Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:12][OH:13])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:7]=2)[CH:3]=1.[H-].[Na+].I[CH3:47]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:12][O:13][CH3:47])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[N:7]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (25 mg, 0.039 mmol) in dimethylformamide (0.5 mL) at 0° C. was added sodium hydride (60%, 3.15 mg, 0.079 mmol). After 5 min, the reaction was treated with iodomethane (4.93 μL, 0.079 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was cooled to 0° C. and quenched by the cautious addition of saturated ammonium chloride. The reaction was diluted with diethyl ether and the layers separated. The ethereal was washed with water (2×). then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25% ethyl acetate/n-hexane) gave 22 mg (86%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 8.00 (s, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.31 (dd, J=8.9, 5.2 Hz, 2H), 7.02 (dd, J=8.9, 8.5 Hz, 2H), 6.74 (s, 1H), 5.67 (d, J=10.7 Hz, 1H), 5.63 (d, J=10.7 Hz, 1H), 5.06 (dd, J=7.3, 2.7 Hz, 1H), 3.50-3.80 (m, 6H), 3.48 (d, J=9.2 Hz, 1H), 3.41 (d, J=9.2 Hz, 1H), 3.33 (s, 3H), 3.06 (m, 2H), 2.23 (m, 1H), 2.07 (m, 1H), 1.97 (m, 1H), 1.87 (m, 1H), 1.69 (bs, 1H), 1.44 (s, 9H), 0.91 (t, J=8.2 Hz, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=245 Hz), 155.1, 145.7, 138.84, 138.82, 130.8, 128.9 (d, J=7.7 Hz), 128.1, 124.3, 122.8, 122.2, 118.3, 115.2 (d, J=21), 81.9, 79.4, 78.7, 77.9, 76.1, 67.7, 59.4, 41.4, 40.2 (br), 32.4, 32.0, 28.6, 17.9, −1.4. Mass spec.: 648.38 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:22]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:21]2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:22]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (531 mg), lithium hydroxide monohydrate (128 mg), tetrahydrofuran (6 ml), ethanol (4 ml) and water (4 ml) was stirred at room temperature for 2 hours and acidified by adding 1N hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (451 mg, yield: 90%). This was recrystallized from ethyl acetate-hexane. Melting point: 124–125° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([S:27]([NH:30][C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])=[CH:5][C:6]2[O:10][C:9](=[O:11])[N:8]([C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH3:13])[C:7]=2[CH:26]=1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>O>[Cl:2][C:3]1[C:4]([S:27]([NH:30][C:31]2[S:35][N:34]=[CH:33][N:32]=2)(=[O:29])=[O:28])=[CH:5][C:6]2[O:10][C:9](=[O:11])[N:8]([C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH2:21][CH2:22][N:23]([S:53]([CH3:52])(=[O:55])=[O:54])[CH2:24][CH:25]=3)[CH3:13])[C:7]=2[CH:26]=1
Reactant: C[C@H](c1ccccc1C1=CCNCC1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(Cl)cc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1ccccc1C1=CCN(S(C)(=O)=O)CC1)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To round bottom flask was added (R)-5-chloro-2-oxo-3-(1-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride (34-6) (10 mg, 0.018 mmol), followed by NMP (1 ml), then DIPEA (50 μl, 0.286 mmol), followed by METHANESULFONYL CHLORIDE (6.80 μl, 0.087 mmol). The reaction mixture was then capped (not under N2) & stirred at room temperature. Followed by LC/MS. After 2 minutes; the reaction mixture was diluted with H2O, then MeOH, & purified (without workup) by reverse phase chromatography (5-75% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions concentrated (GENEVAC), then dissolved in MeOH/DCM & concentrated to yield (R)-5-chloro-2-oxo-3-(1-(2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)ethyl)-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo-[d]oxazole-6-sulfonamide hydrochloride (36-1). MS [M+H] calculated; 596.1 observed; 596.0. 