Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:42](=[O:44])[CH3:43])=[CH:21][C:20]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
The 3-(4-amino-2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (5.56 g, 11.3 mmol) was dissolved in 100 mL methylene chloride, and triethylamine (2.8 mL) is added. One equivalent of acetyl chloride was added and stirred at room temperature. Additional portions of acetyl chloride were added approximately every 30 min until the starting material was consumed. (A total of 1.5 equivalents of acetyl chloride was used over about 2 hours.) The solvent was removed and replaced with ethyl acetate. The organic solution was washed twice with 5% cold HCl, then once with water, once with saturated potassium carbonate, then once with brine. The solution was dried over anhydrous magnesium sulfate, filtered and the solvent removed. The product was chromatographed with 30% chloroform/ethyl acetate, to yield 5.16 g (85%) of 3-(4-acetylamino-2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic tert-butyl ester acid as a yellow foam. 1H NMR (CDCl3) 7.73 (1H, d, J=8.42 Hz), 7.6-7.5 (4H, m), 7.5-7.3 (3H, m), 6.9 (1H, d, J=8.6 Hz), 5.85 (1H, d, J=9.52), 5.3-5.1 (2H, m), 4.8-4.6 (1H, m), 3.56 (3H, s), 2.92 (3H, s), 2.7-2.38 (2H, m), 2.14 (3H, s), 1.40 (9H, s).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)=[CH2:2].[Br:13][C:14]1[N:19]2[C:20](=[O:23])[NH:21][N:22]=[C:18]2[CH:17]=[CH:16][CH:15]=1.[OH-].[K+]>CN1C(=O)CCC1.C(Cl)Cl>[Br:13][C:14]1[N:19]2[C:20](=[O:23])[N:21]([CH2:2][CH2:1][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)[N:22]=[C:18]2[CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]nc2cccc(Br)n12
Reactant: C=Cc1ccc2ccccc2n1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: O=c1n(CCc2ccc3ccccc3n2)nc2cccc(Br)n12
Temperature: 130 °C
Yield: 9.3 %

Procedure:
2-Vinylquinoline (1-2) (218 mg, 1.40 mmol) and triazolopyridinone 2-3 (250 mg, 1.17 mmol) were placed in a microwave vial and dissolved in NMP (2 mL). To the mixture was added catalytic powdered KOH (10 mg, 0.18 mmol), and the vial was capped and heated at 130° C. under microwave irradiation for 20 min. After cooling, the mixture was diluted with CH2Cl2 (100 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash column chromatography (40 g cartridge), eluting with 25-100% EtOAc/hexanes. The fractions containing the desired product (2-4) were pooled, and after solvent removal in vacuo, 40 mg (9%) of a white solid were obtained. 1H NMR (400 MHz, CHCl3-d): δ 8.08 (d, J=8.4 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.69 (m, 1H), 7.50 (app t, J=7.6 Hz, 1H) 7.32 (d, J=8.8 Hz, 1H), 7.00 (d, J=11.6 Hz, 1H), 6.81 (dd, J=9.6, 7.2 Hz, 1H), 6.57 (d, J=7.2 Hz, 1H), 4.51 (t, J=7.2 Hz, 2H), 3.52 (t, J=7.2 Hz, 2H). HRMS (ES) 369.0346 (M+H) found, 369.0349 required.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]12[CH2:32][C:29]([CH2:33]O)([CH2:30][CH2:31]1)[CH2:28][CH2:27][CH2:26]2.C([Li])CCC.CCCCCC>O1CCCC1>[N:25]12[CH2:32][C:29]([CH2:33][O:11][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:12])([CH2:30][CH2:31]1)[CH2:28][CH2:27][CH2:26]2
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: OCC12CCCN(CC1)C2
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(OCC12CCCN(CC1)C2)c1c[nH]c2ccccc12
Reaction time: 1 h
Yield: 52.4 %

Procedure:
A solution of indole-3-carboxylic acid (1.45 g, 9 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.53 g, 9.4 mmol), stirred for one hour, and degassed with a stream of nitrogen over 10 minutes. Meanwhile, a cooled (-10° C.) solution of 1-azabicyclo[3.2.1]octane-5-methanol (1.42 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated (via syringe) with 2.5N n-butyllithium/hexane (9.7 mmol), stirred for 30 minutes, concentrated in vacuo, and taken up in anhydrous tetrahydrofuran (10 mL) under nitrogen. The acid 1,1'-carbonyldiimidazole adduct (suspension) was transferred into this solution, and the mixture was stirred overnight (18 hours) and concentrated in vacuo. The residue was partitioned