Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].Cl[C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:16][O:17][C:18]=2[N:19]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:5][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:16][O:17][C:18]=2[N:19]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Reactant: CC(C)CO
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)COc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a solution of isobutyl alcohol (0.16 mL) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-isobutoxy-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.33 g, 58%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1.CC(N)[CH2:15][C:16]1[CH:21]=CC=CC=1.OP(O)(O)=O.[Br-].C1([Zn+])CC1>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([CH:21]2[CH2:16][CH2:15]2)[C:5]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(Cl)nc1Cl
Reactant: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Agent: [Br-]
Agent: [Zn+]C1CC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(Cl)nc1C1CC1
Temperature: 80 °C
Yield: 31.5 %

Procedure:
A 20 mL glass microwave tube was charged with methyl 2,4-dichloropyrimidine-5-carboxylate (Aldrich, St. Louis, Mo., 831 mg, 4.01 mmol and Amphos (Aldrich, St. Louis, Mo., 71.1 mg, 0.100 mmol) were treated with cyclopropylzinc(II) bromide (Rieke Metals, Lincoln, Nebr., 0.5 M in THF, 16.1 mL, 8.03 mmol) via syringe under an atmosphere of argon. The solution was then heated in the microwave at 80° C. for 20 min. The reaction mixture was treated with EtOAc and then with 1 N NaOH resulting in a white suspension as the zinc hydroxide salts precipitated. It was extracted with EtOAc (50 mL) a second time and washed with brine and dried over anhydrous Na2SO4, filtered and concentrated. Purification of the crude residue on the ISCO Combiflash Rf (40 g Redisep column, using 100% DCM) afforded two readily separable peaks. The first eluting peak was found to be methyl 2-chloro-4-cyclopropylpyrimidine-5-carboxylate (269 mg, 1.26 mmol, 31.5% yield) as a white amorphous solid upon concentration. MS (ESI, pos. ion) m/z: 213.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.91 (1H, s), 3.97 (3H, s), 3.12-3.20 (1H, m), 1.34-1.40 (2H, m), 1.20-1.27 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Cl.C[O-].[Na+].[CH2:12]([SH:15])[CH2:13][CH3:14]>O>[CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][S:15][CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)CCCCl
Reactant: CCCS
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CCCSCCCC(=O)OC
Reaction time: 1 h

Procedure:
Into a 1 liter reaction flask equipped with electric stirrer, reflux condenser, thermometer, addition funnel and cooling bath are placed 68.2 grams (0.5 moles) of methyl-4-chlorobutyrate having the structure: ##STR129## The methyl-4-chlorobutyrate is cooled to 20° C. The mixture of sodium methoxide and n-propyl mercaptan is then poured into the addition funnel. Over a period of 30 minutes while maintaining the pot temperature at 20°-30° C. the premix of n-propyl mercaptan and sodium methoxide is added slowly to the methyl-4-chlorobutyrate reactant. The reaction is exothermic and requires cooling. At the end of the 0.5 hour period, the reaction mass is stirred for a period of 1 hour and the temperature of the reaction mass is permitted to rise to 43° C. The reaction mass is then combined with 500 ml water and transferred to a separatory funnel. The resulting product is then extracted with three 50 ml portions of methylene dichloride. The methylene dichloride extract is then dried over anhydrous sodium sulfate, filtered and distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:29][O:30][C:31]1[CH:52]=[CH:51][C:34]([CH2:35][O:36][C:37]([NH:39][C:40]2[CH:45]=[CH:44][N:43]([CH2:46][C:47](O)=[O:48])[C:42](=[O:50])[N:41]=2)=[O:38])=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[N:16][N:17]=1)(=[O:12])=[O:11])[C:47](=[O:48])[CH2:46][N:43]1[CH:44]=[CH:45][C:40]([NH:39][C:37]([O:36][CH2:35][C:34]2[CH:51]=[CH:52][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[O:38])=[N:41][C:42]1=[O:50])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1
