Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1.Br[C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:33]1[CH2:38][CH2:37][N:36]([S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:19][N:2]([CH2:3][C:4]1[CH:9]=[C:8]([C:21]2[CH:22]=[C:23]3[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=2)[NH:26][CH:25]=[C:24]3[CH:33]2[CH2:34][CH2:35][N:36]([S:39]([CH2:42][CH3:43])(=[O:40])=[O:41])[CH2:37][CH2:38]2)[CH:7]=[N:6][CH:5]=1)[CH3:1]
Reactant: CN(C)Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CN(C)C)c4)cc23)CC1
Yield: 16 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), a 2 M solution of dimethylamine in THF (0.065 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 23 mg of crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 5.4 mg of the title compound (16%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[N:3]=1
Reactant: Cc1cccc(CBr)n1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.7 %

Procedure:
To a solution of 3-iodo-4-nitro-1H-indazole (172 mg, 0.596 mmol) in dry N,N-dimethylformamide (3 mL) under an atmosphere of dry nitrogen was added 2-(bromomethyl)-6-methylpyridine (122 mg, 0.656 mmol) and potassium carbonate (165 mg, 1.19 mmol) with magnetic stirring. The mixture was stirred at ambient temperature for 3 days. The reaction mixture was diluted with water (20 mL) and extracted into ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified using preparative chromatography on silica, eluting with hexane/ethyl acetate (3:1) to give 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (213 mg).
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:16][CH3:17]>O1CCCC1.C(OCC)C.[Br-].[Zn+2].[Br-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:20]([O:19][C:15](=[O:18])[C:16]#[C:17][C:9]1[CH:14]=[N:13][CH:12]=[CH:11][N:10]=1)[CH3:21]
Reactant: CCOC(=O)CC
Reactant: Ic1cnccn1
Agent: [Pd]
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C#Cc1cnccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
To a dry solution of zinc bromide (6.49 g, 28.8 mmol) in tetrahydrofuran (60 mL) was added triethylamine (16 mL, 115.2 mmol), iodopyrazine (4.95 g, 24 mmol), ethyl proprionate (3.66 mL, 36 mmol) and tetrakis(triphenylphosphine) palladium (832 mg, 0.72 mmol). The reaction mixture was allowed to stir at ambient temperature for 16 h, diluted with diethyl ether, washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography (40% ethyl acetate in heptane) to yield the title compound as an orange oil (2.19 g, 52% yield). LCMS (m/z): 176.97 (M+).
Reaction SMILES: [CH:1]1([CH2:10][CH2:11]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.CS(Cl)(=O)=O.[N:34]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]([NH2:48])=[O:47])=[CH:42][CH:41]=2)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(C(C)C)CC)(C)C>O1CCCC1.O.C(O)CO>[CH:1]1([CH2:10][CH2:11][N:37]2[CH2:36][CH2:35][N:34]([C:40]3[CH:41]=[CH:42][C:43]([C:46]([NH2:48])=[O:47])=[CH:44][CH:45]=3)[CH2:39][CH2:38]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OCCC1C=Cc2ccccc21
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: OCCO
Product: NC(=O)c1ccc(N2CCN(CCC3C=Cc4ccccc43)CC2)cc1
Reaction time: 0.75 h