between methylene chloride (100 mL) containing a little 2-propanol and saturated aqueous sodium carbonate (50 mL), and the organic layer was separated. The aqueous solution was extracted with methylene chloride (2×50 mL), and the combined organic solution was dried (Na2SO4), concentrated in vacuo, and filtered through alumina (eluted with 5% methanol/methylene chloride). The concentrated filtrate was recrystallized from acetonitrile (2 crops) to afford 1.34 g (52%) of colorless solid; mp 183.5°-185.0° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:24]=1.CON(C)[C:28](=[O:30])[CH3:29].O>O1CCCC1>[C:28]([C:7]1[CH:8]=[CH:9][C:10]2[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:24]=1)(=[O:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc2c(c1)CN(C(=O)OC(C)(C)C)CCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
n-Butyllithium (2.5 Min hexane, 2.31 mL, 5.8 mmol) was added to a solution of 1,1-dimethylethyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.56 g, 4.76 mmol) in tetrahydrofuran (20 mL) and the resulting mixture was stirred at −78° C. for one hour. A solution of N-methoxy-N-methylacetamide (0.97 g, 9.4 mmol) in tetrahydrofuran (5 mL) was added to the reaction mixture dropwise then warmed to room temperature and stirred for an additional hour. Water (50 mL) was added and the resulting mixture was extracted with ethyl acetate (3×40 mL). The combined organic extract was washed with water, then brine solution (80 mL each), dried over sodium sulfate, filtered, concentrated to give 1,1-dimethylethyl 7-acetyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.34 g, 97% yield); MS (EI) for C16H21NO4: 292 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.[NH2:12][C:13]([NH2:15])=[S:14].C>O.C(O)C>[NH2:15][C:13]1[S:14][CH:2]=[C:3]([C:5](=[O:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:12]=1
Reactant: CCOC(=O)C(=O)C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
195 g of ethyl bromoacetylglyoxylate are added dropwise to a solution of 66 g of thiourea in 450 ml of water and 450 ml of ethanol at 5° and after the addition has ended, the mixture is stirred at room temperature for 30 minutes and at 50° for 30 minutes and, after adding active charcoal, the resulting reaction mixture is then filtered. The filtrate is brought to pH 7 by adding sodium bicarbonate solution, whereupon ethyl 2-amino-thiazol-4-ylglyoxylate crystallizes out in crystals of melting point 147°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13](O)[CH2:14][CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[O:7]1[CH2:13][CH2:14][CH2:15][O:16][CH:6]1[C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: OCCCO
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(C2OCCCO2)ccc1O
Yield: 85.3 %

Procedure:
A mixture of 8 g of 4-hydroxy-3-nitrobenzaldehyde, 16 g of 1,3-propanediol, a catalytic amount of pyridinium p-toluenesulfonic acid and 250 ml of toluene was azeotropically dehydrated with heating under reflux. The reaction mixture was cooled, washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was recrystallized from toluene-n-hexane to obtain 9.2 g of 4-(1,3-dioxan-2-yl)-2-nitrophenol.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13])[NH2:2].O=[C:17]([CH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(OCC)C>C(O)(=O)C>[CH2:21]([O:20][C:18]([C:17]1[C:23]2[CH2:27][CH2:26][CH2:25][C:24]=2[N:1]([C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=2[C:12]([F:13])([F:14])[F:15])[N:2]=1)=[O:19])[CH3:22]
Reactant: NNc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)C(=O)C1CCCC1=O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1nn(-c2ccc(C(=O)O)cc2C(F)(F)F)c2c1CCC2

Procedure:
4.0 g (18.2 mmol) of 4-hydrazino-3-trifluoromethylbenzoic acid is dissolved in 20 mL of glacial acetic acid, combined with 3.3 g (18.2 mmol) of ethyl oxo-(2-oxocyclopentyl)acetate, and refluxed for 2 hours under a nitrogen atmosphere. After cooling, it is stirred with diethyl ether and the precipitate is suction filtered. Yield: 2.9 g (43%).