Reactant: COc1ccc(COC(=O)Nc2ccn(CC(=O)O)c(=O)n2)cc1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2[N+](=O)[O-])s1)C(=O)Cn1ccc(NC(=O)OCc2ccc(OC)cc2)nc1=O

Procedure:
The title compound was synthesized by the reaction of N-{2-[5-(4-chloro-2-nitrophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester with [4-N-(4-methoxybenzyloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of example 13. 1H NMR (500 MHz; DMSO-d6) δ 10.69 (s, 1H), 9.21 (brs, 0.6H), 9.09 (brs, 0.4H), 8.40 (s, 1H), 8.07–7.96 (m, 2H), 7.92 (d, 0.6H), 7.86 (d, 0.4H), 7.36 (d, 2H), 7.02 (d, 0.6H), 7.01 (d, 1H), 6.94 (d, 2H), 5.12 (s, 2H), 4.81 (s, 1.2H), 4.64 (s, 0.8H), 4.37 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (s, 1.2H), 4.08 (q, 1.2H), 3.76 (s, 3H), 3.62 (t, 1.2H), 3.47 (t, 1.2H), 3.43 (t, 0.8H), 3.28 (t, 0.8H), 1.24 (t, 1.2H), 1.17 (t, 1.8H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:5]=2[NH:4][C:3](=[O:15])[CH2:2]1.[OH-].[Na+].CO>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[NH:4][C:3](=[O:15])[CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1COc2ccc(C(=O)O)cc2N1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
In a 250 ml round-bottomed flask were place the preceding methyl 1,4-benzoxazine-3-one-6-carboxylate (5.8 g, 28 mmole), 50% aqueous sodium hydroxide (9.0 g, 112 mmole), methanol (125 ml), and water (19 ml). The resulting mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature and the solvent eliminated in the rotary evaporator. The crude reaction product was taken up in water and the resulting aqueous solution was washed with hexane (2×50 ml) and acidified to pH=1 with concentrated aqueous hydrochloric acid. The solid which formed was separated by suction filtration, and dried in a vacuum oven yielding 5.1 g of the expected 1,4-benzoxazine-3-one-6-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[F:13][C:14]([F:21])([F:20])[C:15](B(O)O)=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:12][C:4]1[CH:3]=[C:2]([C:15]([C:14]([F:21])([F:20])[F:13])=[CH2:16])[CH:7]=[C:6]([CH3:8])[C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: C=C(B(O)O)C(F)(F)F
Reactant: Cc1cc(Br)cc(C)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(C)c([N+](=O)[O-])c(C)c1)C(F)(F)F
Temperature: 25 °C
Yield: 105.1 %

Procedure:
5-bromo-1,3-dimethyl-2-nitrobenzene (10.0 g), [1-(trifluoromethyl)vinyl]boronic acid (purity: 60%, 13.4 g) and potassium carbonate (14.4 g) was dissolved in the mixed solvent of THF and water, which was then degassed three times. To the solution was added dichloro bis(triphenylphosphine) palladium (II) (1.5 g), and the mixture was heated to reflux for 3 hours under argon atmosphere. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 1,3-dimethyl-2-nitro-5-[1-(trifluoromethyl)vinyl]benzene (11.2 g). 1H-NMR (CDCl3) δ: 2.34 (6H, s), 5.78-5.80 (1H, m), 6.03-6.04 (1H, m), 7.20 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:10]([CH3:13])[NH:11][CH3:12])=[O:9])[C:5]([NH:14][C:15]([C:17]2[N:18]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:19]=[C:20]([Br:22])[CH:21]=2)=[O:16])=[C:4]([CH3:30])[CH:3]=1.Cl[C:32]([O:34][CH3:35])=[O:33]>N1C=CC=CC=1>[CH3:35][O:34][C:32]([N:11]([CH3:12])[N:10]([C:8]([C:6]1[C:5]([NH:14][C:15]([C:17]2[N:18]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:19]=[C:20]([Br:22])[CH:21]=2)=[O:16])=[C:4]([CH3:30])[CH:3]=[C:2]([Cl:1])[N:7]=1)=[O:9])[CH3:13])=[O:33]