Procedure:
A mixture of 2-(inden-1-yl)ethanol (CXVI-B, EXAMPLE 86, 0.8 g, 5 mmol), dimethylaminopyridine (0.02 g, 0.2 mmol) and triethylamine (1.7 ml, 12.5 mmol) in tetrahydrofuran (10 ml) is cooled to 0° and methanesulfonyl chloride (0.43 ml, 5.5 mmol) is added dropwise. After 45 min, 4-(piperazinyl)benzenecarboxamide (LXV, 1.23 g, 6 mmol), diisopropylethylamine (1.0 ml, 6 mmol) and ethyleneglycol (10 ml) are added and heated at 85° for 60 hr. The mixture is diluted with water and extracted with methylene chloride. The organic phase is separated, washed with saline, dried (magnesium sulfate), filtered and concentrated. Crystallization from ethyl acetate gives the title compound, mp 207°; NMR (CDCl3, TMS) 7.75-6.90, 6.28 and 3.39-2.68 δ.
Reaction SMILES: [N:1]([C:4]([CH3:23])([CH3:22])[CH2:5][C:6]([N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:9])=O)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:10]([N:8]([CH3:9])[CH2:6][CH2:5][C:4]([CH3:23])([NH2:1])[CH3:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCN(C)C(=O)CC(C)(C)N=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCN(C)CCC(C)(C)N
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
3-Azido-N-dodecyl-N,3-dimethylbutanamide (7.28 g, 22.4 mmol) was dissolved into anhydrous THF (50 mL) and added dropwise to a suspension of LAH (1.70 g, 2.0 equiv, 44.8 mmol) in anhydrous THF (100 mL) to maintain the reaction at reflux (30 min). After complete addition, the flask was fitted with a condenser and the reaction heated in a 70° C. oil bath for 8 h. The reaction mixture was cooled in an ice bath and water (1.7 mL) was added dropwise over 20 min. Then 15% NaOH solution (1.7 mL) was added dropwise over 10 min. The suspension was stirred for a further 10 min and water (1.7 mL) was added in one portion and the mixture stirred for 30 min to a give fine white suspension. The suspension was filtered through a pad of Celite® and washed with diethyl ether (2×100 mL). The combined filtrate was concentrated with a bath temperature between 10-13° C. to an orange liquid (5.61 g, 88.0%). LRMS (ESI+) for C18H40N2 (284.3); Found: 285 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]=2[C:13]2[O:14][CH:15]=[C:16]([CH:18]=[CH2:19])[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26]O>[Pd]>[C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:12]=2[C:13]2[O:14][CH:15]=[C:16]([CH:18]([CH3:26])[CH3:19])[N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: C=Cc1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Agent: [Pd]
Product: CC(C)c1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 2-(3,5-diphenylpyridazin-4-yl)-4-vinyloxazole (70 mg, 0.20 mmol) in methanol (5 mL), 10% Pd/C (35 mg, wt/wt) was added and the resulting reaction mixture was stirred at rt under hydrogen atmosphere for 2 h. The reaction mixture was filtered through celite bed, washed with methanol and evaporation of solvent under reduced pressure gave the crude product which was purified by column chromatography to furnish 2-(3,5-diphenylpyridazin-4-yl)-4-isopropyloxazole (compound 23) (25 mg, 95%) as pale yellow gummy liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:44]([CH3:46])[CH3:45])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([O:36]CC5C=CC=CC=5)=[O:35])[CH2:29]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.O[Li].O>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH:44]([CH3:45])[CH3:46])[CH:28]4[CH2:29][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH2:31]4)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C(C)C)C3CC(CCC(=O)OCc4ccccc4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN(C(C)C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 123 %

Procedure:
To a solution of benzyl 3-(3-((((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(isopropyl)amino)cyclobutyl)propanoate (2.7 g, 3.78 mmol) in THF/MeOH (15 mL/15 mL) was added a solution of LiOH.H2O (1.6 g, 37.82 mmol) in water (5 mL). The mixture was stirred at 30° C. for 2 h. The volatiles were removed under reduced pressure. To the residue was diluted with water (10 mL) and extracted with EA (15 mL×2). The suspension water layers were adjusted to pH=3-4 with 1 N HCl solution and extracted with EA (30 mL×3). The combined organic layers were washed with brine (50 in L). The organic phase was dried over Na2SO4, filtered and concentrated to afford the desired compound as a yellow solid (2.9 g). 1H NMR (500 MHz, MeOD): δH 8.20 (s, 1H), 7.92 (s, 0.5H), 7.38-7.32 (m, 3H), 7.28-7.23 (m, 1.5H), 7.14 (d, J=8.5 Hz, 1H), 6.68 (brs, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.44 (d, J=8.5 Hz, 1H), 6.25 (s, 1H), 5.51-5.47 (m, 1H), 5.18-5.13 (m, 1H), 4.66 (s, 2H), 4.61 (s, 1H), 4.43-4.40 (m, 1H), 3.96-3.90 (m, 0.5H), 3.85 (s, 3H), 3.77 (s, 3H), 3.65-3.58 (m, 0.5H), 3.50-3.40 (m, 2H), 2.46-2.36 (m, 1H), 2.20-2.00 (m, 4H), 1.98-1.70 (m, 2.5H), 1.70-1.58 (m, 4.5H), 1.40 (s, 3H), 1.18 (d, J=5.0 Hz, 3H), 0.90 (t, J=6.0 Hz, 3H) ppm; ESI-MS (m/z): 624.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:36][CH:37]1[CH2:39][O:38]1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:36][CH:37]3[CH2:39][O:38]3)[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1c[nH]nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cn(CC2CO2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.9 %

