Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=O)[O:9][C:8]([CH3:12])=[N:7][C:6]=2[CH:13]=1.[OH-].[NH4+:15]>>[Br:1][C:2]1[CH:13]=[C:6]2[C:5]([C:10](=[O:9])[NH:15][C:8]([CH3:12])=[N:7]2)=[CH:4][CH:3]=1
Reactant: Cc1nc2cc(Br)ccc2c(=O)o1
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1nc2cc(Br)ccc2c(=O)[nH]1
Temperature: 80 °C
Yield: 56.4 %

Procedure:
7-bromo-2-methyl-4H-benzo[d][1,3]oxazin-4-one 7.25 (400 mg, 1.58 mmol) was taken up in 26% aqueous ammonium hydroxide (5 mL, 33.38 mmol) and heated in a sealed tube at 80° C. for 4 hours. Mixture was cooled to room temperature and solid was filtered, washing with water. Solid was dried in-vacuo to yield 7-bromo-2-methylquinazolin-4(3H)-one 7.26 (213 mg), which was used in the next step without further purification.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.CCOC(C)=O>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:2]2[C:7]([CH:8]3[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:26][CH:25]=1
Reactant: OC1CCC(c2cccnc2F)C1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: OC1CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)C1
Temperature: 130 °C
Reaction time: 9 h

Procedure:
A suspension of 3-(2-fluoropyridin-3-yl)cyclopentanol (869 mg, 4.80 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (2324 mg, 9.59 mmol) and cesium carbonate (3281 mg, 10.07 mmol) in N-methyl-2-pyrrolidinone (8 mL) was heated to 130° C. under nitrogen. After 9 h, the reaction was cooled to 23° C., diluted with EtOAc (500 mL) and washed with 1N NaOH solution (6×150 mL) and brine (150 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 1-4% methanol/dichloromethane), affording the product as a tan solid. MS (ESI, pos. ion) m/z: 404.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:22])[C:20]=1[OH:21])[C:16]#[N:17].Cl[C:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)=O>O1CCOCC1>[C:16]([C:15]1[CH:18]=[C:19]([CH3:22])[C:20]2[O:21][C:24]([C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=3)=[N:12][C:13]=2[CH:14]=1)#[N:17]
Reactant: Cc1cc(C#N)cc(N)c1O
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc3cc(C#N)cc(C)c3o2)cc1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a solution of 117 mg of toluenesulfonic acid in 40 ml of dioxane was added 3-amino-4-hydroxy-5-methylbenzonitrile (101 mg) and methyl 4-(chlorocarbonyl)benzoate (149 mg) The mixture was heated to reflux under N2 for 15 h. The mixture was then cooled to room temperature and the dioxane was removed in vacuo. To the residue was added 80 ml of toluene and the solution was heated to reflux overnight (15 h). Purification by flash chromatography (Rf in 2/1 hexanes/ethyl acetate=0.58) on a Biotage Horizon, 65i column, eluting with 1 column volume of 30% ethyl acetate in hexanes, followed by a linear gradient of ethyl acetate in hexanes from 30 to 100% over 10 column volumes provided 134 mg (67%) of the title compound. Mass spectrum (ESI) 293.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.35 (d, J=8.2 Hz, 2H), 8.22 (d, J=8.4 Hz, 2H), 7.95 (s, 1H), 7.49 (s, 1H), 3.98 (s, 3H), 2.65 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13][C:6]2([NH:10]C(=O)N[C:7]2=[O:12])[CH2:5][CH2:4]1.Cl.[OH-:20].[Na+]>>[NH2:10][C:6]1([C:7]([OH:12])=[O:20])[CH2:5][CH2:4][C:3]([O:2][CH3:1])([C:15]([F:18])([F:17])[F:16])[CH2:14][CH2:13]1
Reactant: [OH-]
Reactant: COC1(C(F)(F)F)CCC2(CC1)NC(=O)NC2=O
Agent: Cl
Agent: [Na+]
Product: COC1(C(F)(F)F)CCC(N)(C(=O)O)CC1
Reaction time: 72 h

Procedure:
10.00 g (37.56 mmol) of 8-methoxy-8-(trifluoromethyl)-1,3-diazaspiro[4.5]decane-2,4-dione (Example 14A) were suspended in 125 ml of 3-molar aqueous sodium hydroxide solution and stirred under reflux conditions for 3 days. Subsequently, the pH was adjusted to 6 using concentrated aqueous hydrochloric acid, and the precipitated product was filtered off, washed with water and dried under reduced pressure. This gave 12.20 g (135% of theory; the product contains inorganic salts) of the title compound as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13]>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(F)cc1
Product: N#Cc1ccc(C=CC(=O)c2ccc(F)cc2)cc1