Reactant: CNN(C)C(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)N(C)N(C)C(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid [6-chloro-2-(N,N′-dimethyl-hydrazinocarbonyl)-4-methyl-pyridin-3-yl]-amide (250 mg) was dissolved in pyridine (3 mL), methyl chloroformate (150 μL) was added and the reaction mixture was stirred at room temperature. After 30 min, 1 h and 1.5 h, methyl chloroformate (each 75 μL) was added. After 1 h stirring at room temperature, the reaction mixture was quenched with water and 3× co-evaporated with toluene. The residue was dissolved in water and ethyl acetate, the layers were separated and the aqueous layer was extracted 2× with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, hexane/ethyl acetate=1:1, Rf=0.20) to afford 223 mg of compound (9) of the present invention of the formula
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:9]([CH2:10][CH3:11])=[C:8]([F:12])[CH:7]=[CH:6][C:5]=1[CH2:13][CH3:14].[CH2:16]([NH2:19])[CH2:17][NH2:18]>>[CH2:10]([C:9]1[C:8]([F:12])=[CH:7][CH:6]=[C:5]([CH2:13][CH3:14])[C:4]=1[CH2:3][C:2]1[NH:18][CH2:17][CH2:16][N:19]=1)[CH3:11]
Reactant: CCc1ccc(F)c(CC)c1C=C(Br)Br
Reactant: NCCN
Product: CCc1ccc(F)c(CC)c1CC1=NCCN1

Procedure:
2-(2,6-Diethyl-3-fluoro-benzyl)-4,5-dihydro-1H-imidazole was prepared from 2-(2,2-dibromo-vinyl)-1,3-diethyl-4-fluoro-benzene and ethylenediamine in analogy to Example 1e): yellow crystals; MS (ISP): 235.3 ([M+H]+, 100%).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[CH2:6]([Si:9]([CH2:24][CH:25]=[CH2:26])([CH2:21][CH:22]=[CH2:23])[CH2:10][CH2:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16](CO)=[CH:15][CH:14]=1)[CH:7]=[CH2:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:24]([Si:9]([CH2:6][CH:7]=[CH2:8])([CH2:21][CH:22]=[CH2:23])[CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:1][Br:5])=[CH:19][CH:20]=1)[CH:25]=[CH2:26]
Reactant: C=CC[Si](CC=C)(CC=C)CCCc1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=CC[Si](CC=C)(CC=C)CCCc1ccc(CBr)cc1
Reaction time: 1 h
Yield: 77 %

Procedure:
5 ml of methylene chloride and CBr4 (4.97 g, 15.0 mmol) were slowly added to 4-{3-(triallylsilyl)propyl}benzyl alcohol (5) (3.0 g, 10.0 mmol) and triphenylphosphine (PPh3) (3.93 g, 15.0 mmol) under a nitrogen atmosphere, and the mixture was stirred for 1 hour. Cooled distilled water was added to the reaction mixture. The aqueous layer was extracted with methylene chloride, and the combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under a reduced pressure to give a crude product. The crude product was purified by separating by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=20/1) to give 4-{3-(triallylsilyl)propyl}benzyl bromide (6) (yield amount: 2.80 g, yield: 77%), as shown in the following chemical reaction formula.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH:23]2[CH2:35][OH:36])=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:19][C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][CH:23]2[CH:35]=[O:36])=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccc2)CC1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC1CN(Cc2ccccc2)CCN1C(=O)Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 107.8 %

Procedure:
A solution of dimethylsulphoxide (369 mg) in dry dichloromethane (3 ml) was added to a stirred solution of oxalyl chloride (300 mg) in dry dichloromethane (7 ml) at -60° under nitrogen and the resulting solution was stirred at -60° to -64° for 30 minutes. The product of stage (i) (774 mg) in dry dichloromethane (5 ml) was added dropwise and the reaction mixture was stirred between -60° to -63° for 2.5 h. Triethylamine (995 mg) was added and the mixture was allowed to warm to -20°, and quenched with water (15 ml). The layers were separated and the aqueous phase was further extracted with dichloromethane (2×15 ml). The combined organic extracts were dried and evaporated to give the title compound as an oil (830 mg).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.[CH2:14]([O:17][CH2:18][C:19](Cl)=[O:20])[CH2:15][CH3:16]>>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:19](=[O:20])[CH2:18][O:17][CH2:14][CH2:15][CH3:16])=[C:7]([CH3:12])[CH:6]=1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Reactant: CCCOCC(=O)Cl
Product: CCCOCC(=O)Nc1ccc(OC(=O)NC)cc1C

Procedure:
According to the procedure of Example 5, 3-methyl-4-aminophenyl N-methylcarbamate was reacted with n-propoxyacetyl chloride to yield a viscous oil as the product.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:38]=[CH:37][CH:36]=[CH:35][C:24]=3[CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH:27]3[C:31]([O:33]C)=[O:32])[CH:8]=2)[N:3]=1.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:38]=[CH:37][CH:36]=[CH:35][C:24]=3[CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH:27]3[C:31]([OH:33])=[O:32])[CH:8]=2)[N:3]=1
Reactant: COC(=O)C1CCCN1Cc1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CN3CCCC3C(=O)O)ccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
280 mg of methyl 1-{2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzyl}pyrrolidine-2-carboxylate are dissolved in 5 ml of tetrahydrofuran. 5 ml of 2N sodium hydroxide solution are added, and the mixture is stirred at 25° C. for 16 h. The mixture is evaporated in vacuo and acidified using 2N hydrochloric acid, during which the product precipitates out. Filtration and drying at 40° C. in vacuo gives 1-{2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzyl}pyrrolidine-2-carboxylic acid.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=3)[N:18]([CH3:31])[N:17]=2)[CH2:9]1.[OH:33][C:34]1([C:41]2[S:45][CH:44]=[N:43][CH:42]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1>>[OH:33][C:34]1([C:41]2[S:45][CH:44]=[N:43][CH:42]=2)[CH2:35][CH2:36][CH:37]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:23]=4)[N:18]([CH3:31])[N:17]=3)[CH2:9]2)[CH2:38][CH2:39]1
Reactant: O=C1CCC(O)(c2cncs2)CC1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(O)C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(O)(c4cncs4)CC3)C2)c2cc(C(O)C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 60, Step B) and 4-hydroxy-4-thiazol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:31][CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:33]5[CH2:34][CH2:35][CH2:36][C@H:32]5[CH3:31])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: CC1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@H]5C)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (600 mg, 1.35 mmol) in dimethyl sulfoxide (10 mL) was added of 20 drops of acetic acid and 2-methylpyrrolidine (1.37 mL, 13.5 mmol). The resulting mixture was stirred at room temperature for 6 h followed by an addition of sodium triacetoxyborohydride (2.86 g, 13.5 mmol). The reaction was stirred at room temperature overnight then purified by Gilson Preparatory HPLC. This compound was then separated to give the title compound as 98.6% chirally pure.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C([O:13][C@H:14]1[O:23][C@H:18]([O:19][CH2:20][CH:21]=[CH2:22])[C@H:17]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:16]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:15]1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=O)C.[NH4+].[Cl-].OS(O)(=O)=O>C1(C)C=CC=CC=1.C(Cl)Cl.O>[OH:13][C@H:14]1[O:23][C@H:18]([O:19][CH2:20][CH:21]=[CH2:22])[C@H:17]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:16]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@@H:15]1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: C=CCO[C@H]1O[C@H](OC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCO[C@H]1O[C@H](O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