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.00 g, 2.47 mmol) in N,N-dimethylformamide (10 mL), Cs2CO3 (970 mg, 2.977 mmol) was added and stirred for 10 minutes at room temperature. Then 2-(chloromethyl)oxirane (2.28 g, 24.64 mmol) was added dropwise at room temperature. The resulting mixture was stirred for 14 hour at room temperature and diluted with ethyl acetate (100 mL), washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/petroleum ether (60/40) to give 500 mg (44%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(oxiran-2-ylmethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 24), [M+H]+=461.1, RT=1.30 min.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.Cl.Cl.N1([S:41]([CH2:44][CH2:45][CH2:46][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)(=[O:43])=[O:42])CCNCC1.CCN(C(C)C)C(C)C>C1COCC1>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:41]([CH2:44][CH2:45][CH2:46][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)(=[O:43])=[O:42])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: O=S(=O)(CCCN1CCOCC1)N1CCNCC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCCN3CCOCC3)CC2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) (150 mg, 0.378 mmol), 4-[3-(1-piperazinylsulfonyl)propyl]morpholine dihydrochloride (WO 2006/046040) (172 mg, 0.491 mmol) and DIPEA (0.40 mL, 2.27 mmol) in THF was stirred at room temperature for 17 hrs. The solvent was removed under vacuum, and the residue was diluted with water and extracted with CH2Cl2. The CH2Cl2 was dried (Na2SO4) and removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (98:2) followed by recrystallization from CH2Cl2/hexanes gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[3-(4-morpholinyl)propyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (188 mg, 78%). Treatment with methanesulfonic acid in CH2Cl2/MeOH and recrystallization from MeOH/EtOAc gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-{[3-(4-morpholinyl)propyl]sulfonyl}-1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole methanesulfonate: mp 216-218° C.; 1H NMR (DMSO-d6) δ9.50 (br s, 1H), 7.89 (d, J=8.2 Hz, 1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 4.01-3.93 (m, 6H), 3.98 (s, 3H), 3.82 (m, 4H), 3.70 (br s, 4H), 3.63 (t, J=12.1 Hz, 2H), 3.45 (d, J=12.6 Hz, 2H), 3.32 (m, 4H), 3.21 (t, J=7.1 Hz, 4H), 3.09 (dd, J=21.2, 11.8 Hz, 2H), 2.30 (s, 3H), 2.09 (m, 2H); Anal. Calcd for C28H41F2N9O8S2: C, 45.8; H, 5.6; N, 17.2. Found: C, 45.7; H, 5.6; N, 17.2%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:35]=[N:36][S:37][CH:38]=2)=[CH:30][CH:29]=1>CC(N(C)C)=O>[S:37]1[CH:38]=[C:34]([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]3[CH:10]=[CH:9][C:8]4[NH:7][C:6]5[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=5[C:4]=4[CH:3]=3)=[CH:29][CH:30]=2)[N:35]=[N:36]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Reactant: BrCc1ccc(-c2csnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(-c4csnn4)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
In a 4 mL vial were placed ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (64.8 mg, 0.250 mmol), cesium carbonate (81 mg, 0.250 mmol), and 4-(4-(bromomethyl)phenyl)-1,2,3-thiadiazole (63.8 mg, 0.250 mmol). DMA (1 mL) was added and the reaction was stirred at room temperature overnight. The solid was removed by filtration and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (42.7 mg). LCMS m/z=434.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]2[O:13][CH:12]=[CH:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[OH:2][CH2:3][C:5]1[C:14]2[O:13][CH:12]=[CH:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)c1cccc2c1OC=CO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCc1cccc2c1OC=CO2
Reaction time: 0.5 h