Reaction SMILES: [S:1]([C:4]1[NH:5][CH:6]=[C:7]([C:9](=[O:25])[C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)[CH:8]=1)C#N.[OH-].[K+].Cl>CO.O>[SH:1][C:4]1[NH:5][CH:6]=[C:7]([C:9](=[O:25])[C:10]2[CH:15]=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)[CH:8]=1
Reactant: CC(C)(C)c1cc(C(=O)c2c[nH]c(SC#N)c2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(C(=O)c2c[nH]c(S)c2)cc(C(C)(C)C)c1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
2-Thiocyano-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (10.0 g) was dissolved in methanol (80 ml) and cooled to -10° C. Potassium hydroxide (3.2 g) in methanol (20.0 ml) and water (20.0 ml) was added at such a rate that the temperature did not exceed 0° C. After stirring for 1 hour at the same temperature, one half of the resulting solution was converted to the title compound by acidification with 20% HCl. The product was filtered, dissolved in methylene chlorede, dried and the solvent evaporated to dryness. The residue was chromatographed on silica gel (500 g) and the product eluted with hexane:ethyl acetate (1:1) to yield 1.56 g of the purified title compound, 2-mercapto-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole, after recrystalization from ethyl acetate-hexane [mp 213°-215° C.; 1H nmr: 1.46s (18H), 5.46s (OH), 6.93m (1H), 7.46m (1H), 7.76s (2H), 7.91 (NH); MS m/e 331 (M+)].
Reaction SMILES: [C:1]([O:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]([OH:21])([CH3:20])[CH3:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)C.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28].S(=O)(=O)(O)O>N1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][C:10]([C:18]([O:21][C:26](=[O:30])[C:27]([CH3:29])=[CH2:28])([CH3:20])[CH3:19])([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)C12CC3CC(C1)CC(C(C)(C)O)(C3)C2
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: C=C(C)C(=O)OC(C)(C)C12CC3CC(CC(C(=O)OC(C)(C)C)(C3)C1)C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
In a flask equipped with a stirrer, a thermometer, a dropping funnel, and a Dimroth condenser, 50 g of 3-(1-hydroxy-1-methylethyl)adamantane-1-carboxylic acid t-butyl ester, 200 mL of dichloroethane, and 80 g of pyridine were put, and 71.7 g of methacrylic acid chloride was dropped thereto at 60° C. over 2 hours. After the dropping was completed, the resultant substance was stirred at 60° C. for another 8 hours. Then, the resultant substance was neutralized with 320 g of 10% aqueous solution of sulfuric acid while the flask was ice-cooled. The reaction solution was separated into an organic layer and a water layer. The organic layer was washed twice with 500 mL of ion exchanged water, and then was concentrated. The obtained raw product was purified by silica gel column chromatography. As a result, 25 g of 3-(1-methacryloyloxy-1-methylethyl)adamantane-1-carboxylic acid t-butyl ester was obtained as a white solid. White solid 2, which was obtained, was identified with 1H-NMR, 13C-NMR and IR (see FIGS. 2, 3 and 4).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)O)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
