Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26](O)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@H:7]2[CH2:31][CH3:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH2:64]([N:71]1[CH2:76][CH2:75][O:74][C@H:73]([CH2:77][NH2:78])[CH2:72]1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:64]([N:71]1[CH2:76][CH2:75][O:74][C@H:73]([CH2:77][NH:78][C:26]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:13]3[N:12]=[CH:11][C:10]4[N:9]([CH3:29])[C:8](=[O:30])[C@@H:7]([CH2:31][CH3:32])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:15]=4[N:14]=3)=[C:25]3[O:24][CH2:23][CH2:22][C:21]=23)=[O:27])[CH2:72]1)[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Reactant: NC[C@@H]1CN(Cc2ccccc2)CCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@@H]4CN(Cc5ccccc5)CCO4)c4c3OCC4)nc2N1C1CCCC1
Yield: 93.9 %

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (276 mg, 0.63 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (202 mg, 0.63 mmol) were dissolved in 20 mL of anhydrous dichloromethane, added with diisopropylethylamine (0.2 mL, 1.4 mmol), [(2R)-4-benzylmorpholin-2-yl]methanamine 15a (130 mg, 0.63 mmol) successively with stirring. The reaction solution was stirred for 3 hours. The resulting solution was added with 10 mL saturated sodium carbonate solution and 10 mL of dichloromethane successively, and seperated. The organic phase was washed with sodium carbonate solution (50 mL×2), water (50 mL) and saturated sodium chloride solution (50 mL) successively, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound N-[[(2R)-4-benzylmorpholin-2-yl]methyl]-7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 15b (370 mg, yield: 94.0%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[C:19]1([CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Reactant: O=C(Cl)CCCc1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NCCC1CCc2ccc(NC(=O)CCCc3ccccc3)c(O)c21
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), 4-phenylbutanoyl chloride (74.1 mg, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (96.8 mg, yield 69%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][CH:10]=2)=O)C.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].C(=O)(O)[O-].[Na+]>>[N:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:25][C:4]=1[C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][CH:10]=2
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]c2ccc(Cl)cc2cc1-c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 6-chloro-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (7-2, 43 mg, 0.17 mmol, 1 equiv) and 1,2-phenylenediamine (37 mg, 0.34 mmol, 2.0 equiv) in polyphosphoric acid (3 mL) was heated at 200° C. for 2.5 h. The hot reaction mixture was poured into ice water (20 mL), and the resulting mixture was allowed to stand until all polyphosphoric acid had dissolved. The acidic suspension was neutralized with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (50 mL). The organic layer were dried over sodium sulfate and concentrated. The residue was suspended in ethyl ether (50 mL) aided by sonication, and the solids were filtered to give 3-(benzoimidazol-2-yl)-6-chloro-quinolin-2-one (7-3) as a yellow solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.66 (br s, 1H), 12.58 (br s, 1H), 9.11 (s, 1H), 8.11 (d, 1H, J=2.2 Hz), 7.73 (m, 1H), 7.66 (m, 1H), 7.65 (dd, 1H, J=8.8, 2.4 Hz), 7.44 (d, 1H, J=8.8 Hz), 7.22 (m, 2H); HRMS (electrospray FT/ICR) calculated for C16H11N3O [M+H]+ 296.0591, found 296.0602.
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([NH:21][C:22]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:29]=2)=[O:23])[CH:13]=1)[CH3:4]>C(O)C>[CH2:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:20]=[CH:19][C:15]([C:16]([O-:18])=[O:17])=[C:14]([NH:21][C:22]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:29]=2)=[O:23])[CH:13]=1)[CH3:4].[Na+:2]
Reactant: CCNc1ccccc1-c1ccc(C(=O)O)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNc1ccccc1-c1ccc(C(=O)[O-])c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethanol (18 mL) and a 1.0 mol/L aqueous solution of sodium hydroxide (1.3 mL) were sequentially added to the obtained 4-(2-(ethylamino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid (0.60 g), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and a 10% aqueous solution of ethanol was added to the obtained residue. The solid substance was collected by filtration to obtain 0.57 g of sodium 4-(2-(ethylamino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a light yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:42]=[CH:43][CH:44]=4)[C:28]([NH:30][C@@H:31]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:32]([OH:34])=[O:33])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:46]>CO>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:42]=[CH:43][CH:44]=4)[C:28]([NH:30][C@@H:31]([CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:32]([O-:34])=[O:33])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:46]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)[O-])c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a solution of (2S)-2-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl)methyl}benzoylamino}-3-phenylpropionic acid (85.4 mg, 0.147 mmol) in MeOH (3 ml) was added 1N sodium hydroxide (0.147 ml, 0.147 mmol) at 5° C . The reaction mixture was stirred at the same temperature for 30 minutes, and evaporated in vacuo. To the residue was added ethyl ether, and the resulting solid was collected by filtration to give sodium (2S)-2-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoylamino}-3-phenylpropionate (84.9 mg, 96%).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]>[Br-].[Zn+2].[Br-].C1(C)C=CC=CC=1>[CH3:8][C@H:7]1[CH2:9][C@@H:10]([OH:11])[C@H:4]([C:2]([CH3:3])=[CH2:1])[CH2:5][CH2:6]1
Reactant: CC(C)=CCCC(C)CC=O
Agent: [Br-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reaction time: 4 h

