Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:8]=[C:7]([N+]([O-])=O)[C:6]([CH3:12])=[CH:5][N+:4]=1[O-:13].Cl.[CH3:15][OH:16]>C(OCC)(=O)C>[CH3:15][O:16][C:7]1[C:6]([CH3:12])=[CH:5][N+:4]([O-:13])=[C:3]([CH3:2])[CH:8]=1
Reactant: CO
Reactant: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: COc1cc(C)[n+]([O-])cc1C

Procedure:
12.2 g of sodium were dissolved in 2 l of methanol under argon, whereupon 60 g of 2,5-dimethyl-4-nitropyridine 1-oxide were added portionwise and the solution was left to boil under reflux overnight. The pH was adjusted to 7 with 5N hydrogen chloride in ethyl acetate while cooling and the mixture was evaporated in vacuo. The residue was taken up in 1 l of methylene chloride, the solution was filtered through silica gel, which was rinsed with 0.4 l of methylene chloride, and the combined filtrates were evaporated in vacuo. The residue crystallized from methylene chloride/petroleum ether and there was obtained 4-methoxy-2,5-dimethylpyridine 1-oxide of melting point 99°-101°.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].FC(S(O)(=O)=O)(F)F.ClC(Cl)(Cl)C(=N)O[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:19]([CH:2]([OH:3])[C:1]([O:5][CH3:6])=[O:4])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)CO
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(O)Cc1ccccc1

Procedure:
To a solution containing methyl glycolate (2.5 mL, 32 mmol) and trifluoromethyl-sulfonic acid (150 mL) in CH2Cl2 (10 mL) was added benzyl 2,2,2-trichloro-acetimidate (7.0 mL, 37 mmol). After stirring for several min, the mixture was poured into aqueous NaHCO3 and extracted with Et2O. The organic extract was washed with saturated aqueous NaCl, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with a solvent gradient of 9-17% EtOAC/Hex to afford the title compound: 1H NMR CDCl3): d 7.34 (m, 5H); 4.62 (s, 2H); 4.11 (s, 2H); 3.78 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([C:6]1[C:14]([CH3:15])=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1)[CH:3]([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:47]([O:50][C:51]1[C:60]([CH3:61])=[CH:59][C:54]([C:55]([NH:57][NH2:58])=[O:56])=[CH:53][C:52]=1[CH3:62])[CH:48]=[CH2:49]>C(Cl)Cl.CC(=O)OCC>[CH2:47]([O:50][C:51]1[C:60]([CH3:61])=[CH:59][C:54]([C:55]([NH:57][NH:58][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([CH3:15])[C:6]([CH2:2][CH:3]([CH3:4])[CH3:5])=[N:7][CH:8]=2)=[O:56])=[CH:53][C:52]=1[CH3:62])[CH:48]=[CH2:49]
Reactant: C=CCOc1c(C)cc(C(=O)NN)cc1C
Reactant: Cc1cc(C(=O)O)cnc1CC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCOc1c(C)cc(C(=O)NNC(=O)c2cnc(CC(C)C)c(C)c2)cc1C
Yield: 97.7 %

Procedure:
To a solution of 6-isobutyl-5-methyl-nicotinic acid hydrochloride (50 mg, 0.22 mmol), DIPEA (0.12 mL, 0.7 mmol) and TBTU (97 mg, 0.30 mmol) in DCM (5 mL) is added at 0° C. 4-allyloxy-3,5-dimethyl-benzoic acid hydrazide (50.6 mg, 0.23 mmol) and the mixture is stirred at 0° C. for 4 h. The mixture is diluted with EA (15 mL) and washed with 1M aq. NaH2PO4 (5 mL), 1M aq. NaOH (5 mL) and water (5 mL). The org. phase is dried (MgSO4), filtered and evaporated to provide 6-isobutyl-5-methyl-nicotinic acid N′-(4-allyloxy-3,5-dimethyl-benzoyl)-hydrazide (85 mg); LC-MS: tR=0.81 min, [M+1]+=396.20.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][CH2:15][CH:16]=[CH2:17]>C(O)C.O>[CH2:17]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCCOc1ccc(C(=O)O)cc1

