Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: Oc1cccc(F)c1
Product: Fc1cccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-fluoro-phenol to give [1-(3-fluoro-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 321 (MH+).
Reaction SMILES: CI.Cl[CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8].[CH3:10][C:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[O:26])[C:15]=2[CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>CCOCC>[CH3:10][C:11]1[C:21]2[CH:20]=[CH:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16]([CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])([OH:26])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CCCCl
Reactant: Cc1cccc2c(=O)c3ccccc3ccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: Cc1cccc2c1C=Cc1ccccc1C2(O)CCCN(C)C
Temperature: 45 °C
Reaction time: 5 h

Procedure:
20 g. of Gilman alloy are covered with 40 ml. of dry ether and treated with 0.5 ml. of methyl iodide. After the vigorous reaction has subsided somewhat, a solution containing 80 ml. of 1-chloro-3-dimethylaminopropane in 360 ml. of dry ether is added dropwise in such a way that the reaction mixture is maintained at boiling. The mixture is stirred at 45° C. under reflux conditions for an additional 5 hours. The reaction mixture is then cooled with ice-water and a solution containing 43.6 g. of 1-methyl-5H-dibenzo[a,d]cyclohepten-5-one in 820 ml. of dry ether is added over a one-hour period. Subsequently, the mixture is boiled and stirred at reflux for another 17 hours. After about 12 hours, it is once more cooled with ice water and decomposed with a cold saturated ammonium chloride solution. The organic layer is separated, washed with water, dried over sodium sulfate and evaporated. The 1-methyl-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene obtained is recrystallized from high-boiling petroleum ether and has a melting point of 141°-143° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([CH:17]=O)[CH2:13][CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[F:19][CH:20]([F:23])[CH2:21][NH2:22].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][NH:22][CH2:21][CH:20]([F:23])[F:19])[CH2:13][CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: NCC(F)F
Reactant: O=CC1CCN(c2nc(Cl)nc3ccoc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: FC(F)CNCC1CCN(c2nc(Cl)nc3ccoc23)CC1
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
1-(2-Chlorofuro[3,2-d]pyrimidin-4-yl)piperidine-4-carbaldehyde (0.672 g, 2.53 mmol; Preparation #P.1), 2,2-difluoroethanamine (0.226 g, 2.78 mmol, Matrix), and AcOH (0.217 mL, 3.79 mmol) were combined in DCE (25.3 mL) at rt. After about 10 min of stirring, NaBH(OAc)3 (0.804 g, 3.79 mmol) was added in one portion and the mixture was stirred for about 24 h. The mixture was diluted with DCM (50 mL) and saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer extracted with DCM (3×15 mL). The combined organics were then washed with saturated aqueous NaHCO3 (25 mL), brine (25 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (80 g silica gel, 50-100% EtOAc/heptane) to provide N-((1-(2-chlorofuro[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-2,2-difluoroethanamine (0.748 g, 89%): LC/MS (Table 2, Method c) Rt=1.52 min.; MS m/z: 331, 333 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([CH3:29])[C:14]=1[CH2:15]C(Br)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)C.O>[CH3:12][C:13]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([CH3:29])[C:14]=1[CH2:15][NH:1][C:2]1[C:10]2[NH:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc2cccc(N)c2[nH]1
Reactant: Cc1cc(F)cc(C)c1CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: Cc1nc2cccc(NCc3c(C)cc(F)cc3C)c2[nH]1
Temperature: 75 °C
Yield: 22.4 %

