38])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+:40].[Br-]>CO.O>[OH-:32].[K+:40].[C:1]1([C@H:7]2[CH2:11][CH2:10][C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]2[C:18](=[O:39])[CH2:19][NH:20][C:21](=[O:38])[NH:22][C:23]2[CH:24]=[CH:25][C:26]([S:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CSc1ccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2c2ccccc2)cc1
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)CSc1ccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2c2ccccc2)cc1
Product: [OH-]

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 1.3 g of tert-butyl cis-{4-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}-phenylthio}acetate in solution in 20 cm3 of methanol and 0.17 g of potassium hydroxide in solution in 4 cm3 of water, and after treatment, 0.5 g of cis-{4-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylthio}-acetic acid, melting at about 200° C., is obtained [proton NMR (200 MHz, DMSO D6, δ in ppm), 1.8 to 2.4 (m, 4H, CH2 --CH2); 3.35 (s, 2H, CH2S); 3.3 and 3.85 (ABX, 2H, CH2N): 5.1 (m, 2H, 2 CHN); 6.5 (t, 1H exchangeable, NH); 7.1 to 7.4 (m, 14H, aromatic); 9 (s, 1H exchangeable, NH)], [infrared spectrum (KBr), characteristic bands in cm-1 3400, 3090, 3060, 3030, 2975, 2875, 1640, 1595, 1540, 1495, 1450, 1400, 825, 760, 700].