Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1.[CH3:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[C:22]([N:28]2[CH2:29][CH2:30][N:31]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:19])=[CH:8][C:9]=3[N+:16]([O-:18])=[O:17])=[O:13])[CH2:32][CH2:33]2)=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1[N+](=O)[O-]
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3[N+](=O)[O-])CC2)c(C)c1
Yield: 63 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-nitrobenzoic acid (1.05 g) described in Preparation Example 24 and 1-(3,5-dimethylpyridin-2-yl)piperazine (0.70 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (1.06 g) was obtained.
Reaction SMILES: [O:1]([C:8]1[CH:39]=[CH:38][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]([O:20]CC)=[O:19])[C:15]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[N:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[O:1]([C:8]1[CH:39]=[CH:38][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:27][CH:26]=3)=[N:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
After a mixture of ethyl 1-(4-phenoxybenzyl)-3-(4-phenoxybenzyloxy)-1H-pyrazole-4-carboxylate (500 mg), 1N sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 1-(4-phenoxybenzyl)-3-(4-phenoxybenzyloxy)-1H-pyrazole-4-carboxylic acid (450 mg, yield: 95%). This was recrystallized from acetone-hexane. Melting point: 141–142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:12][C:13]([CH3:22])=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1.[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]([CH3:25])[C:13]([CH3:22])=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:15]=1
Reactant: COc1ccc(-c2nc(-c3cccnc3)c(C)[nH]2)c(OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(-c3cccnc3)c(C)n2C)c(OC)c1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(2,4-dimethoxyphenyl)-5-methyl-4-(3-pyridyl)imidazole (0.80 g) in N,N-dimethylformamide (12 ml) was added sodium hydride (0.13 g, 60% suspension in oil), and the mixture was stirred for 10 minutes. Then methyl iodide (0.34 ml) was added thereto, and the reaction was stirred at ambient temperature for 5 hours. The solution was poured into water (100 ml), and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and chromatographed on silica gel (25 g) eluting with chloroform. The fractions were collected and evaporated, and the residue was triturated with a mixture of ethyl acetate and diisopropyl ether (1:1 V/V) to give 2-(2,4-dimethoxyphenyl)-1,5-dimethyl-4-(3-pyridyl)imidazole (70 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[C:19](#[N:21])[CH3:20].Cl>O1CCOCC1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[S:3][C:2]3[N:1]=[C:19]([CH3:20])[NH:21][C:7](=[O:9])[C:6]=3[CH:5]=2)=[CH:17][CH:16]=1
Reactant: CC#N
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)sc1N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2sc(-c3ccc(F)cc3)cc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of ethyl 2-amino-5-(4-fluorophenyl)thiophene-3-carboxylate (0.3 g, 1.13 mmol) and acetonitrile (0.56 ml, 11.3 mmol) in dioxane (4 ml) was added 4M HCl in dioxane (4 ml). The mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure. The residue was diluted with water and made alcaline with a saturated aqueous sodium bicarbonate solution. The precipitate was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 60:1) to yield the title compound as a white solid (0.29 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[N:13]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29])[C:14](=[O:18])OCC.[H-].[Na+]>C(O)C>[Br:8][C:6]1[CH:5]=[C:4]([C:9]([F:10])([F:12])[F:11])[C:3]2[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:28][CH3:29])[C:14](=[O:18])[NH:1][C:2]=2[CH:7]=1
Reactant: CCOC(=O)N(Cc1ccc(OC)cc1OC)c1c(N)cc(Br)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cn2c(=O)[nH]c3cc(Br)cc(C(F)(F)F)c32)c(OC)c1
Yield: 106.4 %

Procedure:
To a solution of ethyl 2-amino-4-bromo-6-(trifluoromethyl)phenyl(2,4-dimethoxybenzyl)carbamate (1.1345 g) in ethanol (75 ml) was added sodium hydride (60%) (225.5 mg). The reaction mixture was heated at reflux for 33 hours. The solvent was removed to about one third in vacuo. To the reaction mixture was added 1N hydrochloric acid, and the mixture was basified with saturated aqueous sodium bicarbonate solution, and extracted 5 times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (1090.7 mg, quantitative yield). HPLC retention time: 34.49 min (condition 2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1.O[CH2:24][CH:25]1CC1>CCO.CCO.CCO.CCO.[Ti].[F-].[K+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18][CH:19]4[CH2:25][CH2:24]4)=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: OCC1CC1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: [Ti]
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: CN1Cc2c(C(=O)OCC3CC3)ncn2-c2ccc(F)cc2C1=O
Reaction time: 8 h