Procedure:
1.62 g (8.44 mmol) of the unsaturated ester obtained in Step C are added to a suspension of 0.64 g (16.84 mmol) of lithium aluminium hydride in 40 ml of anhydrous ether. The mixture is then heated at reflux for 30 minutes under an inert atmosphere and subsequently allowed to cool. The solution is hydrolysed with, in succession, 0.64 ml of water, 0.64 ml of a 15% sodium hydroxide solution and finally 1.92 ml of water. After 30 minutes' stirring, the salts are filtered off and then the filtrate is concentrated under reduced pressure. The title alcohol is obtained pure in the form of a white solid after chromatography over silica gel (eluant:AcOEt/PE:40/60).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]2[N:25]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[N:26]=[CH:27][C:20]=12.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:19]2[N:24]=[CH:23][N:22]=[C:21]3[N:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[N:26]=[CH:27][C:20]=23)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: Clc1ncnc2c1cnn2C1CCCCO1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Temperature: 90 °C
Yield: 81.4 %

Procedure:
4-(Methylsulfonyl)-phenol (Oakwood Products, Inc., West Columbia, S.C., USA; 516 mg, 3 mmol) and cesium carbonate (1.63 g, 5 mmol) were added to a solution of 4-chloro-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Step 1; 610 mg, 2.56 mmol) in dimethylformamide (15 mL). The mixture was heated at 90° C. for 1 h, then cooled, poured into saturated aqueous sodium bicarbonate solution, and extracted three times with ethyl acetate. The combined organic extracts were washed with twice with water and once with brine, dried (magnesium sulfate), filtered, and evaporated to give 4-(4-methanesulfonyl-phenoxy)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (780 mg, 58%).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2].N.[Li].C(O)C>O1CCCC1.CCOCC.O>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20][CH3:21])[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4

Procedure:
Add 13β-Ethyl-3-methoxy-gona-1,3,5(10)-trien-17β-ol (0.5 g.) in tetrahydrofuran (50 cc.) to stirred liquid ammonia (150 cc.), followed by lithium foil (0.5 g.) and then add ethanol (6 cc.) during 20 minutes. When the blue color is discharged, add water and work up the product with ether, to yield 13β-ethyl-3-methoxy-gona-2,5(10)-dien-17β-ol as a solid (0.47 g.).
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[C@@H:20]5[O:29][C@@H:21]53)=[CH:16][C@H:15]4[OH:31])[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.CCCCCC>CC(C)=O>[O:29]1[C@H:20]2[C@H:19]([OH:30])[CH2:18][C:17]3[C@:22]([CH3:23])([C@@H:21]12)[C@@H:24]1[C@H:14]([C@H:13]2[C@:27]([CH3:28])([CH2:26][CH2:25]1)[C@@H:10]([CH:8]([CH:5]=[O:4])[CH3:9])[CH2:11][CH2:12]2)[C@H:15]([OH:31])[CH:16]=3
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.6 %

Procedure:
In 2.5 ml of acetone was dissolved 2.2 mg (0.005 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-ene-3β,7α-diol, followed by addition of 0.5 ml of a 1 mmol/1 solution of p-toluenesulfonic acid in acetone (containing 0.0005 mmole of p-toluenesulfonic acid). The mixture was stirred at room temperature for 12 hours. From the reaction mixture thus obtained, the solvent was distilled off under reduced pressure and methylene chloride was added to the residue. This methylene chloride solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:ethyl acetate-hexane=1:5, v/v) to recover 1.2 mg of 1α,2α-epoxy- 3β,7α-dihydroxypregna-5-ene-20-carbaldehyde (yield: 67%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Si:64]([O:71][CH2:72][CH2:73][NH:74][CH:75]([CH3:77])[CH3:76])([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Si:64]([O:71][CH2:72][CH2:73][N:74]([CH:75]([CH3:77])[CH3:76])[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:29])([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65]
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (437) (180 mg, 0.44 mmol) in dimethylformamide (5 mL), N,N-diisopropylethylamine (0.22 mL, 1.33 mmol), HATU (253.5 mg, 0.667 mmol), and [2-(tert-Butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8b) were added, then this reaction mixture was allowed to stir for 16 h at room temperature while silica thin layer chromatography was performed (50% ethyl acetate in hexane; Rf=0.5). The reaction was quenched with ice cold water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined extracts were dried, concentrated under vacuo and the resulting crude product was purified by normal silica gel (100-200 mesh) column chromatography using 30-40% ethyl acetate in hexane as gradient polarity mobile phase to get 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylicacid[2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (438) (160 mg, 60%) as a yellow gummy liquid.