Procedure:
4-amino-2-methylbenzimidazole (0.6 g, 4,1 mmol) was dissolved in acetonitrile (10 ml). To the solution were added 2,6-dimethyl-4-fluoro-benzylbenzylbromide (0.89 g, 4,1 mol) and potassium carbonate (0.68 g, 4.9 mmol) and the mixture was warmed at 70-80° C. for 3 h. The reaction mixture was cooled to room temperature and methylene chloride (25 ml) and water (25 ml) was added. The organic layer was separated, dried over sodium sulfate and was evaporated under reduced pressure. The residue was crystallized twice from ethyl acetate and was purified by column chromatography on silica gel, using methylene chloride containing 10% methanol as eluent. There was obtained 0.26 g (22%) of the title compound.
Reaction SMILES: [C:1](=[O:34])(OC1C=CC=CC=1)[O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:24])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:14]=3[N:13]=[C:12]2[CH2:25][CH3:26])=[CH:7][CH:6]=1.[CH3:35][N:36]1[CH:40]=[C:39]([S:41]([NH2:44])(=[O:43])=[O:42])[N:38]=[C:37]1[CH3:45]>>[Cl:24][C:17]1[C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]2[N:13]=[C:12]([CH2:25][CH3:26])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][O:2][C:1](=[O:34])[NH:44][S:41]([C:39]4[N:38]=[C:37]([CH3:45])[N:36]([CH3:35])[CH:40]=4)(=[O:42])=[O:43])=[CH:6][CH:7]=3)[C:15]=2[CH:16]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Reactant: Cc1nc(S(N)(=O)=O)cn1C
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cn(C)c(C)n2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 243 from 2-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}ethyl phenyl carbonate and 1,2-dimethyl-1H-imidazol-4-ylsulfonamide.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH:32]2[CH2:34][CH2:33]2)=[CH:26][CH:25]=1>>[CH:32]1([N:31]([CH2:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)[CH2:34][CH2:33]1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: Fc1ccc(CNC2CC2)cc1
Product: O=C(O)c1ccnc(-c2cn(CCN(Cc3ccc(F)cc3)C3CC3)cn2)c1
Yield: 9 %

Procedure:
The title compound was prepared in 9% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and N-[(4-fluorophenyl)methyl]cyclopropylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 0.16 (2H, m), 0.39 (2H, m), 1.82 (1H, m), 2.87 (2H, t, J=6.4 Hz), 3.74 (2H, s), 4.10 (2H, t, J=6.2 Hz), 7.09 (2H, t, J=8.9 Hz), 7.28 (2H, dd, J=7.1 Hz and 2.7 Hz), 7.51 (1H, d, J=4.5 Hz), 7.67 (2H, d, J=1.6 Hz), 8.25 (1H, s), 8.47 (1H, d, J=4.8 Hz). [M+H] Calc'd for C21H21FN4O2, 381. Found, 381.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[CH3:7][C:8](=[CH2:10])[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-]>O>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([OH:1])[CH2:9][C:8]([CH3:10])=[CH2:7]
Reactant: C=C(C)C
Reactant: O=CC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: C=C(C)CC(O)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of anhydrous chloral (738 g), isobutylene (309 g), and petroleum ether (boiling range 40° to 60° C, 800 ml) was stirred at a temperature in the range -5° to -8° C whilst aluminium chloride (54.5 g) was added in small portions over a period of 2 hours. The mixture was stirred for a further period of one hour at 0° C. Water (450 ml) was then added over 15 minutes, the temperature being maintained at 0° C, after which the mixture was allowed to attain to the ambient temperature. The organic phase was separated, washed with brine (3 × 250 ml) and dried over anhydrous magnesium sulphate. After removal of the solvent by evaporation under reduced pressure the residual oil was distilled under reduced pressure and the fraction boiling range 101° to 111° C at 16 to 18 mm Hg pressure collected. This was shown by gas liquid chromatographic examination to consist of approximately 90%, 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene and approximately 10% 1,1,1-trichloro-2-hydroxy-4-methyl-3-pentene. Careful distillation afforded almost pure (by g.l.c.) 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene as a colourless oil (boiling point 99° -100° C/16 mm Hg).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2].[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:28]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:29])[CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(NC(=O)C3CCCCC3)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of 4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridylamine (0.80 g, 2.7 mmol) in tetrahydrofuran (10 mL) were added cyclohexanecarbonyl chloride (0.40 mL, 3.0 mmol) and triethylamine (0.39 mL, 2.8 mmol) sequentially, and the mixture was stirred for 1 hour at room temperature. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with an aqueous sodium hydrogen carbonate solution, then, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=20:1 to 4:1) to obtain a crystal. This crystal was washed with hexane to obtain a title compound (0.83 g, yield 75%).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:21][F:22])([CH3:20])[C:4](=[O:19])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO>[F:1][CH2:2][C:3]([CH2:21][F:22])([CH3:20])[CH:4]([OH:19])[CH:5]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1
Reactant: CC(CF)(CF)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CC(CF)(CF)C(O)C(Oc1ccc(Cl)cc1)n1ccnc1
Reaction time: 15 h
Yield: 69.2 %

