Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:7]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([N:34]=[N+:35]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[CH:1]1([S:7]([C:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:21]([CH3:24])(=[O:22])=[O:23])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N+:34]=[N-:35])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CS(=O)(=O)Oc1ccc(S(=O)(=O)CS(=O)(=O)C2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)Oc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCCCC2)cc1
Reaction time: 0.17 h
Yield: 38 %

Procedure:
The cyclohexylsulfonyl(4-methanesulfonyloxyphenylsulfonyl)methane in Synthesis Example 12, 10 g (0.025 mol), was dispersed in 150 g of dichloromethane. To the dispersion was added 4.6 g (0.03 mol) of p-toluenesulfonylazide. With stirring under ice cooling, 4.9 g (0.025 mol) of DBU was added to the dispersion, and after 10 minutes, 100 g of a 0.2N aqueous hydrochloric acid was added to stop reaction. The organic layer was separated and washed with 100 g of water. The organic layer was concentrated and 13 g of the residue was purified by silica gel column chromatography using dichloromethane as an elute. The thus obtained oily product was combined with 20 g of hexane for crystallization, followed by filtration and vacuum drying. There was obtained 4.0 g (yield 38%) of fine yellow crystals.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[C:23]([I:30])[CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]2[CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[O:26])=[C:23]([I:30])[CH:22]=1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: O=C(O)c1ccc(F)cc1I
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
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (0.4 g, 1.549 mmol), 4-fluoro-2-iodobenzoic acid (0.374 g, 1.4 mmol), DIPEA (0.49 mL, 2.8 mmol) and HATU (0.53 g, 1.4 mmol) in DMF (10 mL) was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate and washed with satd. aq. NaHCO3 and brine successively. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/hex) to afford the title compound. MS (ESI) 507 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:28]1[N:29]=[C:30]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][C@@H:43]2[CH3:48])[C:31]2[CH2:36][N:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][C:32]=2[N:33]=1>>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:28]3[N:29]=[C:30]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][C@@H:43]4[CH3:48])[C:31]4[CH2:36][N:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:34][C:32]=4[N:33]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(O)c3)cc2)OC1(C)C
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)Nc4cccc(O)c4)cc3)nc(N3CCOC[C@@H]3C)c2C1

Procedure:
Method as intermediate 5 using 1-(3-hydroxyphenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea and (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) as starting materials. Reaction mixture was concentrated in vacuo and purified by prep. HPLC (low pH) to afford a brown solid, 22 mg (8% over 2 steps).
Reaction SMILES: [C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Ni]
Product: CC(C)(C)c1c[nH]c2cc(N)ccc12
Reaction time: 3 h
Yield: 75.9 %

Procedure:
A suspension of 3-tert-butyl-6-nitro-1H-indole (3.0 g, 14 mmol) and Raney Nickel (0.5 g) was hydrogenated under H2 (1 atm) at room temperature for 3 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel (petroleum ether/ethyl acetate=4:1) to give 3-tert-butyl-1H-indol-6-amine (2.0 g, 77%) as a gray solid. 1HNMR (CDCl3) δ7.58 (m, 2H), 6.73 (d, J=1.2 Hz, 1H), 6.66 (s, 1H), 6.57 (dd, J=0.8, 8.6 Hz, 1H), 3.60 (br, 2H), 1.42 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][CH:6]=1.[C:17](N1C2C(=CC=CC=2)C(CC(O)=O)=C1)(=[O:19])[NH2:18]>>[C:17]([N:7]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:5]([CH2:4][C:3]([OH:2])=[O:16])=[CH:6]1)(=[O:19])[NH2:18]
Reactant: NC(=O)n1cc(CC(=O)O)c2ccccc21
Reactant: COC(=O)Cc1c[nH]c2ccc(OC)cc12
Product: COc1ccc2c(c1)c(CC(=O)O)cn2C(N)=O