1H NMR (499 MHz, DMSO): δ 8.47 (s, 1H); 7.94 (s, 1H); 7.73 (d, J=7.8 Hz, 1H); 7.37 (d, J=7.6 Hz, 2H); 7.13 (d, J=9.8 Hz, 2H); 5.77-5.73 (m, 2H); 5.46 (s, 1H); 3.75-3.51 (m, 3H); 3.04-2.95 (m, 1H); 2.89 (s, 3H); 1.89-1.74 (m, 4H). Note: Peaks overlapping with water or solvent can not be accurately accounted for.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[C:25](=[O:27])[N:24]([CH2:28][CH2:29][C:30]1[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=1)[N:23]=[CH:22]2.O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:1]1[CH:6]=[CH:5][C:4]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[C:25](=[O:27])[N:24]([CH2:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=2)[N:23]=[CH:22]3)=[CH:3][CH:2]=1
Reactant: O=c1c2c(Cl)cccc2cnn1CCc1ccc2ccccc2n1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=c1c2c(-c3ccncc3)cccc2cnn1CCc1ccc2ccccc2n1
Temperature: 100 °C

Procedure:
A reaction tube was charged with pyridin-4-ylboronic acid (0.223 mmol), K2CO3 (61.7 mg, 0.447 mmol) under a dry nitrogen atmosphere. A solution of 8-chloro-2-(2-quinolin-2-yl-ethyl)-2H-phthalazin-1-one (50 mg, 0.186 mmol) in 1,4-dioxane (5 mL) along with PdCl2(dppf) (5.45 mg, 7.45 μmol) was added. After addition of water (1 mL), the resulting mixture was heated at 100° C. overnight. After removal of the solvent under reduced pressure, the title compound was obtained as a crude product. It was purified by Prep-HPLC.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:5])C.[H-].[Na+].C(O)C.Cl>C1(C)C=CC=CC=1>[O:5]=[C:4]1[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][O:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]1=2
Reactant: CCOC(=O)CCCOc1ccccc1C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1CCOc2ccccc2C1=O
Temperature: 82.5 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
A mixture of ethyl 4-(2-ethoxycarbonylphenyloxy)-butyrate (13.0 g, 46.4 mmol), 60% sodium hydride (5.56 g, 139 mmol), ethanol (2.5 ml) and toluene (250 ml) was stirred at 80-85° C. for 2 hours. The reaction mixture was poured into cold 1N hydrochloric acid and extracted twice with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; ethyl acetate:n-hexane=3:97) to obtain 9.05 g of ethyl 1,2,3,4-tetrahydro-5-oxo-benz[b]oxepine-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:13]3[C:12](=[CH:14][C:15]#[N:16])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.N.C(O)C>C(O)C.[Co]>[CH3:1][C:2]1[O:3][C:4]2[C:13]3[C:12](=[CH:14][CH2:15][NH2:16])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2ccc3c(c2o1)C(=CC#N)CC3
Agent: [Co]
Agent: N
Solvent: CCO
Product: Cc1nc2ccc3c(c2o1)C(=CCN)CC3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-methyl-6,7-dihydro-8H-indeno[5,4-d][1,3]oxazol-8-ylidene)acetonitrile (290 mg, 1.38 mmol) in ethanol (8 mL) were added Raney cobalt (3 g) and 2N ammonia/ethanol solution (4 mL), and the mixture was stirred at room temperature for 3 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure to give the title compound. The obtained title compound was used for the reaction of Examples 3 and 5 without further purification.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=O>>[C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]1(=[N:9][OH:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NCCCCCC(=O)O
Agent: O=C1CCCCCN1
Product: ON=C1CCCCC1

Procedure:
ε-Caprolactam is a precursor for the preparation of Nylon-6. Nylon-6 was first made in 1899 by heating 6-aminohexanoic acid. Commercially feasible synthesis of Nylon-6 from ε-caprolactam was discovered by Paul Schlack at I. G. Farbenindustrie in 1938. Currently, approximately 95% of the world's ε-caprolactam is produced from cyclohexanone oxime via the Beckmann rearrangement. The starting material for cyclohexanone can be cyclohexane, phenol, or benzene. Through a series of reductions and/or oxidations, cyclohexanone is formed. The latter is then reacted with a hydroxylamine salt usually the sulfate, to form the oxime and ammonium sulfate. The oxime is rearranged in concentrated sulfuric acid, and the resulting lactam sulfate salt is neutralized with ammonia to form ε-caprolactam and additional ammonium sulfate. Subsequently, pure ε-caprolactam is obtained through numerous separation and purification steps. The current process is extremely capital intensive and generates large quantities of waste.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:8]([C:7]1[CH:6]=[C:5]([O:10][CH3:11])[N:4]=[CH:3][C:2]=1[O:1][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21])=[O:9]
Reactant: COC(=O)c1cncc(CCl)c1
Reactant: COc1cc(C=O)c(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(COc2cnc(OC)cc2C=O)c1
Temperature: 60 °C
Yield: 50.6 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (352 mg, 2.29 mmol, 1 eq.), methyl 5-(chloromethyl)nicotinate hydrochloride (506 mg, 2.29 mmol, 1 eq.), and K2CO3 (1.26 g, 9.16 mmol, 4 eq.) in DMF (8.0 mL) was heated at 60° C. for 3 h. The mixture was cooled and added into water (50 mL) dropwise. The precipitate was filtered, washed with water, and dried to give methyl 5-((4-formyl-6-methoxypyridin-3-yloxy)methyl)nicotinate (350 mg, 85%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 9.26 (d, J=2.0 Hz, 1H), 8.90 (d, J=2.2 Hz, 1H), 8.42 (t, J=2.1 Hz, 1H), 8.09 (s, 1H), 7.15 (s, 1H), 5.29 (s, 2H), 4.01 (s, 3H), 3.95 (s, 3H). LRMS (M+H+) m/z 303.1.
Reaction SMILES: C(=O)([O-])O.[Na+].CS(C)=O.Cl.[NH2:11][OH:12].[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]#[N:33])=[N:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]>O>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32](=[N:11][OH:12])[NH2:33])=[N:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: NO
Reactant: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C(N)=NO)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Process 2: Sodium hydrogen carbonate (2.02 mg, 24.0 mmol) was added to dimethyl sulfoxide solution (20 mL) of hydroxylamine hydrochloride (1.42 g, 20.4 mmol) and stirred for 1 hour at 40° C. Dimethyl sulfoxide solution (3 mL) of 2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}benzonitrile (430 mg, 0.987 mmol) was added to the reaction mixture and stirred for 19 hours at 90° C. The reaction mixture was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residues were subjected to silica gel column chromatography (ethyl acetate) to give 2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}-N′-hydroxybenzimidamide (430 mg, 93%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:21]4[C:16](=[CH:17][C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH:20]=4)[CH:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.[CH3:37][CH2:38]O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:37]([O:23][C:22]([C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[N:13]([CH2:12][C:9]1[CH:8]=[C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:11][N:10]=1)[C:14]([C:25](=[O:36])[NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:35])[CH2:29][CH2:28]1)=[CH:15]2)=[O:24])[CH3:38]
Reactant: CC(C)N1CCC(NC(=O)c2cc3cc(C(=O)O)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reactant: CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)cc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.6 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-indole-5-carboxylic acid in 10 ml DMF sequentially 0.4 ml EtOH, 110 mg DMAP and 256 mg DCC were added and the reaction mixture was stirred for 16 h at room temperature. The precipitate was then filtered off and the filtrate was concentrated and purified by chromatography on silica gel eluting with DCM/MeOH/AcOH/H2O 95:3:0.5:0.5. The fractions containing the product were collected and the solvent evaporated under reduced pressure.