A 2 liter three necked flask equipped with a mechanical stirrer is charged with racemic 2-(4-nitrophenyl)propionic acid (40.55 grams, 0.208 mol) and ethyl acetate (1600.0 mL). To this solution at 30° C. was then added S(−)-α-methylbenzylamine (13.49 mL, 0.104 mol) all at once. Reaction exothermed to 38° C. with massive formation of a white precipitate in less than 15.0 minutes. The reaction mixture was then heated at ethyl acetate reflux for 10.0 minutes and allowed to equilibrate to room temperature with stirring overnight. The precipitate was then filtered to give a semi-dried white product, (2R)-2-(4-nitrophenyl)propanoic acid, S(−)-α-methylbenzylamine (wet cake=25.43 grams). Reslurried the wet cake in ethyl acetate (1600.0 mL) at reflux for 10.0 minutes, stirred to room temperature overnight, and filtered the white precipitate, (2R)-2-(4-nitrophenyl)propanoic acid, S(−)-α-methylbenzylamine, (wet cake=21.02 grams, ee=91.4%). Repeated the later again and dried the precipitate at 40° C. in a vacuum oven for 24.0 hours, (2R)-2-(4-nitrophenyl)propanoic acid, S(−)-α-methylbenzylamine, (18.02 g, 55%, ee=95%); 1H nmr (DMSO, 300 MHz) δ 1.31-1.32 (d, 3H), 1.37-1.38 (d, 3H), 3.56-3.60 (m, 1H), 4.18-4.20 (m, 1H), 7.27-7.53 (aromatic, 7H), 8.09-8.12 (aromatic, 2H);
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH2:25][CH2:26][CH2:27]I)[CH:13]=3)=[CH:11][C:3]=12.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>ClCCl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH2:25][CH2:26][CH2:27][N:39]4[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]4)[CH:13]=3)=[CH:11][C:3]=12
Reactant: C1CCNCC1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCI
Solvent: ClCCl
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCN1CCCCC1
Yield: 62.3 %

Procedure:
a solution of 0.3 g of 3-[4-chloro-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1-(3-iodopropyl)-5,6-dimethoxy-1H-pyrrolo[3,2-b]pyridine and 0.382 g of piperidine in 40 cm3 of dichloromethane is refluxed for about 6 hours. After diluting the reaction mixture with 100 cm3 of dichloromethane, the solution is washed with three times 40 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/methanol (98/2 by volume)], 0.175 g of 3-[4-chloro-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-(3-piperidin-1-ylpropyl)-1H-pyrrolo[3,2-b]pyridine is thus obtained as a resin with the following characteristics:
Reaction SMILES: [F:1][C:2]([F:78])([O:63][C:64]1[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:72][CH2:73][C:74]([F:77])([F:76])[F:75])=[CH:66][CH:65]=1)[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][C:25]=2[CH2:33][O:34][C:35](=[O:62])/[CH:36]=[CH:37]/[C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:61])([F:60])[O:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][C:56]([F:59])([F:58])[F:57])=[CH:48][CH:47]=3)=[CH:40][CH:39]=2)=[O:12])=[CH:5][CH:4]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:78])([O:63][C:64]1[CH:69]=[CH:68][C:67]([O:70][CH2:71][CH2:72][CH2:73][C:74]([F:76])([F:77])[F:75])=[CH:66][CH:65]=1)[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][C:25]=2[CH2:33][O:34][C:35](=[O:62])/[CH:36]=[CH:37]/[C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:61])([F:60])[O:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54][CH2:55][C:56]([F:57])([F:58])[F:59])=[CH:48][CH:47]=3)=[CH:42][CH:43]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1COC(=O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccc(N)cc2COC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)c(COC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 87 %

Procedure:
9.22 g (8.38 mmol) of [4,4′-dinitro-2′-({[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)-phenoxy]-methyl}phenyl)prop-2-enoyl]oxy}methyl)-1,1′-biphenyl-2-yl]methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 400 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yielded 7.59 g of [4,4′-diamino-2′-({[(2E)-3-(4-{difluoro[4-(4,4,4-tri-fluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoyl]oxy}methyl)-1,1′-biphenyl-2-yl]methyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[C:9]([CH3:17])[N:8]=1.[CH:19]1([C:22]2[C:23]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:24][CH:25]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[C:23]([N:31]3[CH2:32][CH2:33][N:34]([C:11]([C:10]4[C:9]([CH3:17])=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:16][CH:15]=4)=[O:13])[CH2:35][CH2:36]3)=[N:24][CH:25]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[CH:27]=2)[CH2:20][CH2:21]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)nc1C