Procedure:
A mixture of 5 g (16.5 mmol) of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 1.8 g (8 mmol) of tetraethyl orthotitanate and 16.5 g (230 mmol) of hydroxymethyl-cyclopropane is stirred at 110° overnight, evaporated to dryness, the residue is taken up in methylene chloride and the solution obtained is stirred for 0.5 hour with 50 ml of a saturated potassium fluoride solution. The emulsion obtained is filtered through siliceous earth, the separated organic phase is washed with water, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate there is obtained cyclopropylmethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 156-157°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]Br.[OH-].[Na+]>S(=O)(=O)(O)O.O>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[Br:9]
Reactant: BrBr
Reactant: Cc1cccc(N)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Br)c(N)n1
Temperature: 0 °C
Yield: 55.2 %

Procedure:
32.4 g (0.3 mole) of 6-aminopicoline was dissolved in a mixture of 28 g of conc. sulfuric acid and 120 ml of water and the resulting solution was cooled in ice water. 52.8 g (0.33 mole) of bromine was added dropwise to the solution over 30 minutes at 0° C. The reaction solution was stirred for 20 minutes at room temperature and neutralized with cold aqueous NaOH solution. The resultant was filtered and the solid was purified with column chromatography using methylene chloride and ethyl acetate as an eluent to obtain 31 g of the title compound (yield 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([CH2:13][OH:14])[CH2:8]2.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:14][CH2:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[CH:12][C:3]=3[O:2][CH3:1])[CH2:8]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COc1cccc2c1CCC(CO)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1cccc2c1CCC(COS(=O)(=O)c1ccc(C)cc1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
To a solution of (5-methoxy-1,2,3,4-tetrahydro-2-naphthyl)methanol (1.00 g) in dry pyridine (10 ml) was added p-toluenesulfonyl chloride (1.15 g) under ice bath cooling. The mixture was stirred for 1 day at room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with water (twice), 1N hydrochloric acid and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate =10:1) to give (5-methoxy-1,2,3,4-tetrahydro-2-naphthyi)methyl p-toluenesulfonate (1.70 g) as a white powder.
Reaction SMILES: [OH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O.C1(C)C=CC=CC=1>[Pt].C(O)C>[NH2:15][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:5]=1[NH:4][CH2:3][C:2]([OH:1])([CH3:18])[CH3:19])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(O)CNc1c(N)cnc2ccccc12

Procedure:
Using the method of Example 16, 7.0 g (0.027 mole) of 4-(2-hydroxy-2-methylpropylamino)-3-nitroquinoline, 1 g of platinum on charcoal, 200 ml of toluene and 150 ml of ethanol was hydrogenated on a Paar apparatus. The solution was filtered, then evaporated to dryness to provide 3-amino-4-(2-hydroxy-2-methylpropylamino)quinoline as a solid residue. To the residue was added 50 ml of triethyl orthoformate and 5 drops of formic acid. The solution was heated at 135° to 140° C. for one hour, then allowed to stand for about 16 hours. The product was separated by filtration, dissolved in hydrochloric acid and reprecipitated with sodium hydroxide solution. The product was recrystallized from ethanol to provide 1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline hydrate, m.p. 169°-170° C. Analysis: Calculated for C14H15N3O. H2O: % C, 64.8; % H, 6.6; % N, 16.2; Found: % C, 65.1: % H, 6.6; % N, 16.4.
Reaction SMILES: C[S:2][C:3](=S)[O:4][CH:5]([CH3:7])[CH3:6].[C:9]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)(=[O:11])[CH3:10].CC(C)([O-])C.[K+].Cl>C(O)(C)(C)C>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[C:9](=[O:11])[CH2:10][C:3](=[S:2])[O:4][CH:5]([CH3:7])[CH3:6]
Reactant: CSC(=S)OC(C)C
Reactant: CC(=O)c1ccco1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)OC(=S)CC(=O)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A mixture of isopropyl (methylsulfanyl)methanethioate (7.0 g, 46.7 mmol), 2-acetyl furan (5.14 g, 46.7 mmol), potassium t-butoxide (10.5 g, 93.5 mmol) and t-butanol (35 mL) was stirred overnight at room temperature. Ice was added to the reaction solution, followed by acidifying with 5 N hydrochloric acid. The solid was collected by filtration and washed with water, to give the title compound (3.7 g, 37%).
Reaction SMILES: Br[CH:2]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:3]([O:5]CC)=[O:4].CC(C)([O-])C.[K+]>O1CCCC1.C(O)(C)(C)C>[F:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9]/[C:8]/2=[CH:2]\[C:3]([OH:5])=[O:4])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Br)C1CCCc2ccc(F)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C(O)/C=C1\CCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
A mixture of ethyl 2-bromo-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthyl)acetate (2.2 g, 7.0 mmol), 1N potassium tert-butoxide in tetrahydrofuran (14 mL, Aldrich) and tert-butanol (140 mL) was stirred for 5 h at room temperature. The resulting suspension was concentrated in vacuo, diluted with water (200 mL) and washed with diethyl ether. The aqueous layer was acidified by adding 1N hydrochloric acid (14 mL) and extracted with diethyl ether. The ether extract was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and chromatographed on Silica Gel 60 using ethyl acetate-hexane (1:1) as eluent. The fractions containing only (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid were combined and concentrated in vacuo to give a white solid (0.8 g, 55%); NMR (DMSO-d6): d 12.22 (br s, 1H, COOH), 7.57 (d of d, Jm =2.6 Hz, Jo =11.0 Hz, 1H, Ar), 7.12-7.28 (m, 2H, Ar). 6.36 (s, 1H, =CH, E), 3.04 (t, 2H, ArCH2), 2.74 (t, 2H, CH2), 1.74 (m, 2H, CH2); steady-state nOe: irradiation at 6.36, observed 25% nOe at 7.57.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNS(=O)(=O)c2ccccc2)no1

