Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2)[CH3:2].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1.O>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([S:26]([CH3:25])(=[O:28])=[O:27])[CH:20]=[CH:19]2)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCn1c(-c2ccc3[nH]ccc3c2)c(C#N)c2ccc(OC)cc21
Solvent: c1ccncc1
Solvent: O
Product: CCn1c(-c2ccc3c(ccn3S(C)(=O)=O)c2)c(C#N)c2ccc(OC)cc21
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of 1-ethyl-6-methoxy-1H,1′H-[2,5′]biindolyl-3-carbonitrile (70 mg, 0.22 mmol), prepared as described in Example 1Gb, in pyridine (2 mL) is treated with methanesulfonyl chloride (0.034 mL, 0.44 mmol) and stirred overnight. The reaction mixture is then diluted with H2O and extracted with ethyl acetate (3×). The organic phase is washed with H2O and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-80%) to afford 70 mg (81%) of 1-ethyl-1′-methanesulfonyl-6-methoxy-1H,1′H-[2,5′]biindolyl-3-carbonitrile as a tan solid.
Reaction SMILES: [BH4-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[NH:21][C:22](Br)=[C:23]([N+:25]([O-:27])=[O:26])[N:24]=1>O1CCOCC1>[Br:19][C:20]1[NH:21][CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[N:24]=1
Reactant: O=[N+]([O-])c1nc(Br)[nH]c1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1c[nH]c(Br)n1
Yield: 70785.4 %

Procedure:
Into 1,4-dioxane (1 ml) solution of tetra-n-butylammonium borohydride (638 mg) was added dropwise 1,4-dioxane (1 ml) solution of 2,5-dibromo-4-nitroimidazole (89.5 mg) at a room temperature, after being refluxed the reaction mixture for 23 hours, excessive reagents were quenched by adding concentrated hydrochloric acid, then water and ethyl acetate were added. The organic layer was washed with an aqueous solution being saturated with sodium chloride, then dried over anhydrous sodium sulfate, and purified by a thin layer chromatography (developing agent: ethyl acetate) to obtain 2-bromo-4-nitroimidazole (44.9 g, yield: 71%) of white powdery product.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15]>CO>[CH3:11][O:12][CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Br)cn1
Reactant: COCCN
Solvent: CO
Product: COCCNc1cnc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.9 %

Procedure:
A mixture of 2-bromo-5-nitropyrazine (500 mg, 2.45 mmol) and 2-methoxyethylamine (276 mg, 3.67 mmol) in methanol (15 mL) was stirred at 25° C. for 5 h. After such time, the reaction was concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/3 to 1/4 hexanes/ethyl acetate) afforded (2-methoxy-ethyl)-(5-nitro-pyrazin-2-yl)-amine (291 mg, 60%) as a yellow solid: mp 116.0–117.3° C.; EI-HRMS m/e calcd for C7H10N4O3 (M+) 198.0753, found 198.0751.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([F:19])[C:12]=3[C:14]#[C:15][C:16]([CH3:18])=[CH2:17])[C:7](=[O:21])[C:6]([C:22]([O:24]CC)=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([F:19])[C:12]=3[C:14]#[C:15][C:16]([CH3:18])=[CH2:17])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=C(C)C#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: C=C(C)C#Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 80.4 %