Reaction SMILES: ClC1C=C(C2ON=C(CN3CCCCN4C(C5C=CN=CC=5)=NN=C34)N=2)C=CC=1.Cl[CH2:31][C:32]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[O:34][N:33]=1.[F:44][C:45]([F:57])([F:56])[C:46]1[N:50]2[CH2:51][CH2:52][CH2:53][CH2:54][NH:55][C:49]2=[N:48][N:47]=1>CC(=O)OCC>[Cl:43][C:39]1[CH:38]=[C:37]([C:35]2[O:34][N:33]=[C:32]([CH2:31][N:55]3[CH2:54][CH2:53][CH2:52][CH2:51][N:50]4[C:46]([C:45]([F:57])([F:44])[F:56])=[N:47][N:48]=[C:49]34)[N:36]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: FC(F)(F)c1nnc2n1CCCCN2
Reactant: ClCc1noc(-c2cccc(Cl)c2)n1
Agent: Clc1cccc(-c2nc(CN3CCCCn4c(-c5ccncc5)nnc43)no2)c1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1nnc2n1CCCCN2Cc1noc(-c2cccc(Cl)c2)n1
Yield: 61 %

Procedure:
The title compound was prepared analogous to 9-{[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-3-pyridin-4-yl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a][1,3]diazepine from 3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (89 mg, 0.39 mmol), 3-(trifluoromethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-α][1,3]diazepine (73 mg, 0.35 mmol. Column chromatography (hep./EA 1:1) afforded 85 mg (61%) of the title compound. 1H NMR: 1.88 (m, 2H), 1.94 (m, 2H), 3.26-3.35 (m, 2H), 3.98-4.07 (m, 2H), 4.83 (s, 2H), 7.46 (m, 1H), 7.50-7.57 (m, 1H), 7.98 (m, 1H), 8.09 (m, 1H)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26]Br)[CH:22]=[N:23][C:24]=1[Cl:25]>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[CH:22]=[N:23][C:24]=1[Cl:25]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: Clc1cc(CBr)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cnc(Cl)c(Cl)c1
Yield: 73.2 %

Procedure:
By using (3,3,3-trifluoropropyl)malononitrile (480 mg), N,N-dimethylformamide (6 ml), potassium carbonate (420 mg) and 5,6-dichloro-3-(bromomethyl)pyridine (720 mg) according to the similar method described in Production Example 4 was obtained 698 mg of 2-((5,6-dichloro-3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (15)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15](=[O:26])[N:14]([CH2:27][CH2:28][CH2:29][OH:30])[C:13]=2[C:31]([O:33][CH3:34])=[O:32])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15](=[O:26])[N:14]([CH2:27][CH2:28][CH2:29][O:30][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=3)[C:13]=2[C:31]([O:33][CH3:34])=[O:32])[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COC(=O)c1c(-c2cc(Br)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1CCCO
Reactant: O=C(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2cc(Br)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1CCCOC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of the compound obtained in Example 184 (190 mg) in dimethylformamide (3 ml) are added nicotinoyl chloride (69 mg) and triethylamine (0.11 ml), and the mixture is stirred at room temperature overnight To the reaction mixture are added nicotinoyl chloride (69 mg) and triethylamine (0.11 ml), and the mixture is stirred overnight. After the reaction is complete, to the mixture are added ethyl acetate and water. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure to give 4-(3-bromo-4,5-dimethoxyphenyl)-6,7-dimethoxy-3-methoxycarbonyl-2-[3-(nicotinoyloxy)propyl]-1(2H)-isoquinolinone (170 mg) as listed in Table 16.