Procedure:
69.1 g (0.5 mol) of p-hydroxybenzoic acid were dissolved in 400 ml of ethanol and treated with a solution of 56.1 g (1 mol) of KOH in 250 ml of water. The reaction batch was heated under reflux. While so doing 74.26 g (0.55 mol) of 4-bromo-1-butene were slowly added dropwise. After 5 hours the ethanol was removed on a rotary evaporator. The aqueous phase was brought to a pH value of 10 with NaOH and extracted repeatedly with diethyl ether. The aqueous phase was poured into a mixture of 46 ml of concentrated HCl and 500 ml of ice-water. The separated acid was filtered off, washed with a small amount of water and recrystallized from methanol/water (2:1). After drying at 60° C. in a water-jet vacuum 40 g of 4-(but-3-enyloxy)-benzoic acid remained behind as a white powder; phase succession (° C.): C 120 N 141 I.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([O:6][CH2:7][CH2:8][N:9]2[C@@H:18]([C:19]([NH:21][C@H:22]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)[CH3:23])=[O:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+].[ClH:38].O1CCOCC1>CO.O1CCCC1>[ClH:38].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][N:9]2[C@@H:18]([C:19]([NH:21][C@H:22]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)[CH3:23])=[O:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10]2)=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2CCOc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)[C@H]1Cc2ccccc2CN1CCOc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Dissolve methyl 4-[(1S)-1-[[(3R)-2-(2-(4-fluorophenoxy)ethyl)-3,4-dihydro-1H-isoquinoline-3-carbonyl]amino]ethyl]benzoate (550 mg, 1.15 mmol) in a mixture of methanol (10 mL) and tetrahydrofuran (10 mL). Add a 5 N aqueous solution of sodium hydroxide (0.462 mL, 2.31 mmol), then stir the mixture at room temperature overnight. Concentrate the mixture under reduced pressure to furnish a white solid. Add a 4 M solution of hydrogen chloride in 1,4-dioxane (10 mL, 40 mmol), and stir the mixture at room temperature for 10 min Remove the suspended solids by filtration, rinsing the solids with THF (5 mL). Concentrate the combine filtrate under reduced pressure to furnish a white solid. Triturate the material in hot diethyl ether (10 mL), and filter to furnish the title compound as a white solid (535 mg, 93% yield). Mass spectrum (m/z): 463 ([M+H]+), 485 ([M+Na]+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:19]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N>CN(C)C=O.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([NH2:19])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
To a solution of 2-benzyloxycarbonylamino-2-methylpropionic acid (1 g) in N,N-dimethylformamide (10 mL) were added 1-hydroxybenzotriazole (0.63 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.21 g), triethylamine (1.76 mL) and 28% aqueous ammonia solution (2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 mol/L hydrochloric acid, water, 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2-benzyloxycarbonylamino-2-methylpropionamide (0.26 g). This material was dissolved in methanol (5 mL). To the solution was added 10% palladium-carbon powder (30 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.11 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:19]2[C@H:23]([CH2:24][O:25][CH3:26])[CH2:22][O:21][C:20]2=[O:27])[CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])(=[O:4])=[O:3].Cl[C:29]1[C:34]([Cl:35])=[CH:33][C:32]([Cl:36])=[CH:31][N:30]=1>>[Cl:35][C:34]1[C:29]([N:16]2[CH2:17][CH2:18][N:13]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([N:19]4[C@H:23]([CH2:24][O:25][CH3:26])[CH2:22][O:21][C:20]4=[O:27])=[CH:6][C:5]=3[S:2]([CH3:1])(=[O:3])=[O:4])=[O:12])[CH2:14][CH2:15]2)=[N:30][CH:31]=[C:32]([Cl:36])[CH:33]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)c(S(C)(=O)=O)c1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)c(S(C)(=O)=O)c1
Yield: 45.5 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-3-[3-methanesulfonyl-4-(piperazine-1-carbonyl)phenyl]-4-methoxymethyloxazolidin-2-one (1.19 g) described in Preparation Example 172 and 2,3,5-trichloropyridine (1.09 g), the title compound (740 mg) was obtained.
Reaction SMILES: [CH:1]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].C([N+]1(C)[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)C.C([O-])(O)=O.[Na+]>C(O)C.O>[CH:1]1([N:11]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[N+]1(C)CCC(=O)CC1
Reactant: NC1CCCCCCCCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: O
Product: O=C1CCN(C2CCCCCCCCC2)CC1
Temperature: 0 °C
Yield: 84.3 %