Procedure:
0.001 mmol zinc bromide is initially introduced into 70 ml toluene under an inert gas. The reaction solution is then temperature-controlled at 85° C. and 0.05 mol citronellal are metered into the reaction solution. The heterogeneous reaction mixture is then stirred at this temperature for 4 h. Thereafter, the reaction mixture is washed with 50 ml 15% strength sodium hydroxide solution and, after washing neutral, the solvent is removed from the reaction mixture under reduced pressure.
Reaction SMILES: [NH3:1].[S:2]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])(O)(=[O:4])=[O:3]>>[S:2]1(=[O:4])(=[O:3])[C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=[O:9])[NH:1]1
Reactant: N
Reactant: O=C(O)c1ccccc1S(=O)(=O)O
Product: O=C1NS(=O)(=O)c2ccccc21

Procedure:
In the third step the reaction of ammonia is reacted with the reaction product produced in the second step. It is possible to react the components by injecting ammonia into the reaction mixture after the second step. Thus, it is preferable to react ammonia and the second step product by mixing an aqueous solution of ammonia with the reaction mixture after the second step. The amount of ammonia employed is preferably in a range of 3.5 - 4.5 mole per mole of the o-sulfobenzoic acid (I) or the alkali metal salt or alkaline earth metal salt thereof. Preferably, a 4 - 28 % of an aqueous solution of ammonia is used. The reaction temperature is usually in the range of 5° - 35° C, and if desired, the reaction is conducted while cooled. After the reaction with ammonia, the ammonium salt of 1.2-benzoisothiazole-3-on-1.1-dioxide (III) is obtained. The desired compound, i.e. 1.2-benzoisothiazole-3-on-1.1-dioxide (III) can be separated by precipitation by treating the solution with a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or the like. In accordance with the process of the invention, the desired 1.2-benzoisothiazole-3-on-1.1-dioxide compound (III) having high purity can be easily produced in substantial industrial efficiency in yields greater than 80 % based on the o-sulfobenzoic acid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:13]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([CH2:50][NH2:51])[CH:43]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH2:31][NH2:32])[CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH2:6]([N:13]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[C:44]([CH2:50][NH:51][S:2]([CH3:1])(=[O:4])=[O:3])[CH:43]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([CH2:31][NH:32][S:2]([CH3:1])(=[O:4])=[O:3])[CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCN(CCCCCCN(CCc2ccc(OC)c(CN)c2)Cc2ccccc2)Cc2ccccc2)cc1CN
Solvent: c1ccncc1
Product: COc1ccc(CCN(CCCCCCN(CCc2ccc(OC)c(CNS(C)(=O)=O)c2)Cc2ccccc2)Cc2ccccc2)cc1CNS(C)(=O)=O
Reaction time: 8 h

Procedure:
Following the procedure of Example 6, 2.5 g. of methanesulfonyl chloride is added to a solution of 6.78 g. (0.01 m.) of N,N'-dibenzyl-N,N'-bis[2-(3-aminomethyl-4-methoxyphenyl)-ethyl]-hexamethylenediamine in 30 ml. of pyridine and the mixture is allowed to stand at room temperature overnight to yield N,N'-dibenzyl-N,N'-bis[2-(3-methanesulfonamidomethyl-4-methoxyphenyl)-ethyl]-hexamethylenediamine. The latter as the dihydrochloride is demethylated and then debenzylated as described in Example 9 to furnish the product N,N'-[2-(4-hydroxy-3-methanesulfonamidomethylphenyl)-ethyl]-hexamethylenediamine dihydrochloride.
Reaction SMILES: [NH2:1][C:2]([CH3:10])([CH3:9])[CH2:3][NH:4][S:5]([CH3:8])(=[O:7])=[O:6].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1.CCN(CC)CC>C1COCC1>[Cl:11][C:12]1[N:17]=[C:16]([NH:1][C:2]([CH3:10])([CH3:9])[CH2:3][NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: CC(C)(N)CNS(C)(=O)=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CNS(C)(=O)=O)Nc1nc(Cl)ncc1Cl
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 48.2 %

