Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Cl[C:10]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:11]=1[C:12]#[N:13].Cl>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:10]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cc(Cl)ccc1Cl
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.4 %

Procedure:
Under a nitrogen atmosphere, in a round-bottom flask were placed 880 mg (22mmol) of 60% sodium hydride (NaH) and 12 ml of N,N-dimethylformamide. To the system were added 2.9 ml (4 g, 40 mmol) of 2,2,2-trifluoroethanol via syringe over a period of 15 minutes and the mixture was stirred at room temperature for 20 minutes. To the system were added 1.72 g (10 mmol) of 2,5-dichlorobenzonitrile, and the mixture was heated at 90° C. for three days. The mixture was cooled to room temperature, poured into 50 ml of 2M aqueous HCl and extracted with three portions of ether. The combinedorganic fractions were dried (Na2SO4) and concentrated to afford2.5 g of a solid. The crude material was purified by flash column chromatography using 1:49 ethyl acetate/hexanes as the eluant to obtain 1.4 g of 5-chloro-2-(2,2,2-trifluoroethoxy)benzonitrile as a white solid.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH:26]=O)=[CH:23][CH:24]=3)[CH:19]=[N:18]2)=[CH:13][CH:12]=1>C1C=CC=CC=1.C(O)(=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH:26]=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:23][CH:24]=3)[CH:19]=[N:18]2)=[CH:15][CH:16]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)C(=Cc1ccc2c(cnn2-c2ccc(F)cc2)c1)C(=O)OC
Yield: 86.7 %

Procedure:
To solution of dimethyl malonate (0.22 mL, 1.65 mmol) in benzene (15 mL) and acetic acid (3 drops) was added 1-(4-fluorophenyl)-1H-indazol-5-carboxaldehyde (330 mg, 1.38 mmol). The reaction mixture was heated at reflux overnight. The reaction was quenched with sat. KH2PO4 and extracted with EtOAc×3. The organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on SiO2 by MPLC using a 1:9 to 1:3 EtOAc/hexane gradient. Obtained 424 mg (87% yield) of dimethyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)methylene)malonate. MS found: (M+H)+=355.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:15]2[C:10](=[C:11]([F:20])[CH:12]=[CH:13][C:14]=2[O:16][CH2:17][CH2:18][CH3:19])[C:9](=[O:21])[C:8]([C:22]2[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=2)=[CH:7]1)[CH3:2].ClCCl.B(Br)(Br)Br.O>ClCCl>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:15]2[C:10](=[C:11]([F:20])[CH:12]=[CH:13][C:14]=2[O:16][CH2:17][CH2:18][CH3:19])[C:9](=[O:21])[C:8]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:7]1)[CH3:2]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CC(=O)OCC)c12
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(O)cc3)cn(CC(=O)OCC)c12
Reaction time: 2 h
Yield: 70.4 %

Procedure:
Ethyl[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetate (4.0 g, 9.6 mmol) was dissolved in dichloromethane (20 ml). A 1M-boron tribromide dichloromethane solution (35 ml, 35 mmol) was added dropwise to the dissolution at −10° C. After stirring at the same temperature for 2 hours, water was added to the reaction mixture, followed by extraction with dichloromethane. The thus-obtained organic layer was concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=50:1→15:1). The purified product was concentrated to dryness under reduced pressure, giving a yellow powder of ethyl[5-fluoro-3-(4-hydroxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]acetate (2.7 g, yield: 57%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([O:23][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:14]#[C:13][CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a stirred solution of 1-(tert-butoxycarbonyl)-2-[2-(4-ethoxycarbonylphenyl) ethynyl]pyrrolidine (2.75 g, 8 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL), and the resulting mixture was stirred overnight. The mixture was concentrated in vacuo and made basic with sat. NaHCO3 and extracted with CHCl3. The extract was washed with brine, dried over MgSO4, evaporated to give 1.95 g (q.y.) 2-[2-(4-ethoxycarbonylphenyl) ethynyl]pyrrolidine as a light yellow oil. 1H-NMR (CDCl3) δ 1.38 (3 H, t, J=6.8 Hz), 1.82–2.16 (4 H, m), 3.01–3.48 (2 H, m), 4.00–4.11 (1 H, m), 4.37 (2H, q, J=6.8 Hz), 4.54–4.77 (1 H, m), 7.44–7.46 (2 H, m), 7.95–7.97 (2 H, m).