Reaction SMILES: S(Cl)([Cl:3])=O.O[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[N:8][C:7]=1[C:16]([O:18][CH3:19])=[O:17]>>[Cl:3][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[N:8][C:7]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1nnc2ccccc2c1O
Product: COC(=O)c1nnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (8.15 g, 5 ml) was added dropwise under inert atmosphere to methyl 4-hydroxycinnoline-3-carboxylate (0.50 g, 2.45 mmol). The mixture was heated to reflux for 1.5 h, cooled to room temperature and excess thionyl chloride was removed under vacuum. Toluene (5 ml) was added to the residue. The mixture was stirred at room temperature overnight. The solids were collected by filtration and dried under vacuum. The title compound was isolated as a brown solid (248 mg, 1.11 mmol, 45%). LCMS: m/z 223 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:6](Cl)=[O:7])[C:3](Cl)=[O:4].I.[CH3:10][S:11][C:12](=[NH:18])[NH:13][N:14]=[C:15]([CH3:17])[CH3:16].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][N:2]1[C:6](=[O:7])[NH:18][CH:12]([S:11][CH3:10])[N:13]([N:14]=[C:15]([CH3:17])[CH3:16])[C:3]1=[O:4]
Reactant: CSC(=N)NN=C(C)C
Reactant: CN(C(=O)Cl)C(=O)Cl
Agent: I
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CSC1NC(=O)N(C)C(=O)N1N=C(C)C
Yield: 75.1 %

Procedure:
15.6 g (0.1 mole) of N-methyl-bis-(chlorocarbonyl)-amine were dissolved in 100 ml of benzene and added dropwise, whilst stirring, to 27.3 g (0.1 mole) of acetone-S-methyliso-thio-semicarbazone hydroiodide suspended in 100 ml of benzene. Thereafter, 30.3 g (0.3 mole) of triethylamine in 50 ml of benzene were slowly added dropwise. The mixture was stirred for a further hour and the precipitate was filtered off. The precipitate was introduced into 100 ml of chloroform and 100 ml of water and extracted by shaking. The chloroform phase was separated off, dried over calcium chloride and evaporated in vacuo, together with the benzene filtrate. The resudue was recrystallized from isopropanol. 17.3 g (76%) of 1-methyl-3-isopropylideneamino-4-methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione were obtained as a colorless powder; melting point 130-132° C.
Reaction SMILES: [P:1]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])([O:7]CCCC)[O:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].BrCCCC>>[CH2:13]([O:12][P:1]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([O:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:7])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOP(OCCCC)OCCCC
Reactant: CCOC(=O)CBr
Solvent: CCCCBr
Product: CCCCOP(=O)(CC(=O)OCC)OCCCC
Temperature: 120 °C
Yield: 88 %

Procedure:
100 parts by weight of tributyl phosphite and 66 parts by weight of ethyl bromoacetate were put into a reactor equipped with a distillation tube, and the inside of the reactor was substituted by nitrogen. Subsequently, the reactor was heated at 120° C. to start a reaction. Since bromobutane as a by-product began to distill out immediately, the reaction was maintained until the distillation-out of bromoethane slowed down. When the distillation-out of bromoethane became moderate, the reactor was further heated at 170° C. to continue the reaction for 3 hours. The reaction mixture was distilled at 180° C. under a reduced pressure to obtain an achromatic transparent liquid (yield of 88%, boiling point of 249° C./760 mmHg).
Reaction SMILES: [CH:1]1([C:4]2[N:9]([CH2:10][C:11](O)=[O:12])[C:8](=[O:14])[C:7]([NH:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[CH2:23][CH2:22][CH2:21][NH:20][C:19]=4[N:18]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[NH2:28][C@H:29]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C@H:29]([NH:28][C:11](=[O:12])[CH2:10][N:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][CH:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[CH2:23][CH2:22][CH2:21][NH:20][C:19]=3[N:18]=2)[C:8]1=[O:14])[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=1)[CH3:35]
Reactant: O=C(O)Cn1c(C2CC2)ccc(NCc2ccc3c(n2)NCCC3)c1=O
Reactant: CCOC(=O)C[C@H](N)c1cccc(F)c1
Agent: Cl
Product: CCOC(=O)C[C@H](NC(=O)Cn1c(C2CC2)ccc(NCc2ccc3c(n2)NCCC3)c1=O)c1cccc(F)c1

Procedure:
Following the procedure described for the preparation of 16-5, the acid 17-7 was coupled with the amine 17-8 to yield the title compound 17-9.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Li][C:12](C)(C)[CH3:13].C(I)C>C1COCC1>[CH2:12]([C:7]1[S:6][C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[CH:8]=1)[CH3:13]
Reactant: [Li]C(C)(C)C
Reactant: Cc1ccc2sccc2c1
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc2cc(C)ccc2s1

Procedure:
2-ethyl-5-methylbenzo[b]thiophene was prepared in the same manner as described in Example 40A. Reaction of 5-methylbenzo[b]thiophene (3.4 mmoles, 0.50 g), t-BuLi (1.7 m, 5.1 mmoles, 3.0 ml) and ethyl iodide (6.8 mmoles, 0.54 ml) in THF (10 ml) yielded 0.58g (97%) of a light yellow liquid.