Procedure:
N-(2-Amino-2-methyl-propyl)-methanesulfonamide (1.15 g, 6.90 mmol, 1.2 eq.) in THF (20 mL) was cooled to 0° C. and 2,4,5-trichloropyrimidine (1.05 g, 5.75 mmol, 656 μL, 1.0 eq.) was added. The reaction was stirred for 5 minutes and then NEt3 (2.07 mL) was added. After 5 minutes, external cooling was removed and the reaction was heated at 60° C. overnight under a nitrogen atmosphere. The reaction was then partitioned between CH2Cl2 (150 mL) and sat. NaHCO3 (150 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (75 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated under reduced pressure onto basic alumina. Purification by basic alumina chromatography (dry loaded) using a gradient of 0-60% EtOAc/hex as the eluting solvent to obtain N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-2-methyl-propyl]-methanesulfonamide as a white solid (868 mg, 48%). m.p.=156-158° C.; LCMS (m/e) 313 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.04 (s, 1H), 5.57 (bs, 1H), 5.25-5.16 (m, 1H), 3.54 (d, 2H, J=6.8 Hz), 3.00 (s, 3H), 1.53 (s, 6H).
Reaction SMILES: N[C:2]1C=C(C)NC(=O)N=1.FC1C=CC(B(O)O)=CC=1.NC1C=CN(C2C=CC(F)=CC=2)C(=O)N=1.[Cl:35][CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][N:42]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)[C:41](=[O:52])[N:40]2[CH:53]=1>>[Cl:35][CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[C:43]([CH3:2])[N:42]([C:45]3[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=3)[C:41](=[O:52])[N:40]2[CH:53]=1
Reactant: Cc1cc(N)nc(=O)[nH]1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Agent: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Agent: OB(O)c1ccc(F)cc1
Product: Cc1cc2nc(CCl)cn2c(=O)n1-c1ccc(F)cc1