At -78°, DIBAH (2.8 ml of a 20% solution in toluene, ca. 2.9 mmol) was added dropwise to a solution of 7 (553 mg, 0.96 mmol) in CH2Cl2 (20 ml). After 15 min., a sat. solution of NH4Cl (2 ml) was added. The mixture was warmed up to r.t., diluted with H2O and a 1M solution of H2SO4 (10 ml). The aq. layer was extracted with CH2Cl2 (3×), the combined org. layers were extracted with brine (2×), dried (MgSO4) and evaporated to yield 499 mg (98%) of crystalline 8 which was used without further purification in the next step. Rf (EtOAc/hexane 1:2) 0.32. 1H-NMR (300 MHz, CDCl3): 2.92 (broad s, OH); 3.33 (dd, J=9.2, 7.8, H--C (4)); 3.60 (dd, J=9.7, 3.7, H--C (2)); 3.99 (t, J=9.5, H--C (3)); 4.07 (ddt, J=12.9, 6.6, 1.2, OAll); 4.23 (ddt, J=12.9, 5.2, 1.4, OAll); 4.65 (d, J=12.0), 4.79 (d, J=12.0, PhCH2); 4.78 (d, J=3.7, H--C (1)); 4.81 (d, J=11.2), 4.89 (d, J=11.9, PhCH2); 4.85 (d, J=10.9), 4.93 (d, J=10.9, PhCH2); 5.06 (d, J=7.8, H--C (5)); 5.24 (dq, J=10.3, 1.5, OAll); 5.34 (dq, J=17.2, 1.5, OAll); 5.93 (dddd, J=17.1, 10.3, 6.6, 5.2, OAll); 7.28-7.42 (m, 15 arom. H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C@@H:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:29])=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].Cl>C1COCC1.CO>[CH3:29][C:18]1[N:19]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[S:21][C:17]=1[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C@@H:5]([C:6]#[C:7][CH3:8])[CH2:4][C:3]([OH:30])=[O:2])=[CH:14][CH:13]=1
Reactant: CC#C[C@@H](CC(=O)OC)c1ccc(OCc2sc(-c3ccc(C)cc3)nc2C)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC#C[C@@H](CC(=O)O)c1ccc(OCc2sc(-c3ccc(C)cc3)nc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ester 3.2 was dissolved in THF/MeOH/10% NaOH(aq) (1:1:1) solution (15 mL). After stirring at room temperature over 30 minutes, the mixture was acidified with 1N HCl (aq.) until pH=4. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over Na2SO4 and concentrated. The crude residue was triturated with 20% ethyl acetate in hexanes (20 mL). The precipitate was filtered and compound 3 was acquired as a pale yellow powder (315 mg, 0.8 mmol). MS ESI m/e: 406 (M−H). 1H NMR (500 MHz) (CDCl3) δ 7.86 (2H, d, J=7.5 Hz); 7.36 (2H, d, J=9 Hz); 7.26 (2H, d, J=8 Hz); 6.96 (2H, d, J=8.5 Hz); 5.18 (2H, s); 4.1 (1H, m); 2.77 (2H, m); 2.52 (3H, s); 2.43 (3H, s); 1.86 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11](=[C:13]1[CH2:18][CH2:17][C@H:16]2[C@H:19]3[C@H:29]([CH2:30][CH2:31][C@:14]12[CH3:15])[C@:27]1([CH3:28])[C:22]([CH2:23][C@@H:24](O)[CH2:25][CH2:26]1)=[CH:21][CH2:20]3)[OH:12].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C@H:24]2[CH2:25][CH2:26][C@@:27]3([CH3:28])[C:22](=[CH:21][CH2:20][C@@H:19]4[C@@H:29]3[CH2:30][CH2:31][C@@:14]3([CH3:15])[C@H:16]4[CH2:17][CH2:18][C:13]3=[N:11][OH:12])[CH2:23]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ccc(C(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@@H]4[C@@H]3CC[C@]3(C)C(=NO)CC[C@@H]43)C2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
4-Methylbenzoic acid (p-toluic acid) (0.22 g, 1.6 mmol) (0.16 g, 1.6 mmol) was added to the stirred solution of 17-oximino-5-androsten-3β-ol (9) (0.5 g, 1.6 mmol) and dicyclohexylcarbodiimide (DCC) (0.34 g, 1.6 mmol) in anhydrous dichloromethane (30.0 ml). The reaction mixture was stirred for 48 hr at room temperature (20-25°) and completion of the reaction was monitored by TLC. The precipitated dicyclohexylurea (DCU) was filtered, solvent removed under vacuum and the residue was crystallized from ethyl acetate:petroleum ether (60:80) to obtain 12 (0.29 g, 58.0%) mp 135-139° C.