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[CH2:7]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][Cl:25])[CH2:18][CH2:17]1)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:25].[ClH:5].[CH2:7]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][SH:3])[CH2:18][CH2:17]1)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(N)=S
Reactant: ClCCCN1CCN(CC=Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: SCCCN1CCN(CC=Cc2ccccc2)CC1
Yield: 49 %

Procedure:
The procedure described in Example 1(b) was followed, using 3.1 g of thiourea, 7.4 g of 1-cinnamyl-4-(3-chloropropyl)piperazine dihydrochloride, 4,1 g of triethylamine and 100 ml of reagent ethanol. The hydrolysis was effected with 3.0 g of sodium hydroxide in 30 ml of water. Work-up, as described above, gave 3.6 g (52% of theory) of 3-(4-cinnamylpiperazin-1-yl)propanethiol dihydrochloride as a white crystalline solid, M.p. 249°-252° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]1[O:21][C:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1)=[O:13])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]1[O:21][C:22]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:24]=1)=[O:13]
Reactant: O=C(c1cccc(OCc2ccccc2)c1)N1CCCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(c1cccc(O)c1)N1CCCCC1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 7 h
Yield: 127.6 %

Procedure:
A mixture of 1-(3-benzyloxybenzoyl)-2-(4,5-diphenyl-2-oxazolyl)piperidine (95 mg) and 10% Pd—C (50% wet, 15 mg) in ethyl acetate (3 ml)—10% methanolic hydrogen chloride was stirred in the presence of atmospheric H2 gas at room temperature for 7 hours and filtered. The filtrate was evaporated in vacuo to afford 1-(3-hydroxybenzoyl)-2-(4,5-diphenyl-2-oxazolyl)piperidine (100 mg) as a crude oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=2)[N:26]([CH3:34])[CH:25]=1)=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:20][NH:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([O:33][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:30][CH:31]=2)[N:26]([CH3:34])[CH:25]=1)=[O:23]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: CNC(=O)c1cn(C)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1cn(C)c2cc(Oc3ccnc4cc(C(=O)N5CCC(OC)C5)sc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b with 6-hydroxy-1-methyl-1H-indole-3-carboxylic acid methylamide 21b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ 8.53 (1H, d, J=5.5 Hz), 8.25 (1H, d, J=8.7 Hz), 7.96 (1H, d, J=6.2 Hz), 7.86 (1H, s), 7.46 (1H, d, J=1.9 Hz), 7.12 (1H, d, J=8.5 Hz), 6.74 (1H, d, J=5.5 Hz), 4.19–4.11 (1H, m), 4.05–3.95 (2H, m), 3.38 (3H, s), 3.85–3.72 (2H, m), 3.40 (3H, d, J=13.9 Hz), 2.96 (3H, s), 2.30–2.09 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 465. found 465. Anal. (C24H24N4O4S.0.4CH2Cl2) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH2:33]([C:35]1[C:43]2[C:42]([NH2:44])=[CH:41][CH:40]=[CH:39][C:38]=2[N:37]([CH2:45][C:46]2[CH:50]=[CH:49][N:48]([CH2:51][CH3:52])[N:47]=2)[N:36]=1)[CH3:34]>CN1CCCC1=O>[CH2:33]([C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][C:42]=2[NH:44][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:13])[N:37]([CH2:45][C:46]2[CH:50]=[CH:49][N:48]([CH2:51][CH3:52])[N:47]=2)[N:36]=1)[CH3:34]
Reactant: O=C(O)c1cnc2cc(F)ccn12
Reactant: CCc1nn(Cc2ccn(CC)n2)c2cccc(N)c12
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCc1nn(Cc2ccn(CC)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
7-Fluoroimidazo[1,2-a]pyridine-3-carboxylic acid (Preparation I; 224 mg, 1.25 mmol) was dissolved in anhydrous N-methylpyrrolidinone (0.2 M) and treated with triethylamine (0.35 mL, 2.5 mmol). When the mixture was homogeneous 2,4,6-trichlorobenzoyl chloride (0.20 mL, 1.31 mmol) was added dropwise. The mixture was stirred for 30 minutes at ambient temperature. 3-Ethyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (0.30 mg, 1.11 mmol) was added in one portion and the sides of the flask were washed with anhydrous N-methylpyrrolidinone (2 mL). The mixture was heated to 90° C. and stirred for 16 hours. The mixture was allowed to cool and filtered through GF/F paper washing with ethyl acetate. The filtrate was concentration under reduced pressure and diluted with water to give a beige precipitate which was collected by filtration, washed with water and dried under high vacuum to give N-(3-ethyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (259 mg). MS m/z 432.1 (M+1, APCI+).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:13][C:12]=1[CH3:34])([CH3:6])([CH3:5])[CH3:4].CI.[CH3:38]COC(C)=O>CN(C=O)C>[C:3]([O:7][C:8](=[O:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[N:22]([CH3:38])[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])=[CH:13][C:12]=1[CH3:34])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3N(C)c3ccccc32)ccc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