Procedure:
was prepared from 5-methoxy-3-indolylacetic acid methyl ester according to the protocol described scheme A8 for the preparation of (1-carbamoyl-1H-indol-3-yl)-acetic acid. Rf, TLC (EtOAC)=0.2; MS (LC/MS): 248.9 [M+H]+, 271.0 [M+Na]+, 247.1 [M−H]−, 495.1 [2M−H]−, 204.1 [M−CONH2]−; tR (HPLC conditions f): 1.54 min.
Reaction SMILES: C([O:4][CH2:5][C@@:6]([NH:41]C(=O)C)([CH3:40])[CH2:7][CH2:8][C:9]1[N:10]([CH2:38][CH3:39])[C:11]([C:14]([O:25]C(=O)CCCC2C=CC(C)=CC=2)=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:12][CH:13]=1)(=O)C.O.[OH-].[Li+].C(Cl)Cl>O1CCCC1.CO.O>[NH2:41][C@:6]([CH3:40])([CH2:7][CH2:8][C:9]1[N:10]([CH2:38][CH3:39])[C:11]([C:14](=[O:25])[CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: CCn1c(CC[C@](C)(COC(C)=O)NC(C)=O)ccc1C(=CCCc1ccc(C)cc1)OC(=O)CCCc1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(CC[C@@](C)(N)CO)ccc1C(=O)CCCc1ccc(C)cc1
Temperature: 50 °C
Reaction time: 7 h
Yield: 58.7 %

Procedure:
(2R)-1-Acetoxy-2-acetylamino-2-methyl-4-{1-ethyl-5-[4-(4-methylphenyl)-1-(4-(4-methylphenyl)butanoyloxy)but-1-enyl]pyrrol-2-yl}butane (750 mg, 1.20 mmol) obtained in Example 13 (13a) was dissolved in a mixture of tetrahydrofuran (7 mL) and methanol (7 mL), and water (7 mL) and lithium hydroxide monohydrate (530 mg, 12.6 mmol) were added thereto, followed by stirring of the mixture at 50° C. for 7 hours. After cooling, water and methylene chloride were added to the reaction mixture to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by basic silica gel (NH type) chromatography (methylene chloride:methanol, 97:3) to obtain crude (2R)-2-amino-2-methyl-4-{l-ethyl-5-[4-(4-methylphenyl)butanoyl]pyrrol-2-yl}butan-1-ol (251 mg). A 4N hydrochloric acid-dioxane solution (0.360 mL, 1.40 mmol) was added to a solution of the thus obtained crude product in ethanol (5 mL) under ice-cooling and the mixture was stirred for 10 minutes. The mixture was concentrated under reduced pressure, ethyl acetate was added thereto and the precipitated crystal was collected by filtration. The crystal was washed with ethyl acetate and dried under reduced pressure to obtain the title compound (215 mg, yield: 44%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH2:13]([O:15][C:16](=[O:26])[C:17]([CH:24]=O)([CH3:23])[CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16](=[O:26])[C:17]([CH2:23][NH:4][CH:1]1[CH2:3][CH2:2]1)([CH3:24])[CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])[CH3:14]
Reactant: CCOC(=O)C(C)(C=O)CCC(C)C
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(CCC(C)C)CNC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.3 %