Procedure:
To a solution of cyclodecylamine (6.78 g, 44 mmol) in ethanol (80 ml) was added a solution of potassium carbonate (0.60 g, 3.9 mmol) and 1-ethyl-1-methyl-4-oxo-piperidinium iodide (16.2 g, 60 mmol) in water (40 ml) and the mixture was refluxed for 100 min. The reaction mixture was poured into sat. NaHCO3 -solution (120 ml)/ice (400 ml) and extracted with ethylacetate (2×300 ml). The combined organic layers were dried (MgSO4) and evaporated. Column chromatography on silica gel (toluene/ethylacetate 2:1) yielded the title compound (8.8 g, 85%) as a pale brown oil, MS: m/e=238.4 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl[CH2:24][CH2:25][N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]1=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][CH2:25][N:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]4=[O:32])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: O=c1ccccn1CCCl
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCn1ccccc1=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 12.1 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (300 mg, 0.94 mmol), (prepared as described for the starting material in Example 15), 1-(2-chloroethyl)-1,2-dihydro-2-pyridone (175 mg, 1.1 mmol), (J. Am. Chem. Soc. 1951, 73, 3635), and potassium carbonate (260 mg, 1.9 mmol) in DMF (30 ml) was heated at 80° C. for 3 hours, allowed to cool to ambient temperature and stirred for a further 18 hours. The mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol/triethylamine mixtures (100/0/0 increasing to 70/30/0.5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-[2-(2-oxo-1,2-dihydro-1-pyridyl)ethoxy]quinazoline (50 mg, 12%). m.p. 209-211 ° C. 1H NMR Spectrum: (DMSOd6) 3.94(s, 3H); 4.35(t, 2H); 4.41 (t, 2H); 6.22(dd, 1H); 6.40(d, 1H); 7.14(s, 1H); 7.35(dd, 1H); 7.42(ddd, 1H); 7.5-7.6(m, 2H); 7.70(d, 1H); 7.80(s, 1H); 8.35(s, 1H); 9.53(s, 1H) MS-ESI: 441 [MH]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1.[NH2:20][NH2:21]>C1COCC1>[NH:20]([C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1)[NH2:21]
Reactant: NN
Reactant: CCOC(=O)c1cnc(Cl)nc1Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(NN)nc1Cc1ccccc1
Yield: 99 %

Procedure:
The title compound was prepared as described in Example 18, but employing a solution of ethyl 2-chloro-4-benzylpyrimidine-5-carboxylate (0.34 g, 1.2 mmol) and hydrazine (0.2 g, 6.1 mmol) in THF resulting in a 99% yield (0.33 g, oil); GC/MS, 272(M+).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([CH3:26])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[C:24]([CH3:26])[CH:25]=[C:20]([CH3:19])[CH:21]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: Cc1cc(C)cc(B(O)O)c1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(C)cc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)c1
Yield: 85.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3,5-dimethylphenylboronic acid (117 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 186 mg (86%) of the title compound as a white solid. mp 129°-130°. FDMS: m/e =333. α[D]589 =+73.31 (c=1.00, chloroform).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.[NH:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](O)=[O:31].P(C#N)(OCC)(OCC)=O>ClCCl.O>[NH:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:8]2=[O:9])[CH2:3][CH2:2]1)=[O:31]
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Reactant: O=C(O)c1ccc[nH]1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc[nH]1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reaction time: 1 h
Yield: 28.5 %