Procedure:
31.9 g (0.097 mol) of 3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(imidazol-1-yl)-butan-2-one were dissolved in 600 ml of methanol, and 5.45 g (0.14 mol) of sodium borohydride were added in portions at 0° to 5° C. The mixture was subsequently stirred for 15 hours, 15 ml of concentrated hydrochloric acid were added and the mixture was stirred at room temperature for 2 hours. Thereafter, the reaction mixture was stirred into 800 ml of aqueous, saturated sodium bicarbonate solution. It was extracted with 1,000 ml of methylene chloride and the organic phase was washed twice with 1,000 ml of water each time, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. The oil which remained was stirred with isopropyl ether. 22.2 g (67.5% of theory) of 3,3-bisfluoromethyl-1-(4-chlorophenoxy)-1-(imidazol-1-yl)-butan-2-ol of melting point 137° C. were obtained. ##STR77##
Reaction SMILES: [CH3:1]N(C)CCNC.[Li]CCCC.[O:13]1[C:18]2[CH:19]=[CH:20][C:21]([CH:23]=[O:24])=[CH:22][C:17]=2[O:16][CH2:15][CH2:14]1.CI>C1COCC1.Cl>[CH3:1][C:22]1[C:17]2[O:16][CH2:15][CH2:14][O:13][C:18]=2[CH:19]=[CH:20][C:21]=1[CH:23]=[O:24]
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CNCCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(C=O)ccc2c1OCCO2
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To a solution of N,N,N′-trimethylethylenediamine (3.3 g, 32.3 mmol) in THF (100 mL) at −15° C. was dropwise added n-BuLi (19.2 mL, 30.5 mmol, 1.6 M in THF). After stirring at −15° C. for 15 minutes, a solution of solution of 1,4-benzodioxane-6-aldehyde (5.0 g, 30.5 mmol) in THF (10 mL). After 20 minutes, another batch of n-BuLi (5 mL, 3.1 mmol, 1.6 M in THF) was added and stirred for 3 h. The resulting solution was cooled down to −72° C. and the mixture was treated with MeI (25.9 g, 182.5 mmol) slowly. After stirring at −72° C. for 3 h, the mixture was diluted with HCl solution (1M in water). The aqueous layer was extracted several times with diethyl ether. The organic fractions were combined, concentrated and purified with column chromatography (silica, 5-40% ethyl acetate in hexane) to provide the title compound as an off-white compound (1.0 g, 18%): %): MS (ES) m/z 179 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][OH:5].[NH2:9][C:10]1[N:15]=[C:14](Cl)[C:13]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:25][C:26]#[N:27])[CH:21]=[CH:22][C:23]=2[F:24])=[C:12]([CH3:28])[N:11]=1>C(O)CCC>[NH2:9][C:10]1[N:15]=[C:14]([NH:1][C@@H:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][OH:5])[C:13]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:25][C:26]#[N:27])[CH:21]=[CH:22][C:23]=2[F:24])=[C:12]([CH3:28])[N:11]=1
Reactant: Cc1nc(N)nc(Cl)c1Cc1cc(CC#N)ccc1F
Reactant: CCC[C@H](N)CCO
Solvent: CCCCO
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1cc(CC#N)ccc1F
Reaction time: 2 h

Procedure:
(S)-3-Aminohexan-1-ol (101 mg) was added to a stirred solution of the product from step (iv) (100 mg) in butan-1-ol (2 mL). The reaction was performed in a microwave, at 180° C. for 2 h. The solvent was removed and the crude product was purified using chromatography, to give the subtitle compound, 70 mg.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([S:34]([N:37]2[CH2:42][CH2:41][N:40](C(OC(C)(C)C)=O)[CH2:39][CH2:38]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[CH:29]=[CH:30][C:31]([S:34]([N:37]5[CH2:38][CH2:39][NH:40][CH2:41][CH2:42]5)(=[O:36])=[O:35])=[CH:32][N:33]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nc1)N1CCNCC1

Procedure:
Compound 359 was prepared as a white solid (TFA salt) from compound 4 and compound 360 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.59 (1 H, s), 9.29 (1 H, s), 8.72-8.78 (2 H, m), 8.63-8.66 (1 H, m), 8.61 (1 H, d), 8.22 (1 H, dd, J=8.8, 2.4 Hz), 5.51 (1 H, quin, J=8.9 Hz), 3.37 (8 H, s), 2.46-2.60 (2 H, m), 2.13-2.34 (4 H, m), 1.87-2.01 (2 H, m). LCMS-ESI (POS), M/Z, M+1. Found 478.9.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:22]=[CH:21][C:12]([CH:13](O)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:22]=[CH:21][C:12]([CH:13]([C:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:23][C:24]=3[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC(c1ccccc1)c1ccc(OCCN2CCCC2)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1[nH]c2ccccc2c1C(c1ccccc1)c1ccc(OCCN2CCCC2)cc1