Sodium hydride (14 mg, 0.34 mmol) was added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid tert-butyl ester from Example E45 (125 mg, 0.28 mmol) in DMF (2 ml) at 0° C. The mixture was stirred for 20 min at room temperature then cooled down to 0° C. Methyl iodide (0.09 ml, 1.4 mmol) was added and the mixture was stirred for 20 h at room temperature. EtOAc was added and the mixture was washed with 0.3M KHSO4 then brine, dried, concentrated in vacuo and azeotroped with toluene. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (46 mg, 36%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.C(=O)([O-])O.[Na+].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].[H][H]>C(O)C.[C].[Pd].O1CCCC1.O>[C:25]([NH:29][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[NH2:17])([CH3:28])([CH3:27])[CH3:26]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: CC(C)(C)N
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)Nc1ccc(-c2nc3ccccc3o2)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.4 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added sodium hydrogen carbonate (195 mg, 2.32 mmol) and tert-butylamine (212 mg, 2.90 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were added to a tetrahydrofuran (5 mL) solution containing 10% palladium-carbon (50 mg), a hydrogen atmosphere was substituted in the flask and this was stirred at room temperature for 8 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (50.1 mg, 19% yield) as red crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:22]=[C:21]3[C:15]([N:16]([CH3:29])[C:17](=[O:28])[CH2:18][CH2:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:14][N:13]=2)[C:8]([O:30][CH3:31])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.Cl.[CH3:34][N:35]1[CH2:39][CH2:38][C@@H:37]([NH2:40])[CH2:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]2[N:22]=[C:21]3[C:15]([N:16]([CH3:29])[C:17](=[O:28])[CH2:18][CH2:19][N:20]3[CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:14][N:13]=2)[C:8]([O:30][CH3:31])=[CH:7][C:3]=1[C:4]([NH:40][C@@H:37]1[CH2:38][CH2:39][N:35]([CH3:34])[CH2:36]1)=[O:6]
Reactant: CN1CC[C@@H](N)C1
Reactant: COc1cc(C(=O)O)c(Cl)cc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)c(Cl)cc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
2-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-5-methoxy-benzoic acid (Intermediate 231; 100 mg, 0.224 mmol), (3R)-1-methylpyrrolidin-3-amine di Hydrochloride (Intermediate 184; 40 mg, 0.235 mmol), HATU (94 mg, 0.246 mmol) and DIPEA (195 μL, 1.12 mmol) were combined in DMF (3 mL) and stirred at room temperature overnight. The reaction mixture was added to an SCX-2 column (5 g) pre-wet with MeOH (2 column volumes), flushed with MeOH (2 column volumes) and eluted with 2M ammonia in MeOH. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (76 mg, 64%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11]C3CCCCO3)[C:5]=2[O:4][C:3]1=[O:18].Cl>CO>[OH:11][C:10]1[C:5]2[O:4][C:3](=[O:18])[N:2]([CH3:1])[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c(=O)oc2c(OC3CCCCO3)cccc21
Agent: Cl
Solvent: CO
Product: Cn1c(=O)oc2c(O)cccc21
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To a suspension of 3-methyl-7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolone (280 mg) in methanol (2.3 ml) was added 1N hydrochloric acid (0.5 ml) at ambient temperature, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated to ⅓ volume, and water was added thereto. The mixture was extracted with chloroform, and the extract was dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized with diisopropyl ether to give 7-hydroxy-3-methyl-2(3H)-benzoxazolone (164 mg).