Procedure:
Cyclopropylamine (1.00 mL, 14.4 mmol), glacial acetic acid (1.0 mL), and sodium cyanoborohydride (1.82 g, 29.0 mmol) were added sequentially to a solution of crude rac-2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (2.90 g, 14.5 mmol) in ethanol (40 mL) at 25° C. The mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (self-packed glass column, gradient elution: 20-30% ethyl acetate in hexanes) to afford rac-2-cyclopropylaminomethyl-2,5-dimethyl-hexanoic acid ethyl ester (1.33 g, 5.51 mmol, 38%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.00-0.04 (2H, m), 0.12-0.16 (2H, m), 0.62 (6H, d, J=6.4 Hz), 0.76-0.86 (1H, m), 0.88 (3H, s), 1.00 (3H, t, J=6.9 Hz), 1.12-1.25 (2H, m), 1.30-1.38 (2H, m), 1.82-1.87 (1H, m), 2.38 (1H, d, J=11.7 Hz), 2.67 (1H, d, J=11.9 Hz), 3.86 (2H, q, J=6.9 Hz).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:3].C(Cl)(=O)C(Cl)=O.ClCCl.[Br:22][C:23]1[C:27]2[CH:28]=[N:29][C:30]([NH2:32])=[CH:31][C:26]=2[N:25]([CH3:33])[CH:24]=1>C1(C)C=CC=CC=1>[Br:22][C:23]1[C:27]2[CH:28]=[N:29][C:30]([NH:32][C:8](=[O:10])[C:7]3[CH:6]=[CH:5][C:4]([C:2]([CH3:3])=[CH2:1])=[CH:12][CH:11]=3)=[CH:31][C:26]=2[N:25]([CH3:33])[CH:24]=1
Reactant: C=C(C)c1ccc(C(=O)O)cc1
Reactant: Cn1cc(Br)c2cnc(N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C(C)c1ccc(C(=O)Nc2cc3c(cn2)c(Br)cn3C)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
In a 50 ml round bottom flask, 4-(prop-1-en-2-yl)benzoic acid (580 mg, 3.6 mmol) was dissolved in 15 ml toluene, and 2.0 M oxalyl chloride in dichloromethane (3.6 ml, 7.2 mmol) was added slowly. Stirring continued for 3 hours, and then volatiles were evaporated from the reaction mixture. To the residue was added 5 ml toluene and the mixture was concentrated in vacuo to azeotropically remove residual water. The residue was then dissolved in DMA (12 ml) and 3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-amine (400 mg, 1.8 mmol) was added. Stirring continued at 50° C. for another 3 hours. The mixture was then poured into ice water. The precipitate was collected and dried to obtain the product N-(3-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(prop-1-en-2-yl)benzamide (6A, 440 mg, 67%). This was used in the next step without further purification.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][S:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:11][S:12]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(C=O)CC1
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
A solution of dimethylsulfoxide (39 ml, 0.55 mole) in dichloromethane (300 ml) was added slowly to a solution of oxalyl chloride (22.7 ml, 0.264 mole) in dichloromethane (700 ml) at −60° C. After 10 minutes a solution of 1-methanesulfonylpiperidine-4-methanol (46 grams. 0.238 mole) in dichloromethane (500 ml) was added slowly. After 30 minutes at −60° C., triethylamine (167 ml) was added. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (1.2 liters) and water (200 ml). The organic phase was dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give 1-methanesulfonylpiperidine-4-carboxaldehyde (34 grams), m.p. 97° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:15])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([Cl:15])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cccc(CC(=O)Cl)c1
Reaction time: 16 h

Procedure:
A mixture of 3-methoxyphenylacetic acid (47.7 g, 0.287 m), thionyl chloride (50 ml) and N,N-dimethylformamide (6 drops) in toluene (500 ml) was stirred for 16 hours at 25° and concentrated in vacuo to afford 3-methoxyphenylacetyl chloride. The acetyl chloride was dissolved in chloroform (100 ml) and added to a solution of aminoacetaldehyde dimethyl acetal (32.1 g, 0.306 m) and triethylamine (32.4 g, 0.320 m) in chloroform (500 ml) stirred at 5°. The mixture was stirred at 25° for 16 hours, washed with water, 1.5 N hydrochloric acid and water, dried with magnesium sulfate and concentrated in vacuo to give N-(2,2-dimethoxyethyl)-3-methoxybenzeneacetamide.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[CH:16][C:15]=1[O:23][CH3:24].C([Li])CCC.CN(C)[CH:32]=[O:33].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH:20]([C:18]1[CH:17]=[CH:16][C:15]([O:23][CH3:24])=[C:14]([C:3]2[C:2]([CH:32]=[O:33])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[C:5]([O:12][CH3:13])[CH:4]=2)[CH:19]=1)([CH3:22])[CH3:21]
Reactant: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)C)cc1-c1cc(OC)c(C(F)(F)F)cc1C=O
Reaction time: 1 h

Procedure:
2-Bromo-5′-isopropyl-5,2′-dimethoxy-4-trifluoromethyl-biphenyl (1.29 g) is dissolved in dry tetrahydrofuran (30 ml) and thereto is added dropwise 1.6M n-butyllithium in hexane at −78° C., and the mixture is stirred for 1 hour and thereto is added N,N-dimethylformamide (1.2 ml), and the mixture is stirred for 1.5 hours. To the reaction solution are added a saturated aqueous ammonium chloride solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→17:3) to give 5′-isopropyl-5,2′-dimethoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (733 mg). MS (m/z): 353 [M+H]+
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:25]([CH2:26][CH2:27][C@:5]12[CH3:6])[C@:18]1([CH2:19][O:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:13](=[CH:14][C:15](=[O:28])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.COC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>O1CCCC1>[CH3:29][Si:2]([CH3:1])([CH3:30])[O:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:25]([CH2:26][CH2:27][C@:5]12[CH3:6])[C@:18]1([CH2:19][O:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[C@H:13]([CH2:14][C:15](=[O:28])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CC[C@@H]2O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: COC(OC)OC
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CC[C@@H]2O[Si](C)(C)C