Procedure:
0.715 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylate is refluxed for 1.5 hours in a mixture of 10 ml of glacial acetic acid, 0.5 ml of water and 0.2 ml of concentrated sulphuric acid. The reaction mixture is poured into 100 ml of water. The solid which has precipitated is filtered off with suction, washed with water and dried. 0.53 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(3-methyl-but-3-en-1-inyl)-4-oxo-3-quinolinecarboxylic acid is obtained (80% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:56][NH:57][CH:58]1[CH2:63][CH2:62][N:61]([CH3:64])[CH2:60][CH2:59]1>CN(C=O)C>[CH3:56][N:57]([CH:58]1[CH2:63][CH2:62][N:61]([CH3:64])[CH2:60][CH2:59]1)[C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:32]
Reactant: CNC1CCN(C)CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N(C)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), HOBt (33 mg, 1.2 eq.), EDAC.HCl (45 mg, 1.2 eq.) and methyl-(1-methyl-piperidin-4-yl)-amine (284 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.069 mL, 2.5 eq.). After stirring at rt for 2 days, the reaction was concentrated, diluted with DCM and added solid sodium bicarbonate. After stirring at rt for 15 mins, the suspension was loaded onto a silica gel column to give the titled compound as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([O:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][NH:28][C:29]4=O)=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:40])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[C:17]2[C:18]([O:23][C:24]3[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][N:28]=[C:29]4[Cl:40])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cnc3c(-c4cccnc4Oc4c(C)ccc5c(=O)[nH]ccc45)ncnc32)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2cnc3c(-c4cccnc4Oc4c(C)ccc5c(Cl)nccc45)ncnc32)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-6-methylisoquinolin-1(2H)-one (0.76 g, 1.5 mmol) in phosphorous oxychloride (10 mL, 107 mmol) was stirred in a 100° C. oil bath for 1.0 h. The reaction mixture was allowed to cool to RT, diluted with toluene (100 mL) and concentrated in vacuo. The residue was partitioned between DCM (100 mL) and satd NaHCO3 (70 mL). The aqueous layer was extracted with DCM (50 mL). The combined organic layers were washed with satd NaHCO3 (50 mL), water (50 mL) brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 960 mg as a dark red solid. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (80 g), eluting with a gradient of 50% to 80% EtOAc in CH2Cl2, to provide 5-(3-(9-(4-methoxybenzyl)-9H-purin-6-yl)pyridin-2-yloxy)-1-chloro-6-methylisoquinoline as a clear viscous oil that solidified to a white solid upon standing. MS (ESI, pos. ion) m/z: 509.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(F)cc1)C(=O)OC
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(F)cc1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.80 g), 2-(4-fluorobenzyl)-3-oxopentanoic acid methyl ester (1.0 g), polyphosphoric acid (10 g) and dioxane (10 mL) was heated at 130° C. for 17 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phases washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound, 1.5 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[CH:43]1([N:48]([CH:59]([CH3:61])[CH3:60])[CH2:49][CH2:50][NH:51][C:52](N2C=CN=C2)=[O:53])[CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH:43]1([N:48]([CH:59]([CH3:61])[CH3:60])[CH2:49][CH2:50][NH:51][C:52]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]3[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]3)=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)=[O:6])=[O:53])[CH2:44][CH2:45][CH2:46][CH2:47]1
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C1CCCC1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCCN(C(C)C)C4CCCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
Prepared from N-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 10) and N-{2-[cyclopentyl(isopropyl)amino]ethyl}-1H-imidazole-1-carboxamide (Preparation 26) by a similar method to Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH3:10][Li].[Cl-].[NH4+].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[CH3:10])=[N:6][CH:7]=1
Reactant: [Li]C
Reactant: O=Cc1ccc(F)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc(F)cn1
Yield: 33 %

Procedure:
To a −78° C. solution of 5-fluoro-2-formylpyridine (0.66 g, 5.3 mmol) in THF (20 mL) was methyl lithium (1.6 M in diethyl ether, 4.0 mL) added dropwise. After stirring for 1.5 h at −78° C. a saturated solution of ammonium chloride (25 mL) followed by water (25 mL) was added. The mixture was extracted with chloroform and the organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was purified by flash column chromatography (eluent: chloroform:methanol 98:2) affording the title compound (0.25 g, 33% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[F:22])[N:18]([CH3:23])[C:17](=[O:24])[CH2:16][CH2:15]3)[CH:9]=[N:10][CH:11]=1.[Cl:25][C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][CH:31]=1>>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=[O:24])[N:18]2[CH3:23])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:32]([C:27]2[C:26]([Cl:25])=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:33])[CH:11]=[N:10][CH:9]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(OCCN)c3)c(F)cc21
Reactant: O=C(O)c1ncccc1Cl
Agent: Cl
Product: CN1C(=O)CCc2cc(-c3cncc(OCCNC(=O)c4ncccc4Cl)c3)c(F)cc21