Procedure:
3-(4cyanophenyl)-1-(4-fluorophenyl)prop-2-en-1-one is prepared according to the procedure described in Example 4a using 4-cyanobenzaldehyde and 4-fluoroacetophenone as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH:8]=1)[NH2:7].[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([NH:7][S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[CH:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc(Br)ccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cc(Br)ccc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 5-Bromo-2-chloroaniline (100 mg, 0.48 mmol) in DCM (5 ml) is added benzenesulfonyl chloride (280 mg, 202 ul, 1.58 mmol) and pyridine (195 ul, 2.42 mmol). The reaction mixture is stirred at room temperature for 18 hours. EtOAc (20 ml) is added and the reaction mixture is washed with 0.1 m HCl (20 ml), the phases are separated and the organic portion is washed with water (3×), dried over MgSO4, concentrated in vacuo and dried in a vacuum oven to afford the title compound.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[O:5][C:4]([CH3:15])([CH3:14])[CH:3]1[OH:16].[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](OC)=[N:22][C:21]2=[O:30]>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([NH:1][CH:2]1[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=3)[O:5][C:4]([CH3:14])([CH3:15])[CH:3]1[OH:16])=[N:22][C:21]2=[O:30]
Reactant: COc1nc(=O)c2cc(Cl)ccc2[nH]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C(N)C1O
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc(C#N)cc2C(Nc2nc(=O)c3cc(Cl)ccc3[nH]2)C1O

Procedure:
4-Amino-3-hydroxy-2,2-dimethyl-chroman-6-carbonitrile (5 mmoL) and 6-chloro-2-methoxy-1H-quinazolin-4-one (5 mmoL) in toluene (15 mL) in a sealed tube were heated at 150° C. for 4 hrs. The solvent was removed and the residue was purified by silica gel chromatography with hexanes and ethyl acetate to yield the title compound as white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1.[H-].[Na+].[CH:23]1([CH2:26]Br)[CH2:25][CH2:24]1.[NH4+].[Cl-]>CN(C=O)C>[CH:23]1([CH2:26][CH:15]([C:8]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH:7]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:25][CH2:24]1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(OCC2CC2)c1
Reactant: BrCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC1CC1)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Ethyl 2-(3-(cyclopropylmethoxy)-4-nitrophenyl)acetate (5 g, 17.9 mmol) was dissolved in 50 mL anhydrous DMF, NaH (60% wt. in oil, 0.475 g, 19.7 mmol) was added at 0° C. The reaction mixture was stirred for 0.5 h at 25° C. and cyclopropylmethyl bromide (2.67 g, 19.7 mmol) was added drop wise at 0° C. The reaction mixture was stirred at 0° C. for 1 h and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give ethyl 3-cyclopropyl-2-(3(cyclopropylmethoxy)-4-nitrophenyl)propanoate (4 g) as a colorless oil.
Reaction SMILES: ONC(=N)C1C2C(C=CC=1)=NN(CCC(OCC)=O)C=2.[OH:21][NH:22][C:23](=[NH:40])[C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][N:28]2[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][C:50]=1[O:51][CH:52]([CH3:54])[CH3:53])[C:45](O)=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[Cl:41][C:42]1[CH:43]=[C:44]([C:45]2[O:21][N:22]=[C:23]([C:24]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:25]=3[CH:26]=[N:27][N:28]4[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:40]=2)[CH:48]=[CH:49][C:50]=1[O:51][CH:52]([CH3:53])[CH3:54]
Reactant: CCOC(=O)CCn1ncc2c(C(=N)NO)cccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: CCOC(=O)CCn1cc2c(C(=N)NO)cccc2n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)CCn1ncc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc21
Temperature: 120 °C
Yield: 65.8 %