Procedure:
Substantially the same procedure as in Reference Example 5 was repeated using 4-(2-pyrrolidinylethoxy)benzhydrol (19.4 g, 65.1 mmol) and ethyl indole-2-carboxylate (13.55 g, 71.6 mmol) to give 31.2 g (quantitative) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][OH:8].C(O[CH:17](OCC)[CH2:18][NH2:19])C.Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:17]([CH2:18][NH2:19])[O:8][CH2:7][CH2:6]2
Reactant: CCOC(CN)OCC
Reactant: COc1ccc(CCO)cc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)C(CN)OCC2
Reaction time: 48 h

Procedure:
A solution of the starting material of formula II, 3,4-dimethoxyphenethyl alcohol (108 g), described by E. Z. Khafagy and J. P. Lambooy, J. Med. Chem., 9, 936 (1966), and the starting material of formula III, aminoacetaldehyde diethyl acetal (78 g), in dry dioxane (250 ml) is stirred and cooled (ice bath) while being saturated with hydrogen chloride over a period of one hour. The mixture is kept at room temperature for two days. The crystalline precipitate is collected, washed with dry dioxane and then ether to yield the hydrochloric acid addition salt (hydrochloride) of the title compound, m.p. 250°-255° C. (dec.), after recrystallization from methanol.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([NH:15][C:16]([C@:18]23[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:19]2[C@@H:20]2[C@@:33]([CH3:36])([CH2:34][CH2:35]3)[C@@:32]3([CH3:37])[C@@H:23]([C@:24]4([CH3:50])[C@@H:29]([CH2:30][CH2:31]3)[C:28]([CH3:39])([CH3:38])[C@@H:27]([O:40][C:41](=[O:49])[CH2:42][C:43]([CH3:48])([CH3:47])[C:44]([OH:46])=[O:45])[CH2:26][CH2:25]4)[CH2:22][CH2:21]2)=[O:17])[C:12]1([CH3:58])[CH3:57])=[O:10])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:44]([C:43]([CH3:48])([CH3:47])[CH2:42][C:41]([O:40][C@H:27]1[CH2:26][CH2:25][C@@:24]2([CH3:50])[C@@H:29]([CH2:30][CH2:31][C@:32]3([CH3:37])[C@@H:23]2[CH2:22][CH2:21][C@H:20]2[C@@:33]3([CH3:36])[CH2:34][CH2:35][C@@:18]3([C:16]([NH:15][C@@H:13]4[CH2:14][C@H:11]([C:9]([OH:10])=[O:8])[C:12]4([CH3:58])[CH3:57])=[O:17])[CH2:53][CH2:52][C@@H:51]([CH:54]([CH3:56])[CH3:55])[C@@H:19]32)[C:28]1([CH3:39])[CH3:38])=[O:49])([OH:46])=[O:45]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)OCc4ccccc4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3C[C@H](C(=O)O)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
To a stirred solution of 4-((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-((1R,3S)-3-(benzyloxycarbonyl)-2,2-dimethylcyclobutylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yloxy)-2,2-dimethyl-4-oxobutanoic acid (Example 87, 200 mg) in EtOAc (20 ml) at room temperature 10% Pd/C (catalytic amount) were added and the reaction mixture was stirred under H2 gas atmosphere at room temperature for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite bed and the obtained filtrate was concentrated under reduced pressure to afford the debenzylated title compound as a white solid. Wt: 0.100 g: Yield: 56.2%. 1H NMR (300 MHz, CDCl3): δ 5.77 (d, J=7.8 Hz, 1H), 4.54-4.507 (m, 1H), 4.157-4.13 (m, 1H), 2.9-2.80 (m, 1H), 2.7-2.61 (m, 3H), 2.60-2.20 (m, 5H), 2.00-1.93 (m, 1H), 1.80-1.10 (m, 30H), 0.95 (s, 6H), 0.941 (s, 3H), 0.88 (s, 6H), 0.84 (d, J=7.6 Hz, 6H), 0.832 (s, 3H), 0.823 (s, 3H); IR (KBr, cm−1): 3403, 2956, 2620, 1710, 1652, 1648, 1509, 1474, 1367, 1245, 1194, 1148, 1000, 978, 877, 620, 509; M.R: 150.1° C.-282.9° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([O:19][C:20](=[O:22])[CH3:21])[CH2:16]2)=[CH:11][C:10]=1[N+:23]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pt]>[NH2:23][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH:15]([O:19][C:20](=[O:22])[CH3:21])[CH2:14][CH2:13]2
Reactant: CC(=O)OC1CCc2cc([N+](=O)[O-])c(OCc3ccccc3)cc2C1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(=O)OC1CCc2cc(N)c(OCc3ccccc3)cc2C1
Reaction time: 18 h