Procedure:
2-Chloromethyl-6-(4-fluoro-phenyl)-7-methyl-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from 4-amino-6-methyl-1H-pyrimidin-2-one and 4-fluorophenylboronic acid using the methods as described above for the preparation of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: I[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[Cl:21][C:22]1[C:27](B(O)O)=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:21][C:22]1[C:27]([C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: OB(O)c1cccnc1Cl
Reactant: O=c1c(I)cc(-c2ccccn2)cn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(-c2cccnc2Cl)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
3-Iodo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one (200 mg) synthesized by the same method as mentioned in Referential Example 6, 130 mg of 2-chloro-3-pyridyl boronic acid and 250 mg of cesium carbonate were suspended in 10 ml of dimethylformamide, 40 mg of tetrakistriphenylphosphine palladium were added and the mixture was stirred at 100° C. in a nitrogen atmosphere for 3 hours. After allowing to cool, the reaction solution was poured into water, the mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo and the residue was purified by a silica gel column chromatography (hexane-ethyl acetate system) to give 143 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:16]/[C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)/[C:9]#[N:10])=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1cccc(F)c1
Reactant: N#CCc1ccc(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(F)c1)c1ccc(Cl)cc1F
Yield: 99.3 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (3.27 g, 19 mmol) was reacted with 3-fluorobenzaldehyde (Aldrich) (2.87 g, 23 mmol), methanolic solution (25 wt %) of sodium methoxide (4.83 mL, 21 mmol) in methanol (90 mL) at 50° C. for 3 h to give (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-fluoro-phenyl)-acrylonitrile as a white powder (5.2 g, 98%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[CH2:5][CH:6]([C:12]([O:14]CC)=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[OH-].[K+:21]>C(O)C>[CH2:18]([O:17][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O-:14])=[O:13])[CH3:19].[K+:21]
Reactant: CCOC(=O)C(CC(OCC)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CC(OCC)OCC)C(=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To 15 L of dehydrated ethanol solution containing 2.48 Kg (purity: 95.1%., 8.54 mol) of diethyl 2-(2,2-diethoxyethyl)malonate was added 564 g (purity: 85%, 8.54 mol) of potassium hydroxide under argon gas atmosphere, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 2 L of toluene was added to the obtained concentrate and the mixture was concentrated under reduced pressure. This operation of azeotropic dehydration with toluene was repeated three times to obtain 2.45 Kg of the title compound as a yellowish high-viscous oil substantially quantitatively.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C1C(=O)N([I:18])C(=O)C1>CC#N.O>[I:18][C:4]1[NH:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([F:10])([F:9])[F:8]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1nc(C(F)(F)F)c[nH]1
Solvent: O
Solvent: CC#N
Product: Cc1nc(C(F)(F)F)c(I)[nH]1
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 2-methyl-4-(trifluoromethyl)-1H-imidazole (compound 16.2, 1.72 g, 11.46 mmol) in CH3CN (25 mL). NIS (3.87 g, 17.20 mmol) was added to the reaction. The reaction mixture was stirred overnight at 85. The reaction mixture diluted with 50 mL of H2O and extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with 2×20 mL of Na2S2O3(sat.) and 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in 4.32 g (crude) of the title compound as a brown oil.
Reaction SMILES: [Si:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>>[Si:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[CH2:10][CH2:9]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)[Si](C)(C)N1CCNCC1
Product: COC(=O)CCN1CCN([Si](C)(C)C(C)(C)C)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 160.3 g (0.8 mol) of 1-t-butyldimethylsilylpiperazine (Synthesis Example 1) and heated at 70° C. Once the internal temperature became steady, 75.8 g (0.88 mol) of methyl acrylate was added dropwise over 2 hours. Stirring was continued for 4 hours at the temperature. On distillation of the reaction solution, 219.9 g of a fraction having a boiling point of 135-137° C./0.4 kPa was collected.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([O:9][CH:10]([C:12]3[N:13]=[N:14][N:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=4)[N:16]=3)[CH3:11])=[N:7][N:6]=[C:5]2[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:3][CH2:2]1.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH:1]1([N:4]2[C:5]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:6][N:7]=[C:8]2[O:9][CH:10]([C:12]2[N:13]=[N:14][N:15]([C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[C:30]#[N:31])[N:16]=2)[CH3:11])[CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: CC(Oc1nnc(-c2ccncc2)n1C1CC1)c1nnn(-c2cccc(I)c2)n1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(Oc1nnc(-c2ccncc2)n1C1CC1)c1nnn(-c2cccc(C#N)c2)n1

Procedure:
The title compound is prepared from 4-(4-cyclopropyl-5-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethoxy}-4H-[1,2,4]triazol-3-yl)-pyridine (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH3:20][N:21]1[C:25]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[CH:35])[CH:29]=2)=[CH:24][C:23]([CH3:37])=[N:22]1>>[CH3:20][N:21]1[C:25]([NH:26][C:27]([C:28]2[CH:29]=[C:30]([C:34]#[C:35][C:2]3[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=3)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH:31]=[CH:32][CH:33]=2)=[O:36])=[CH:24][C:23]([CH3:37])=[N:22]1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1cccc(C(=O)Nc2cc(C)nn2C)c1
Product: Cc1cc(NC(=O)c2cccc(C#Cc3cncc(C(=O)N=[S@@](C)(=O)c4ccccc4)c3)c2)n(C)n1
Yield: 60.6 %

Procedure:
In a manner similar to that described in Example 460 (step 2), (S)-5-bromo-N-[methyl(oxido)phenyl--sulfanylidene]nicotinamide (0.141 g, 0.418 mmol) and N-(1,3-dimethyl-1H-pyrazol-5-yl)-3-ethynylbenzamide (0.1 g, 0.418 mmol) were reacted to give the title compound (0.126 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C@H:9]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:11]([CH2:39][O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:10]2)=[CH:5][C:6]=1[CH2:7]O.P(Br)(Br)[Br:49].N1C=CC=CC=1>CCOCC>[CH2:32]([O:31][C@H:12]1[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:9]([C:4]2[S:3][C:2]([Cl:1])=[C:6]([CH2:7][Br:49])[CH:5]=2)[O:10][C@@H:11]1[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: CCOCC
Product: Clc1sc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 193.9 %

Procedure:
To a solution of alcohol 37 (3.86 g, 5.75 mmol) in ether (50 mL) were added phosphorus tribromide (0.3 mL, 2.88 mmol) and catalytic amount of pyridine at 0° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 2 hours. The mixture was extracted with EtOAc/H2O (100 mL/150 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield the title compound 38 (4.1 g, 97%), which was carried on to the next step without further purification.