Procedure:
A mixture of ethyl 3-{4-[(hydroxyamino)(imino)methyl]-2H-indazol-2-yl}propanoate & ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}propanoate (D55) (700 mg, 1.27 mmol) (a 3:1 mix of 1 and 2-isomers), 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3) (0.544 g, 2.53 mmol), EDC (0.534 g, 2.79 mmol) and HOBT (0.427 g, 2.79 mmol) in N,N-dimethylformamide (10 ml) was heated at 120° C. for 2 hrs, cooled, diluted with ethyl acetate (60 ml) and washed with water (3×20 ml). The organic layer was dried (MgSO4), evaporated and purified by flash chromatography eluting with EtOAc/hexane 1:4 to give the title compound (380 mg) as a white solid. δH (CDCl3, 400 MHz): 1.17 (3H, t), 1.46 (6H, d), 3.02 (2H, t), 4.10 (2H, q), 4.70-4.77 (3H, m), 7.08 (1H, d), 7.53 (1H, dd), 7.69 (1H, d), 8.05-8.12 (2H, m), 8.29 (1H, d), 8.71 (1H, d). MS (ES): C23H2335ClN4O4 requires 454; found (MH+) 455.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=2)[C:26]([OH:28])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38](I)C>>[C:1]([O:5][C:6]([NH:8][C@:9]([C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([N:32]([CH2:37][CH3:38])[S:33]([CH3:36])(=[O:34])=[O:35])[CH:31]=2)[C:26]([OH:28])=[O:27])=[N:20][N:19]=1)([CH3:17])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(c1cc(C(=O)O)cc(-c2nnc(C(C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Reactant: CCI
Product: CCN(c1cc(C(=O)O)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O