Procedure:
In analogy to the procedure described for the preparation of example 75, 6-[5-(2-amino-ethoxy)-pyridin-3-yl]-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 238) has been coupled with 3-chloro-pyridine-2-carboxylic acid to give the title compound as an off-white solid. MS: 455.3 (M+H+).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:16]([CH:17]=1)[CH2:15][CH2:14][O:13][C:12]1[C:7]2=[CH:8][C:9]([C:19]#[C:20][C:21]([OH:27])([CH3:26])[C:22]([O:24]C)=O)=[C:10]([F:18])[CH:11]=1)(=[O:3])[NH2:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>CO>[CH:28]1([NH:31][C:22]([C:21]([OH:27])([CH3:26])[C:20]#[C:19][C:9]2[C:10]([F:18])=[CH:11][C:12]3[O:13][CH2:14][CH2:15][N:16]4[C:6](=[N:5][C:4]([C:1]([NH2:2])=[O:3])=[CH:17]4)[C:7]=3[CH:8]=2)=[O:24])[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: COC(=O)C(C)(O)C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2
Solvent: CO
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)C(=O)NC1CC1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
Into a 8-mL vial, was placed a solution of methyl 4-[4-carbamoyl-12-fluoro-9-oxa-3,6-diazatricyclo[8.4.0.0[2,6]]tetradeca-1(14),2,4,10,12-pentaen-13-yl]-2-hydroxy-2-methylbut-3-ynoate (120 mg, 0.32 mmol, 1.00 equiv) and cyclopropanamine (1.83 g, 32.05 mmol, 99.72 equiv) in methanol (2 mL). The resulting solution was stirred for 12 h at 40° C. in an oil bath and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30:1). This resulted in 23 mg (18%) of 9-(3-Cyclopropylcarbamoyl-3-hydroxy-but-1-ynyl)-8-fluoro-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide as a yellow solid. LC-MS: (ES, m/z): 399 [M+H]+; 1H-NMR: (300 MHz, DMSO-d6, ppm): δ 8.558 (d, 1H), 7.892 (d, 1H), 7.782 (s, 1H), 7.575 (br s, 1H), 7.126 (br s, 1H), 7.023 (d, 1H), 6.510 (s, 1H), 4.600-4.400 (m, 4H), 2.800-2.600 (m, 1H), 1.600 (s, 3H), 0.633-0565 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.CN(C)C1C=CC=CC=1.Cl[C:21]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[C:26]([Cl:33])[C:22]=1[C:23]([OH:25])=[O:24]>ClCCl>[Cl:33][C:26]1[C:22]([C:23]([OH:25])=[O:24])=[C:21]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][CH:5]=2)[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: CN(C)c1ccc(N)cc1
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CN(C)c1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1

Procedure:
A mixture of 41.0 g of N,N-dimethyl-p-phenylenediamine, 100 ml of N,N-dimethylaniline, and 23.6 g of 2,6-dichloro-3-nitrobenzoic acid was heated for seven hours on a steam bath. The resulting cake was suspended in dichloromethane, filtered, and the solid washed with water. Recrystallization from DMF-ethanol provided 6-chloro-2[[4-(dimethylamino)phenyl]amino]3-nitrobenzoic acid, mp 222°-223° C. (dec).
Reaction SMILES: O[C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:23])[CH2:9][CH2:10][C@@H:11]2[CH:21]=O)[CH2:3]1.P([O-])([O-])(O)=O.[Na+].[Na+].[CH3:31][C:32]([OH:34])=[O:33]>>[C:32]([O:34][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@:8]3([OH:23])[CH2:9][CH2:10][C@@H:11]2[CH3:21])[CH2:3]1)(=[O:33])[CH3:31]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Reactant: CC(=O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C)CC[C@]32O)C1

Procedure:
A solution of 9.1 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723), and p-toluensulphonyl hydrazide (5.6 g) in AcOH (60 mL) was stirred at room temp. for 3 hrs and then poured in a saturated aqueous solution of di-sodium hydrogen phosphate. The mixture was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (200 mL) and zinc iodide (1.2 g) was added. To this solution sodium cyanoborohydride (2.6 g) was added portionwise and the temperature was raised to the boiling point of the reaction mixture. After 3 hrs the solvent was evaporated to dryness under reduced pressure, the crude product was dissolved in ethyl acetate and neutralised with 0.1 N NaOH, the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by chromatography (SiO2) using n-hexane/ethyl ether 75/25 as eluant to give 5.7 g of 3β-acetoxy-14β-hydroxy-17β-methyl-5β-androstane (VIII-a) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=2[O:26][CH3:27])[C:13]([F:28])=[CH:12][N:11]=1>>[Cl:25][C:20]1[C:21]([O:23][CH3:24])=[CH:22][C:17]([NH:16][C:14]2[C:13]([F:28])=[CH:12][N:11]=[C:10]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=3)[N:15]=2)=[C:18]([O:26][CH3:27])[CH:19]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1cc(Nc2nc(Cl)ncc2F)c(OC)cc1Cl
Product: COc1cc(Nc2nc(Nc3cccc(O)c3)ncc2F)c(OC)cc1Cl