Procedure:
Method as for preparation 6 using tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (205 mg, 0.58 mmol) and benzenesulphonylchloride (75 μl, 0.58 mmol) as starting materials.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12].S(OC)(O[CH3:17])(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:17][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12]
Reactant: COS(=O)(=O)OC
Reactant: O=C1Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CN1C(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 67 %

Procedure:
A stirred mixture of sodium hydride (60%, 31 g, 0.79 mol) in dry xylene (500 mL), under a nitrogen atmosphere, was heated to reflux for 30 min. 1,3-Dihydro-indol-2-one 16a (100 g, 0.75 mol) was then slowly added via an addition funnel and stirred at reflux for 1.5 hrs. Dimethyl sulfate (104 g, 0.83 mol) was added drop-wise, whereupon the resulting homogeneous solution was refluxed for an additional 2 hrs. After cooling to room temperature, the reaction mixture was washed with water, dried over Na2SO4, and concentrated under reduced pressure to afford 1-methyl-1,3-dihydro-indol-2-one 16b (74 g, 67.3%), 1H NMR (300 MHz, CDCl3) δ 7.23-7.31 (m, 2H), 7.04 (t, J=7.5 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 3.52 (s, 2H), 3.21 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH:23][S:28]([CH2:27][CH2:26][O:25][CH3:24])(=[O:30])=[O:29])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCS(=O)(=O)Cl
Reactant: Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COCCS(=O)(=O)Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenylamine (2.71 g, 8.84 mmol) stirred in pyridine (25 ml) at 0° C. was charged with 2-methoxy-ethanesulfonyl chloride (2.1 g, 13.26 mmol) dropwise causing a color change from yellow to bright orange. The reaction was allowed to warm to room temperature gradually and stirred 18 h. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 solution (100 mL). The aqueous layer was extracted with CH2Cl2 (2×50 ml) and the organic layer was concentrated to an oil. This was dissolved in EtOAc which caused an oil to separate. The EtOAc layer was separated and washed with saturated aqueous NaHCO3 solution (100 mL). The aqueous layer was extracted with EtOAc (2×50 ml) and the combined organic layer was washed with saturated aqueous NaCl solution (50 ml), dried over Na2SO4, filtered and concentrated to a crude orange liquid (3.77 g, ˜100%). (TLC 75% EtOAc/hexanes Rf 0.48);
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:17]([C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(N(CC)C(C)C)(C)C.O>ClCCl.CCCCCC.C(OCC)(=O)C>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:29]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([C:17]4[C:16]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:23])=[CH:33][CH:32]=3)=[O:30])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
A mixture of 6,11-dihydro-5H-dibenz[b,e]azepine (0.195 g), 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoyl chloride (0.41 g) and 0.155 g of N,N-diisopropylethylamine in 12 ml of dichloromethane is stirred at room temperature for 3 hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with H2O, saturated NaHCO3, H2O, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with dichloromethane. The filtrate is concentrated to dryness to give 0.66 g of a yellow l , solid. Chromatography on thick layer silica gel plates with hexane-ethyl acetate (1.5:1) gives crystals (0.165 g) (from dichloromethane-ethyl acetate), m.p. 224° C.-225° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:24]=O.Cl.[CH2:27]([O:29][NH2:30])[CH3:28]>N1C=CC=CC=1>[CH2:27]([O:29][N:30]=[CH:24][C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:6]=2[C:2]=1[CH3:1])[CH3:28]
Reactant: Cc1c(C=O)oc2cccc(OCCCN(C)Cc3cccnc3)c12
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Product: CCON=Cc1oc2cccc(OCCCN(C)Cc3cccnc3)c2c1C
Reaction time: 7 h