Procedure:
Hydrogenation of 19-hydroxy-5-androstenes by means of 10% palladium on charcoal results in good yields of the corresponding 19-hydroxy-5α-androstanes. Suitable steroid substrates which fulfill the 5-ene requirement for stereoselectivity during the reduction include 3β,19-dihydroxy-5-androstenes, 19-hydroxy-5-androsten-3-ones, 19-hydroxy-5-androsten-3-one 3-cyclic ethyleneketal and 3-alkoxy-3,5-androstadien-19-ols. Typical reduction conditions utilize 2-10parts of the steroid substrate to 1 part catalyst with methanol or ethanol as solvent and hydrogen pressures ranging from 1 to 3 atmospheres. In this manner 1β,17α-dimethyl-5-androstene-3β,17β,19-triol, 7α-methyl-19-tetrahydropyranyloxy-5-androsten-3β,17β-diol and 6α-methyl-3β,19-dihydroxy-5-androsten-17-one are reduced to 1β,17α-dimethyl-5α-androstane-3β,17β,19-triol, 7α-methyl-19-tetrahydropyranyloxy-5α-androstan-3β,17β-diol and 6α-methyl-3β,19-dihydroxy-5α-androstan-17-one, respectively. 19-Hydroxy-1α-methyl-4-androstene-3,17-dione is converted to its cyclic ethyleneketal by heating at reflux temperatures with p-toluenesulfonic acid and ethyleneglycol in benzene. The ketal which forms is then reduced and hydrolyzed to form 19-hydroxy-1α-methyl-5α-androstan-3,17-dione. 17β,19-Di(trimethylsiloxy)-4-androsten-3-one can be converted to the methyl enol ether by the action of trimethylorthoformate, p-toluenesulfonic acid and methanol in tetrahydrofuran. The 3-methoxy-3,5-diene which forms is then catalytically reduced to yield 17β,19-di(trimethylsiloxy)-5α-androstan-3-one. The ethylenol ether of 19-hydroxy-4-androsten-3,17-dione acetate can also be reduced to yield 19-hydroxy-5α -androstane-3,17-dione acetate.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][C:28]1=[O:36]>C1(C)C=CC=CC=1.C1COCC1>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[C:12]2[CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]([CH3:26])[C:28]1=[O:36]
Reactant: CN1C(=O)Cc2ccccc21
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(C3C(=O)N(C)c4ccccc43)c2cc1OC
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
Potassium bis(trimethylsilyl)amide (5 ml of a 0.5M solution in toluene, 2.5 mmol) was rapidly added at ambient temperature to a solution of 4-chloro-6,7-dimethoxyquinazoline (337 mg, 1.5 mmol) and 1-methyloxindole (368 mg, 2.5 mmol), (prepared according to the method described in J. Am. Chem. Soc 1945, 67, 1656), in THF (30ml). After 30 minutes, the precipitate was collected by filtration and washed with ether. A second precipitate was isolated from the filtrate. The two solids were mixed and purified by column flash chromatography using methylene chloride/methanol (96/4 and 94/6) as eluent. During the evaporation of the solvents, the compound crystallised. The solid was filtered off, washed with ether and dried under vacuum to give 6,7-dimethoxy-4-(1-methyloxindol-3-yl)quinazoline (103 mg, 20%) as red orange needles.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4](=[N:6][OH:7])Cl.[CH3:13][O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18].C(N(CC)CC)C>C(OCC)C>[CH3:13][O:14][C:15]([C:16]1[C:4]([C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])=[N:6][O:7][C:17]=1[CH3:18])=[O:19]
Reactant: ON=C(Cl)c1c(F)cccc1F
Reactant: CC#CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)c1c(-c2c(F)cccc2F)noc1C
Yield: 60.9 %