Reaction SMILES: C([Li])CCC.O1CCCC1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:19][C:20](=[O:34])[C:21]3[N:26]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[N:25]=[C:24]([CH3:33])[C:22]=3[N:23]=2)=[C:14]([O:35][CH3:36])[CH:13]=1.[CH3:37][N:38]1[CH2:43][CH2:42][C:41](=[O:44])[CH2:40][CH2:39]1>O>[CH:27]1([N:26]2[C:21]3[C:20](=[O:34])[NH:19][C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:41]5([OH:44])[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)=[CH:13][C:14]=4[O:35][CH3:36])=[N:23][C:22]=3[C:24]([CH3:33])=[N:25]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C2(O)CCN(C)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
In an atmosphere of argon, 0.95 ml of n-butyl lithium (1.59M/hexane solution, 1.51 mmol) was added dropwise at −78° C. to a 10 ml anhydrous tetrahydrofuran solution of 300 mg (0.72 mmol) of the compound obtained in Example 15. The mixture was stirred at −78° C. for 30 minutes, and then 133 μl (1.08 mmol) of 1-methyl-4-piperidone was added, followed by heating the mixture gradually to 0° C. over the course of 1 hour. Then, water was added to the reaction mixture, and then the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to obtain 179 mg (55%) of the captioned compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]2[C:15]([CH3:16])=[CH:14][NH:13][C:7]=2[N:8]=[C:9]([S:11][CH3:12])[N:10]=1.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=2)=[O:23])=[CH:20][CH:19]=1.O>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][N:13]3[C:7]4[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:5]([O:4][CH3:3])[C:6]=4[C:15]([CH3:16])=[CH:14]3)=[CH:26][CH:25]=2)=[O:23])=[CH:32][CH:33]=1
Reactant: COc1nc(SC)nc2[nH]cc(C)c12
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(SC)nc2c1c(C)cn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Yield: 54.2 %

Procedure:
In an argon gas stream, 60% sodium hydride-oil (220 mg) was suspended in anhydrous DMF (5 ml) and a powder of 4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (1.05 g) was added in small portions with ice-cooling and stirring. After completion of addition, the mixture was stirred for 30 minutes and then a solution of 4-(4-chlorobenzoyl)benzyl bromide (1.63 g) in DMF (5 ml) was added. Then, at room temperature, the mixture was stirred for 2 hours. To this reaction mixture was added water (50 ml) and the resulting precipitate was collected by filtration, rinsed with water, dried, and purified by flash column chromatography (silica gel; hexane: ethyl acetate=9:1) to provide the title compound (1.19 g). 1H-NMR (CDCl3) δ: 2.33(3H,d,J=1.2Hz), 2.60(3H,s), 4.08(3H,s), 5.36(2H,s), 6.57(1H,d,J=1.2Hz), 7.28(2H,d,J=8.6Hz), 7.44(2H,d,J=8.6Hz), 7.70(2H,d,J=8.6Hz), 7.72(2H,d,J=8.6Hz).
Reaction SMILES: B(F)(F)F.[CH3:5]COCC.[CH:10]1[C:15](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:14][CH:13]=[C:12]([OH:21])[CH:11]=1>CO>[C:18]([O:20][CH3:5])(=[O:19])/[CH:17]=[CH:16]/[C:15]1[CH:14]=[CH:13][C:12]([OH:21])=[CH:11][CH:10]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC(=O)/C=C/c1ccc(O)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
Boron trifluoride etherate (0.067 mol) is added to a solution of coumaric acid (0.034 mol) in methanol (50 ml) in a 250 ml round bottom flask and the mixture stirred at 70° C. for 2 hours and evaporated to dryness under reduced vacuum. The residual solid is taken up in CH2Cl2, washed with aqueous NaHCO3, dried over MgSO4 and filtered to provide, after evaporation of the CH2Cl2, the desired product as a pale yellow solid in 74.1% yield.