Procedure:
To a solution of 3-methyl-4-[3-(methyl-pyridin-3-ylmethyl-amino)-propoxy]-benzofuran-2-carbaldehyde (the compound of Example 115-b) (29 mg) in pyridine (5 ml) was added O-ethyl hydroxylamine hydrochloride (84 mg) at room temperature. After stirring for seven hours, the mixture was partitioned between ethyl acetate and NH4Cl solution. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography developed by dichloromethane and methanol to give the title compound as a colorless oil (19 mg). ESI-MS: m/z 382 (MH+); 1H-NMR (CDCl3): δ 1.35 (3H, t, J=6.9 Hz), 2.03 (2H, m), 2.27 (3H, s), 2.29 (3H, s), 2.59 (2H, t, J=6.9 Hz), 3.52 (2H, s), 4.11 (2H, t, J=5.9 Hz), 4.32 (2H, q, J=6.9 Hz), 6.60 (1H, d, J=7.6 Hz), 7.05-7.11 (2H, m), 7.21 (1H, t, J=7.9 Hz), 7.58-7.63 (1H, m), 8.12 (1H, s), 8.42 (1H, dd, J=1.7 Hz, 4.9 Hz), 8.52 (1H, d, J=2.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Li]CCCC.CN([CH:25]=[O:26])C.Cl>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:25]=[O:26])=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a suspension of 4-(2-chlorothieno[3,2-d]pyrimidin-4-yl)morpholine 4 (50 g, 195 mmol, 1.0 equiv.) in THF (anhydrous, 800 ml) at −78° C. was added slowly 2.5 M solution of n-BuLi in hexanes (93.9 ml, 234.6 mmol, 1.2 equiv.). The resulting slurry was allowed to warm up to −60° C. and a clear brown solution was observed. The solution was then cooled to −78° C. and DMF (anhydrous, 22.7 ml, 293 mmol, 1.5 equiv.) was added slowly. The resulting solution was stirred at −78° C. for 0.5 hour, then warmed up slowly to 0° C. over a period of 1-1.5 hours. The solution was then poured slowly to a mixture of 0.25 M aq. hydrochloric acid (1.65 L) and ice water (800 ml). The resulting slurry was stirred at 0-10° C. for 0.5 hour, filtered and rinsed with cold water (200 ml). The cake was dried in vacuum oven at 40° C. for 24 hours to afford 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 5 as a light yellow solid (54.9 g, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.76 (t, J=4.9 Hz, 1H), 3.95 (t, J=4.9 Hz, 4H), 8.28 (s, 1H), 10.20 (s, 1H). LCMS (ESI pos) m/e 285 (M+1).
Reaction SMILES: C1(C)C(C)=CC=CC=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=O)[CH:17]([CH3:30])[C:18](=[O:29])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])=O.[Cl:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35]>C(Cl)(Cl)Cl>[Cl:32][C:33]1[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=1[N:35]1[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:19][C:18](=[O:29])[C:17]([CH3:30])=[C:16]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[Cl:9]
Reactant: CC(C(=O)CC(=O)c1ccccc1Cl)C(=O)c1ccccc1Cl
Reactant: Nc1ccccc1Cl
Solvent: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2Cl)n(-c2ccccc2Cl)c(-c2ccccc2Cl)cc1=O
Temperature: 0 °C
Yield: 15.9 %

Procedure:
To 200 ml of xylene were added 6.9 g (0.020 mole) of 1,5-bis(2-chlorophenyl)-2-methyl-1,3,5-pentanetrione, 25.5 g (0.20 mole) of 2-chloroaniline and 20.0 g of Molecular Sieves 5A. After heating the reaction mixture under reflux for 2 hours, the reaction mixture was poured into ice water, followed by addition of 200 ml of chloroform thereto and vigorous stirring of the resultant mixture. One hour later, the reaction mixture was filtered to remove solid matter. The organic layer was washed first wtih 50 ml of 10% hydrochloric acid and then with 50 ml of a 10% aqueous solution of sodium hydroxide. The mixture was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off. The residue was purified by chromatography on a silica gel column (eluent: ethyl acetate) and then recrystallization from acetone to give 1.4 g of 1,2,6-tris(2-chlorophenyl)-3-methyl-4(1H)-pyridinone having a melting point of 205°-207° C.