Procedure:
Prepared using a procedure similar to that employed for the synthesis of Intermediate VI, substituting ethyl iodide in the place of methyl iodide in Step B of the Intermediate III synthesis.
Reaction SMILES: C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C.Cl.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[CH:29]=1.[F:30][C:31]([F:51])([F:50])[C:32]1[CH:33]=[C:34]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[C:39]2[C:47](O)=[O:48])[CH:35]=[CH:36][CH:37]=1>CN(C)C=O>[CH3:28][C:26]1[O:27][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:47]([C:39]3[N:38]([C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:51])([F:30])[F:50])[CH:33]=4)[C:46]4[C:41]([CH:40]=3)=[CH:42][CH:43]=[CH:44][CH:45]=4)=[O:48])=[CH:29][C:24]=2[N:25]=1
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: O=C(O)c1cc2ccccc2n1-c1cccc(C(F)(F)F)c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2cc(NC(=O)c3cc4ccccc4n3-c3cccc(C(F)(F)F)c3)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
0.091 ml (0.6 mmol) of diethylcyanophosphonate, 0.168 ml (0.6 mmol) of triethylamine and 0.111 g (0.6 mmol) of 5-amino-2-methylbenzoxazole hydrochloride are added to a solution of 0.152 g (0.5 mmol) of 1-[3-(trifluoromethyl)phenyl]-1H-indole-2-carboxylic acid (JP2001151771A2) in 3 ml of dimethylformamide. The mixture is stirred overnight at room temperature and concentrated under reduced pressure, and the residue is taken up in water and dichloromethane. After separation of the phases by settling, the organic phase is dried and evaporated under reduced pressure. The residue is purified by preparative chromatography. 0.102 g of solid is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:33][CH3:34]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([CH2:33][CH3:34])[C:19]([O:21][CH3:22])=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 2b (10.0 g, 24.1 mmol) in DMF (20 mL) was added via syringe pump (1.6 mL/min) to a stirred suspension of sodium hydride (964 mg of a 60% wt/wt dispersion in mineral oil, 24.1 mmol) in DMF (60 mL) at 0° C. After 15 min, iodoethane (2.34 mL, 28.9 mmol) was added rapidly dropwise, and the resulting mixture was stirred at 0° C. for 2 h. The reaction was quenched by addition of saturated aqueous ammonium chloride and extracted with ether. The combined organics were washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting crude oil was purified by flash chromatography on silica gel (gradient elution; 0%-20% EtOAc/hexanes as eluent) to afford the title compound 3a. m/z (ES) 465 (MNa)+.
Reaction SMILES: C(OC(C1CCCCC1=O)=O)C.[H-].[Na+].C(Br)CCCCCCC.C([O:26][C:27]([C:29]1([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:34][CH2:33][CH2:32][CH2:31][C:30]1=[O:35])=O)C.[BH4-].[Li+].OCC1(CCCCCCCC)CCCCC1=O>CN(C)C=O.O1CCCC1.C(OC(=O)C)C.C(OCC)C.O>[OH:26][CH2:27][C:29]1([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[OH:35]
Reactant: CCCCCCCCC1(C(=O)OCC)CCCCC1=O
Agent: CCCCCCCCC1(CO)CCCCC1=O
Agent: CCOC(=O)C1CCCCC1=O
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCC1(CO)CCCCC1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
20 g of 2-ethoxycarbonyl-cyclohexanone was dissolved in 15 ml dimethylformamide and stirred. Then, a solution comprising 200 ml dimethylformamide with 6 g sodium hydride dispersed therein was gradually added dropwise to the above 2-ethoxycarbonyl-cyclohexanone solution. After the addition of the sodium hydride solution had been completed, the reaction solution was stirred for 2 hours at room temperature under a nitrogen gas stream. A solution comprising 15 ml dimethylformamide with 25 g octyl bromide dissolved therein was further added dropwise to the reaction solution. After the addition had been completed, the temperature was raised to 100° C. and agitation was conducted for 2 hours. The reaction solution was cooled down, then poured into iced water and extraction with 100 ml diethylether was conducted twice. The diethylether layer was dried with anhydrous sodium sulfate, and then the diethylether was removed to provide a crude reaction product of 2-ethoxycarbonyl-2-octyl-cyclohexanone. This crude reaction product was dissolved in 20 ml of tetrahydrofuran. A solution comprising 80 ml tetrahydrofuran with 2 g lithium borohydride dispersed therein was added dropwise to the above 2-ethoxycarbonyl-2-octyl-cyclohexanone solution under an iced condition while stirring and the stirring was continued for 4 hours. After adding 50 ml ethylacetate and 100 ml distilled water, the solution was acidified by the addition of a 10% sulfuric acid aqueous solution to give a pH of 2. The reaction solution was extracted twice with 50 ml of diethylether. The diethylether layer was dried with anhydrous sodium sulfate, and then the diethylether was removed to provide a crude reaction product of 2-hydroxymethyl-2-octyl-cyclohexanone. This crude reaction product was purified by means of silica gel column chromatography (eluent: chloroform/methanol=97/3) and 18.3 g of 2-hydroxymethyl-2-octyl-cyclohexanol was obtained as a pale yellow, oily substance (yield: 64.3%). In the measurement of the infrared absorption spectrum, a strong absorption by a hydroxyl group at 3,370 cm−1 and, in the mass spectrometric measurement, a peak corresponding to the loss of water from the parent ion peak, were observed. Besides, in the elemental analysis, measured values of C=74.27% and H=12.53% were found (theoretical values of C and H: C=74.33% and H=12.74%). Thus, the production of 2-hydroxymethyl-2-octyl-cyclohexanol was ascertained.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C:6](=[O:22])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[OH:21])[CH2:3]1.C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C(=O)CC5[C@]4(C)CCCC5)[C@@H]2C3)C)O1>>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([CH2:5][C:6](=[O:22])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[OH:21])[CH2:3]1
Reactant: C[C@]12CC[C@H]3[C@@H](C(=O)C=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: C[C@]12CCCCC1CC(=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CC[C@H]3[C@@H](C(=O)CC4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Yield: 95.1 %

Procedure:
3β,17β-Dihydroxyandrostan-7-one was prepared in 96% yield from 3β,17β-dihydroxyandrost-5-en-7-one (700 mg) by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)androstane-7-one (Prepn. 9). The crude product was purified by flash chromatography (SiO2, hexane/acetone/CH2Cl2 10/10/10) to give 3β,17β-dihydroxyandrostane-7-one (670 mg). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.53 (bb, 1H), 4.44 (bb, 1H), 3.47-3.27 (m, 2H), 2.45-2.31 (m, 2H), 2.05-1.91 (m, 1H), 1.89-0.78 (m, 17H), 0.99 (s, 3H), 0.59 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1F)[OH:5].[CH3:13][OH:14]>>[NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:13])[OH:5]
Reactant: NCCC(O)c1ccccc1F
Reactant: CO
Product: COc1ccccc1C(O)CCN