Reaction SMILES: [C:1](OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)CC4)CCC1=C[C@@H](O)C[C@H]2C)(=O)C.[C:27](OC[C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)[C@@H](O)CC4)C[C@H](C)C1=C[C@@H](O)CC2)(=O)C.[C:53]([O:56][CH2:57][C@@:58]12[C@@H:75]3[C@H:66]([C@H:67]4[C@@:71]([CH2:73][CH2:74]3)([CH3:72])[C@@H:70]([O:76][Si:77]([C:90]3[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=3)([C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=3)[C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[CH2:69][CH2:68]4)[CH2:65][CH2:64][C:63]1=[CH:62][C@@H:61]([O:96][Si:97]([C:110]1[CH:115]=[CH:114][CH:113]=[CH:112][CH:111]=1)([C:104]1[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=1)[C:98]1[CH:103]=[CH:102][CH:101]=[CH:100][CH:99]=1)[CH2:60][CH2:59]2)(=[O:55])[CH3:54]>>[C:53]([O:56][CH2:57][C@@:58]12[C@@H:75]3[C@H:66]([C@H:67]4[C@@:71]([CH2:73][CH2:74]3)([CH3:72])[C@@H:70]([O:76][Si:77]([C:90]3[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=3)([C:84]3[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=3)[C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[CH2:69][CH2:68]4)[CH2:65][CH2:64][C:63]1=[CH:62][C@@H:61]([O:96][Si:97]([C:104]1[CH:105]=[CH:106][CH:107]=[CH:108][CH:109]=1)([C:98]1[CH:99]=[CH:100][CH:101]=[CH:102][CH:103]=1)[C:110]1[CH:115]=[CH:114][CH:113]=[CH:112][CH:111]=1)[CH2:60][C@H:59]2[CH3:1])(=[O:55])[CH3:54].[C:53]([O:56][CH2:57][C@@:58]12[C@@H:75]3[C@H:66]([C@H:67]4[C@@:71]([CH2:73][CH2:74]3)([CH3:72])[C@@H:70]([O:76][Si:77]([C:90]3[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=3)([C:84]3[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=3)[C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)[CH2:69][CH2:68]4)[CH2:65][C@H:64]([CH3:27])[C:63]1=[CH:62][C@@H:61]([O:96][Si:97]([C:104]1[CH:105]=[CH:106][CH:107]=[CH:108][CH:109]=1)([C:98]1[CH:99]=[CH:100][CH:101]=[CH:102][CH:103]=1)[C:110]1[CH:115]=[CH:114][CH:113]=[CH:112][CH:111]=1)[CH2:60][CH2:59]2)(=[O:55])[CH3:54]
Reactant: CC(=O)OC[C@]12CC[C@H](O[Si](c3ccccc3)(c3ccccc3)c3ccccc3)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O[Si](c3ccccc3)(c3ccccc3)c3ccccc3)CC[C@@H]12
Reactant: CC(=O)OC[C@]12CC[C@H](O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: CC(=O)OC[C@@]12C(=C[C@@H](O)C[C@H]1C)CC[C@H]1[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@@H]12
Product: CC(=O)OC[C@@]12C(=C[C@@H](O[Si](c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]1C)CC[C@H]1[C@@H]3CC[C@H](O[Si](c4ccccc4)(c4ccccc4)c4ccccc4)[C@@]3(C)CC[C@@H]12
Product: CC(=O)OC[C@]12CC[C@H](O[Si](c3ccccc3)(c3ccccc3)c3ccccc3)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O[Si](c3ccccc3)(c3ccccc3)c3ccccc3)CC[C@@H]12

Procedure:
Substituting 1β-methyl-4-androstene-3β,17β,19-triol 19-acetate and 6α-methyl-4-androstene-3β, 17β,19-triol 19-acetate for the androst-4-ene-3β,17β,19-triol 19-acetate above, results in the preparation of 1β-methyl-3β,17β-di-(triphenylsiloxy)-4-androsten-19-ol acetate and 6α-methyl-3β,17β-di-(triphenylsiloxy)-4-androsten-19-ol acetate.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH3:22][C:23]([CH3:29])([CH2:27][CH3:28])[C:24](Cl)=[O:25].N1C=CC=CC=1.C(Cl)Cl>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:24](=[O:25])[C:23]([CH3:29])([CH3:22])[CH2:27][CH3:28])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCC(C)(C)C(=O)N1CC(NC(=O)OC(C)(C)C)C(=O)Nc2cc(C)ccc21
Yield: 89.8 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.0 g) was suspended in 1,2-dichloroethane (20 ml), and 2,2-dimethylbutanoyl chloride (538 mg) and pyridine (0.33 ml) were added thereto to the suspension, and the mixture was refluxed for 2 hours. Methylene chloride was added to the reaction mixture, washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, crystals so precipitate were washed with ether, to thereby obtain 1.20 g of the title compound (Yield 89.8%).