Procedure:
1-(4-Piperidinyl)-3,4-dihydrocarbostyril (500 mg), triethylamine (1.2 ml) and pyrrole-2-carboxylic acid (314 mg) are dissolved in dichloromethane (10 ml) and thereto is added dropwise diethyl cyanophosphate (0.82 ml) under ice cooling. The mixture is stirred with ice cooling for 1 hour and then stirred at room temperature for 2 hours. The mixture is poured into water, extracted with chlorform, dried with sodium carbonate and purified by silica gel column chromatography (solvent; dichloromethane:methanol=20:1). The resultant is recrystallized from n-hexane/diethyl ether to give 1-[1-(2-pyrrolylcarbonyl)-4-piperidinyl]-3,4-dihyrocarbostyril (0.2 g), as white powder, m.p. 161°-162° C. (decomposed).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][Si](C(C)(C)C)(C)C)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCCO
Reaction time: 1 h

Procedure:
The 2-butyl-1-[4-(tert-butyldimethylsilanyloxy)butyl]-1H-imidazo[4,5-c]quinoline from the previous step and tetrabutylammonium fluoride (142 mL of a I M solution in tetrahydrofuran) were dissolved in tetrahydrofuran (THF) (400 mL) and stirred for 1 hour, then concentrated under reduced pressure to provide 4-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (20.0 g) as a light brown solid after chromatography on silica gel (elution with 10% methanol in dichloromethane).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.P(=O)(O)(O)O>O.CCOCC>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[B:15]([OH:20])[OH:16]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1cc2sccc2cn1
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: OB(O)c1cc2cnccc2s1
Temperature: -44 °C
Reaction time: 1 h

Procedure:
A three neck flask fitted with an internal thermometer containing thieno[3,2-c]pyridine (5.0 g, 37 mmol, 1 equivalent) was evacuated and then filled with a nitrogen gas atmosphere. THF (60 mL) was added and the solution was cooled to −44° C. (CH3CN/dry ice). n-Butyllithium (1.6M/hexane, 25 mL, 41 mmol, 1.1 equivalents) was added over 10 minutes, while maintaining the internal temperature at or below −33° C. The reaction was stirred at −33 to −45° C. for 60 minutes. Triisopropyl borate (10.2 mL, 44 mmol, 1.2 equivalents) was added and the cooling bath removed. The reaction was allowed to proceed for 105 minutes. Then 3.0 mL phosphoric acid (85% aqueous, 3.0 mL, 44 mmol, 1.2 equivalents) was added. A yellow solid formed, which was diluted with water and Et2O (about 150 mL each). A yellow solid was collected by filtration and was dried by suction overnight (5.05 g). Analytical Data: 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.95 (1H, s), 8.09 (1H, d, J=5.9 Hz), 8.34 (1H, d, J=6.1 Hz), 9.09 (1H, s). MS (APCI, M+1) 180.1. Microanalysis for C7H6BNSO2.H3PO4: calculated C, 30.35; H, 3.27; N, 5.06; P, 11.18. Found: C, 41.12; H, 3.19; N, 6.53; P, 0.68%.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.[CH3:19][Mg]Cl.S(=O)(=O)(O)O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([CH3:19])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:12])[O:7]2)=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: C[Mg]Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(c2ccc(Cl)cc2)OC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
Over a period of 30 minutes a solution of 130 g of 2-(4-chlorobenzoyl)benzoic acid in 300 ml of anhydrous tetrahydrofuran was added drop-wise under nitrogen to 900 ml of a stirred 3M solution of methylmagnesium chloride in anhydrous tetrahydrofuran. After the addition the reaction mixture was kept at reflux temperature for 1 hour. Afterwards it was cooled in an ice bath to room temperature and 1 L of an aqueous 2N sulfuric acid solution was added slowly, followed by 600 ml of toluene. The organic layer was separated and washed with brine, dried and evaporated in vacuo. Bulb to bulb destination (0.1 mm Hg/160° C.) afforded 60 g of 3-(4-chlorophenyl)-3-methyl-1(3H)-isobenzofuranone as a yellow oil. M.S. (C.I.) (M/Z): 260 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:3][N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5]1.[CH:22]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH:25]=[CH:24][CH2:23]1>C(Cl)Cl>[CH3:1][C@@H:2]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:28]([CH:22]1[CH2:27][CH2:26][CH:25]=[CH:24][CH2:23]1)=[O:29])[CH2:3][N:4]1[CH2:5][CH:6]=[C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:8][CH2:9]1
Reactant: O=C(Cl)C1CC=CCC1
Reactant: C[C@H](CN1CC=C(c2cccs2)CC1)Nc1ccccn1
Solvent: ClCCl
Product: C[C@H](CN1CC=C(c2cccs2)CC1)N(C(=O)C1CC=CCC1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.2 %