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-N4-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine gave N4-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-primidinediamine. 1H NMR (CD3OD): δ 7.96 (d, 1H, J=4.8 Hz), 7.66 (s, 1H), 7.13 (s, 1H), 7.07 (t, 1H, J=8.7 Hz), 8.86 (m, 2H), 6.57 (dd, 1H, J=3.2 and 8.1 Hz), 3.48 (s, 3H), 3.66 (s, 3H); 19F NMR (CD3OD): −46968.
Reaction SMILES: [CH2:1](I)[CH3:2].[F:4][C:5]1([F:49])[CH2:10][CH2:9][CH:8]([C:11]2[C:20]3[CH:19]([OH:21])[CH2:18][C:17]([CH3:23])([CH3:22])[CH2:16][C:15]=3[N:14]=[C:13]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[N:35]=[CH:34][C:33]([OH:36])=[CH:32][N:31]=4)[CH2:26][CH2:25]3)[C:12]=2[CH:37]([F:48])[C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[CH2:7][CH2:6]1>>[F:49][C:5]1([F:4])[CH2:6][CH2:7][CH:8]([C:11]2[C:20]3[CH:19]([OH:21])[CH2:18][C:17]([CH3:22])([CH3:23])[CH2:16][C:15]=3[N:14]=[C:13]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[N:35]=[CH:34][C:33]([O:36][CH2:32][C@@H:33]([O:36][CH:2]5[CH2:1][CH2:17][CH2:18][CH2:19][O:21]5)[CH3:34])=[CH:32][N:31]=4)[CH2:28][CH2:29]3)[C:12]=2[CH:37]([F:48])[C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:46])([F:45])[F:47])=[CH:42][CH:43]=2)[CH2:9][CH2:10]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Reactant: CCI
Product: C[C@@H](COc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1)OC1CCCCO1

Procedure:
Reactions similar to those of Example 13 were performed except for using (2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl 4-methyl benzene sulfonate which was synthesized by the method described in P. Huszthy et al., Journal of Organic Chemistry, 1992, Vol. 57, pp. 5383-5394, instead of ethyl iodide, and from 50 mg (77 μmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 49 mg (62 μmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-2-[1-(5-{[(2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl]oxy}pyrimidin-2-yl)piperidin-4-yl]-5,6,7,8-tetrahydroquinolin-5-ol was obtained.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([CH3:39])[S:37][CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([CH3:39])[S:37][CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3csc(C)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3csc(C)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(2-methyl-thiazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>CCOCC>[C:4]1([C:1]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH2:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: C1CCNC1
Solvent: CCOCC
Product: C=C(c1ccccc1)N1CCCC1
Temperature: 500 °C

Procedure:
100 g of molecular sieve are heated at 500° C. for 8 hours and then added to a mixture of 20 mmol of acetophenone and 22 mmol of pyrrolidine in 200 ml of anhydrous ether. The reaction mixture is stirred at ambient temperature until, in the infra-red, no more free ketone (C═O 1689 cm−1) is detected in the supernatant and the absorption for the enamine (C═C—N 1600 cm−1) is at a maximum. The mixture is then filtered and the molecular sieve is washed with ether. The solvent is evaporated off under reduced pressure and the crude residue is purified by distillation under reduced pressure.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C.Cl>[C:1]1([S:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:20][CH:21]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(OCCCS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=S(=O)(CCCOc1ccc(CO)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
1.8 g of 4-(3-benzenesulfonylpropyloxy)benzaldehyde were dissolved in 30 ml of ethanol, and the resultant solution was further added with 0.11 g of sodium borohydride and then stirred for 1 hour at room temperature. After completed the reaction, the solvent used was removed by distillation under reduced pressure, and the residue obtained was dissolved in a mixture of ethyl acetate and dilute hydrochloric acid. The ethyl acetate layer resulted was then washed with dilute hydrochloric acid, aqueous solution of sodium hydroxide and water in series. The organic layer resulted was then dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure, thereby affording 1.5 g of 4-(3-benzenesulfonylpropyloxy)benzyl alcohol.