Procedure:
In a fashion similar to that for preparation 15, 2,6-difluorobenzoylchloride oxime (1.00 g, 5.19 mmol), methyl-2-butynoate (1.01 g, 10.4 mmol), triethyl amine (0.94 ml, 6.8 mmol) in diethyl ether (3 ml), and diethyl ether (25 ml) afforded 4-methoxycarbonyl-5-methyl-3-(2,6-difluorophenyl)isoxazole (0.80 g, 61%) after purification by column chromatography (silica gel, hexanes/diethyl ether gradient).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.Cl.[NH2:20][CH:21]([CH2:25][CH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][C:27]1=[O:35])[C:22]([OH:24])=[O:23].[Cl-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:20][CH:21]([CH2:25][CH:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][C:27]2=[O:35])[C:22]([OH:24])=[O:23])=[O:8])=[CH:9][CH:10]=1
Reactant: NC(CC1C(=O)Nc2ccccc21)C(=O)O
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
To a mixture of 4.84 g of p-chlorobenzoic acid and 4 ml of triethylamine with 50 ml of dimethylformamide, was added dropwise a solution of 3.87 g of isobutyl chloroformate with 2 ml of dimethylformamide, the reaction mixture was stirred at a room temperature for 30 minutes. To the reaction mixture was added dropwise a solution of 5.72 g of 2-amino-3-(oxindol-3-yl)propionic acid hydrochloride prepared in reference example 1 with 3 ml of dimethylformamide, then the whole reaction mixture was stirred at at a room temperature for 30 minutes, next was stirred at 50°-60° C. for 1 hour. After the reaction was completed, the reaction mixture was poured into a large amount of a saturated sodium chloride aqueous solution, and extracted with chloroform. The chloroform layer was washed with water, and dried. The solvent was removed by evaporation to obtain crude crystals, then recrystallized from methanol-water to obtain 3.4 g of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate in the form of colorless powdery substance. .Melting point: 133°-135° C. (decomp.) [α]D25 -50.3° (C=1, methanol)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:27]([CH3:28])=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][C:19]=2[CH3:29])=[O:16])[C:12]([CH3:30])=[CH:11][CH:10]=1.O>CN1CCCC1=O>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[N:14]=[C:13]([C:15]([NH:17][C:18]3[C:19]([CH3:29])=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][C:27]=3[CH3:28])=[O:16])[C:12]([CH3:30])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: OC1CCNCC1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(N2CCC(O)CC2)nc1C(=O)Nc1c(C)cc(C(=O)O)cc1C
Temperature: 150 °C
Reaction time: 4 h
Yield: 63.9 %

Procedure:
4-Hydroxypiperidine (171.2 g, 1660 mmoles) is added to a solution of methyl 4-[(6-chloro-3-methyl-pyridine-2-carbonyl)amino]-3,5-dimethyl-benzoate (69 g, 207.3 mmoles) in N-methylpyrrolidone (483 mL) and the mixture is stirred at 150° C. for 4 hours. The mixture is cooled to ambient temperature and poured into water (1000 mL). The mixture is washed with methyl t-butyl ether (300 mL). The aqueous layer is then acidified to pH 2 with aqueous 36% HCl. The mixture is extracted with a solution of 1/1 ethyl acetate/methyl-t-butyl ether (3×250 mL). The organic layer is evaporated to dryness. Water (500 mL) is added to the residue and the resulting mixture is stirred for 30 minutes, filtered and the filtered material dried in an oven vacuum at 45° C. overnight. The dried light brown solid is dissolved in acetone (500 mL) and heated to 50° C. Water (1000 mL) is slowly added and the mixture is stirred at 50° C. for 2 hours. The mixture is cooled to ambient temperature, filtered, and the filtered material dried under reduced pressure at 45° C. The dried material is stirred in ethyl acetate (600 mL) at 50° C. for two hours. The mixture is cooled to ambient temperature, filtered, and the filtered material dried under reduced pressure at 45° C. overnight to give the title compound as a white solid (50.8 g, 64%). Mass spectrum (m/z): 384.2 (M+1). 1H NMR (300 MHz, DMSO): 12.85 (s, 1H), 9.87 (s, 1H), 7.71 (s, 2H), 7.49 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 4.68 (d, J=4.1 Hz, 1H), 4.11-4.04 (m, 2H), 3.70 (m, 1H), 3.15-3.07 (m, 2H), 2.41 (s, 3H), 2.27 (s, 6H), 1.81-1.77 (m, 2H), 1.44-1.32 (m, 2H).