Procedure:
A solution of the starting (R)-[1-methyl-2-(4-thiophen-2-yl-3,6-dihydro-2H-pyrid-1-yl)-ethyl]-pyrid-2-yl-amine (0.46 g, 1.5 mmol) in methylene chloride (20 ml) was cooled to 0° C., after which a solution of cyclohex-3-enecarbonyl chloride (0.222 g, 1.5 mmol) in methylene chloride (10 ml) was dropwise added under exclusion of moisture. The reaction mixture was stirred at ambient temperature overnight, then washed with 2.5N NaOH (10 ml). The separated organic layer was washed with brine (50 ml), dried over magnesium sulfate, filtered, and evaporated to dryness in vacuo. Column chromatography on 50 g of silica gel with chloroform as eluant, followed by trituration in ether with the addition of ethanolic HCl gave 0.27g of the title compound as the dihydrochloride, m.p. 92°-6° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]3[C@H:19]4[C@H:29]([C:30](=[O:32])[CH2:31][C@:14]23[CH3:15])[C@:27]2([CH3:28])[C@H:22]([CH2:23][C:24](=[O:33])[CH2:25][CH2:26]2)[CH2:21][CH2:20]4)=[O:12])[CH2:3][CH2:2]1.C(N(CC)CC)C>C(O)(C)C.O.Cl.Cl.Cl[Ir](Cl)(Cl)Cl>[OH:33][C@@H:24]1[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@@H:22]([CH2:21][CH2:20][C@@H:19]3[C@@H:29]2[C:30](=[O:32])[CH2:31][C@@:14]2([CH3:15])[C@H:16]3[CH2:17][CH2:18][C@@H:13]2[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:12])[CH2:23]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)OCCCN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)OCCCN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 17β(3'-morpholinopropoxycarbonyl)-5α-androstan-3,11-dione (140 mg.) in isopropanol (1 ml.) was added to a "stock" solution of the chloroiridic acid reagent (7 ml.) which had been neutralised to ca. pH 6 with triethylamine immediately prior to the addition. After refluxing for 7 hr., isolation of the product afforded a gum (150 mg.) which, after purification by preparative t.l.c., gave the title compound as a white froth; 112 mg., [α]D + 51° (c, 0.6,).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12].[OH:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:17]=2)[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1Cl
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc(Cl)nc1Oc1cccc(-c2ccccc2)c1

Procedure:
Methyl α-[6-methyl-2,4-dichloro-5-pyrimidinyl]-acetate (4 g, 18 mmol), 3-hydroxybiphenyl (3 g, 18 mmol) and potassium carbonate (11 g, 80 mmol) in dimethylformamide (50 ml) are stiffed at +80° C. for 2 hours. Workup as for example 1a) gives pure methyl α-[6-methyl-2-chloro-4-(3-phenylphenoxy)-5-pyrimidinyl]-acetate.