Procedure:
3-Amino-1-(2-methoxy-phenyl)-propan-1-ol was prepared by the same procedure as 3-amino-1-(2-fluoro-phenyl)-propan-1-ol without adding methanol in the acidification step in example 6. 1H NMR (DMSO-d6) δ 7.45-7.19 (m, 1H), 7.11-7.08 (m, 3H), 6.48 (s, 2H), 6.40 (t, J=7.1 Hz, 1H), 5.10 (d, J=4.7 Hz, 1H), 4.83-4.75 (m, 1H), 3.05-2.95 (m, 2H), 2.25 (s, 3H), 1.81-1.62 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].C[O:21][C:22]([CH:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23].[OH-].[K+]>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[C:19]([C:27]3[CH2:28][CH2:29][CH:24]([C:22]([OH:23])=[O:21])[CH2:25][CH:26]=3)=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: COC(=O)C1CCC(=O)CC1
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCc1cccc(CC)c1-c1cc2c(C3=CCC(C(=O)O)CC3)c[nH]c2cn1
Yield: 40.1 %

Procedure:
A solution of 5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.8 mmol) in MeOH (5 mL) is added to a stirring solution of 4-oxo-cyclohexanecarboxylic acid methyl ester (204 mg, 1.2 mmol) and KOH (163 mg, 2.9 mmol) in MeOH (10 mL) at room temperature. The mixture is heated at reflux for 24 hours. The solvent is removed to dryness in vacuo. The residue is mixed with water and adjusted pH to 7. The mixture is extracted with CH2Cl2 (2×10 mL). The organic layer is washed with brine, dried, and evaporated under reduce pressure to give 120 mg of crude product. The crude product is used for next step without further purification.
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([Cl:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]>C(COC)OC.O>[CH3:1][S:2][C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([Cl:12])=[CH:7][C:6]=1[N+:13]([O-:15])=[O:14]
Reactant: C[S-]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CSc1cc(N)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a suspension of 18.9 g (0.27 mol) of sodium thiomethoxide in 200 ml of dimethoxyethane, with stirring at room temperature, are added portionwise 41.4 g (0.2 mol) of 2,5-dichloro-4-aminonitrobenzene, allowing the temperature to rise to 50°-55° C. and maintaining this temperature for 1/2 hour after the addition is complete. The reaction medium is poured onto 2 liters of ice-water. The crystallized precipitate is drained, re-slurried in water and vacuum-dried at 40° C. over phosphorus pentoxide.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[CH:8][C:9]=2[CH2:11][N:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][CH2:14][C:13]2([CH3:21])[CH3:20])[N:4](C2CCCCO2)[N:3]=1.Cl>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)=[CH:8][C:9]=2[CH2:11][N:12]2[CH2:17][C:16]([CH3:18])([CH3:19])[NH:15][CH2:14][C:13]2([CH3:21])[CH3:20])[NH:4][N:3]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(CN3CC(C)(C)NCC3(C)C)c12
Agent: Cl
Solvent: C1CCOC1
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3CC(C)(C)NCC3(C)C)c12

Procedure:
150 mg 4-[3-methyl-1-(tetrahydro-pyran-2-yl)-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol were dissolved in 10 ml of tetrahydrofurane and 0.65 ml HCl (4N in 1,4-dioxane) were added. After stirring the reaction at r.t. for 30 min the precipitated residue was isolated by filtration and washed with THF.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10]2[C:4]([C:5]3[S:23][CH:22]=[CH:21][C:6]=3[N:7]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH2:8][CH2:9]2)=[N:3]1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[CH:11]=[C:10]2[C:4]([C:5]3[S:23][CH:22]=[CH:21][C:6]=3[N:7]([C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:34](=[O:35])[C:33]4[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:32]=4[Cl:31])=[CH:17][CH:18]=3)=[O:20])[CH2:8][CH2:9]2)=[N:3]1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cn1cc2c(n1)-c1sccc1N(C(=O)c1ccc(N)cc1)CC2
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc2c(n1)-c1sccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice bath cooled mixture of 290 mg of 2,4,5,6-tetrahydro-2-methyl-6-(4-aminobenzoyl)pyrazolo[3,4-d]thieno[3,2-b]azepine in 4.0 ml of methylene chloride and 2.0 ml of dioxane under argon is added 186 μl of triethylamine followed by 156 μl of 2,4-dichlorobenzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours under argon. The reaction mixture is evaporated in vacuo to a residue which is dissolved in 50 ml of methylene chloride and washed with 20 ml each of water, 1N NaHCO3, 2N citric acid and brine. The organic layer is dried (Na2SO4) and filtered. The filtrate is concentrated in vacuo to give a foam residue which is crystallized from ethyl acetate to give 330 mg of the desired product as a white crystalline solid, m.p. 265°-267° C.