Product: Cc1nc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 66.4 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylnicotinate (300 mg) described in Preparation Example 37 and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (297 mg) described in Preparation Example 88 and by the reaction and treatment in the same manner as in Example 109, the title compound (355 mg) was obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][N:13]1[C:22](=[O:23])[N:16]2[CH:17]=[CH:18][CH:19]=[C:20](Br)[C:15]2=[N:14]1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][N:13]1[C:22](=[O:23])[N:16]2[CH:17]=[CH:18][CH:19]=[C:20]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[C:15]2=[N:14]1
Reactant: OB(O)c1ccncc1
Reactant: O=c1n(CCc2ccc3ncccc3n2)nc2c(Br)cccn12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1n(CCc2ccc3ncccc3n2)nc2c(-c3ccncc3)cccn12
Temperature: 100 °C
Yield: 23 %

Procedure:
Triazolopyridinone 10-3 (22 mg, 0.059 mmol) and pyridin-4-ylboronic acid (11 mg, 0.089 mmol) were placed in a microwave vial and dissolved in dioxane (1 mL). To the mixture was added 1 M aq. Cs2CO3 solution (0.12 mL, 0.12 mmol). The mixture was then sparged with N2 gas for 3 min, and bis(tri-tert-butylphosphine)palladium (3.0 mg, 0.006 mmol) was added. The vial was capped and heated at 100° C. under microwave irradiation for 20 min. After cooling, the reaction mixture was diluted with EtOAc (30 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (12 g cartridge), eluting with 0-15% MeOH/CH2Cl2. The fractions containing the desired product (10-4) were pooled, and after solvent removal in vacuo, 5.0 mg (23%) of a semisolid were obtained. 1H NMR (300 MHz, CHCl3-d): δ 8.95 (dd, J=4.2, 1.6 Hz, 1H), 8.63 (dd, J=4.8, 1.5 Hz, 2H), 8.37-8.31 (m, 2H), 7.84 (dd, J=6.9, 1.2 Hz, 1H), 7.71 (dd, J=4.8, 1.8 Hz, 2H), 7.63 (dd, J=8.7, 4.2 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.39 (dd, J=6.9, 1.2 Hz, 1H), 6.64 (t, J=6.9 Hz, 1H), 4.65 (t, J=6.9 Hz, 2H), 3.60 (t, J=6.9 Hz, 2H). HRMS (ES) 369.1443 found (M+H), 369.1461 required.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1CCCC1=O>[C:12]([NH:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNC(=O)c1cccc(Br)c1
Solvent: CN1CCCC1=O
Product: O=C(NNC(=O)c1cccc(Br)c1)c1ccccc1
Yield: 96 %

Procedure:
Next, 5.0 grams (23 mmol) of the 3-bromobenzoylhydrazine obtained in (i) were placed into a 300 mL, three-neck flask, 10 mL of N-methyl-2-pyrrolidone was added thereto, and the mixture was stirred. A mixed solution of 10 mL of N-methyl-2-pyrrolidone and 3.2 mL (28 mmol) of benzoyl chloride were dripped into this mixture through a 50 mL dropping funnel. After completion of the dripping, the mixture was heated and stirred at 80° C. for 3 hours, and the contents of the flask were reacted together. After the reaction was completed, a solid was precipitated out with the addition of water to the reaction solution. A solid was obtained by suction filtration of the precipitate solid. The obtained solid was washed with approximately 1 L of water and removed by suction filtration. After the suction-filtered solid was washed with methanol and a solid was removed by suction filtration, 7.1 grams of a white-colored solid, which was the objective of the synthesis process, were obtained at a yield of 96%.