Procedure:
A mixture of acetic acid 7-benzyloxy-6-nitro-1,2,3,4-tetrahydronaphthalen-2-yl ester (1.01 g, 2.96 mmol) and 5% Pt/C (150 mg) in EtOAc (20 mL) is hydrogenated at 1 atm and at ambient temperature for 18 h. The mixture is filtered through Celite, and the filtrate is concentrated to give the title compound as an oil, which is used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH2:15][CH2:16][CH2:17][C:3]1=2.C[O-].[Na+].[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>CO>[CH3:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[C:15]1[C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][N:7]3[C:2](=[O:1])[C:3]=2[CH2:17][CH2:16]1
Reactant: Cc1ccccc1C=O
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CCC3
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccccc1C=C1CCc2c1nc1ccc(C(=O)O)cn1c2=O
Yield: 42.2 %

Procedure:
1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid (3.12 g) in methanol (145 ml) containing 2.9 g of sodium methoxide was reacted with 4.86 g of 2-methyl-benzaldehyde under stirring at reflux temperature for 144 hours. After cooling and concentration in vacuo to a small volume, the precipitate was filtered and treated with acetic acid and then with water: the crude compound was recovered by filtration, washed with water until neutral and crystallized from CH2Cl2 /methanol and then from dioxane to give 1.9 g of 3-(2-methyl-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid, m.p. 300°-302° C., NMR (CF3COOD) δ ppm: 2.49 (s) (3H, --CH3), 3.36 (s) (4H, cyclopentane protons), 7.42 (m) (3H, phenyl protons), 7.64 (m) (1H, phenyl proton), 7.81 (bs) (1H, =CH--), 8.40 (d) (1H, C-5 proton), 9.11 (d d) (1H, C-6 proton), 10.23 (d) (1H, C-8 proton).
Reaction SMILES: [O:1]1[CH2:10][CH:2]1[CH2:3][C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1.[N:11]1([C:22](=[O:23])[C:21]2[NH:20][CH:19]=[N:18][C:17]=2[N:15]([CH3:16])[C:13]1=[O:14])[CH3:12]>C(O)(C)C.N1C=CC=CC=1>[OH:1][CH:2]([CH2:3][C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH2:10][N:20]1[C:21]2[C:22](=[O:23])[N:11]([CH3:12])[C:13](=[O:14])[N:15]([CH3:16])[C:17]=2[N:18]=[CH:19]1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: Cc1nc(CC2CO2)no1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Cc1nc(CC(O)Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 86 %

Procedure:
1.4 g. 3-(2,3-epoxy-propyl)-5-methyl-1,2,4-oxadiazole and 1.8 g. of theophylline are boiled under stirring in a mixture of 20 cm3 isopropyl alcohol and 0.1 cm3 of pyridine for 8 hours. 2.75 g. (86% yield) of 7-[2-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)-propan-1-yl]-theophylline are obtained.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:6]=2[CH:5]=1)(=O)[CH3:2].O.NN.[OH-].[K+].C1(C)C=CC=CC=1>C(O)CO.O>[Br:13][C:11]1[CH:10]=[CH:9][C:7]2[O:8][C:4]([CH2:1][CH3:2])=[CH:5][C:6]=2[CH:12]=1
Reactant: CC(=O)c1cc2cc(Br)ccc2o1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: OCCO
Solvent: O
Product: CCc1cc2cc(Br)ccc2o1
Temperature: 150 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
2-Acetyl-5-bromobenzo[b]furan (10.00 g) and hydrazine monohydrate (8.00 g) were stirred in ethylene glycol (60 ml) at 150° C. for 2 hr. After cooling, potassium hydroxide (9.00 g) was added and the mixture was stirred at 150° C. for 2 hr. After cooling, toluene (200 ml) and water (100 ml) were added and the separated toluene layer was washed with 10% aqueous solution (100 ml) of ammonium chloride, dried over magnesium sulfate and concentrated to give the objective compound (8.30 g).