Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:27]4[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CC1CN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCN1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (910 mg), 2-methylpiperazine (320 mg, and pyridine (10 ml) was stirred at 80° C. for 1 hour. After evaporating the reaction mixture under reduced pressure, the residue was dissolved in dilute aqueous ammonia and treated with activated carbon. The filtrate was evaporated under reduced pressure and adjusted to pH 7-8. The resulting crystals were collected by filtration, washed with water, and dried to give 1-cyclopropyl-5,6,8-trifluoro-7-(3-methyl 1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (810 mg), m.p. 235°-237° C.
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)[CH:4]=1)=[CH2:2].[C:13]([C:18]([O:20][CH3:21])=[O:19])#[C:14][C:15]([O-:17])=[O:16].[N+]([C:25]1C=CC=CC=1)([O-])=O>>[CH:1]1[C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[C:13]([C:18]([O:20][CH3:21])=[O:19])=[C:14]([C:15]([O:17][CH3:25])=[O:16])[CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: C=Cc1ccc2ccccc2c1
Reactant: COC(=O)C#CC(=O)[O-]
Product: COC(=O)c1ccc2ccc3ccccc3c2c1C(=O)OC

Procedure:
A solution of 65 mmol of 2-vinylnaphthalene and 68 mmol of methyl acetylene-dicarboxylate in 200 ml of nitrobenzene is maintained at reflux for 14 hours. After distillation of the solvent, the reaction medium is chromatographed on silica (eluent: CH2Cl2) in order to obtain the expected product.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH3:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=O)[CH2:8][CH2:7]1>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([CH3:5])[CH2:7][CH2:8]1
Reactant: CON
Reactant: CN1CCC(=O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCN(C)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxylamine hydrochloride (0.88 g, 10.6 mmol) was added to a solution of Example 17A (1.55 g, 9.6 mmol) in pyridine (20 mL) and the mixture stirred overnight at ambient temperature. The mixture was concentrated under reduced pressure and ethyl acetate (200 mL) was added. The organic layer was washed twice with water (200 mL) and brine, dried over sodium sulfate, filtered, and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 0-20% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.76 (t, J=6.61 Hz, 2H), 2.83 (s, 3H), 3.11 (t, J=6.61 Hz, 2H), 3.87 (s, 3H), 6.69 (t, J=7.46 Hz, 1H), 6.75 (d, J=8.48 Hz, 1H), 7.22 (td, J=7.80, 1.70 Hz, 1H), 7.73 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z 191.07 (M+H)+.
Reaction SMILES: P(=O)([O-])[O-].[C:5]([O:9][C:10](=[O:22])[NH:11][C:12]1([CH:20]=O)[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6].[C:23]([O-:26])([O-])=O.[K+].[K+].[CH2:29]1[CH2:33]O[CH2:31][CH2:30]1>CN(C=O)C>[C:5]([O:9][C:10](=[O:22])[NH:11][C:12]1([CH:20]=[CH:31][C:30]2[CH:7]=[CH:5][C:6]([C:23](=[O:26])[CH2:33][CH2:29][CH2:30][CH2:31][CH2:13][CH2:12][CH3:17])=[CH:33][CH:29]=2)[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)NC1(C=O)COC(C)(C)OC1
Reactant: O=C([O-])[O-]
Agent: O=[PH]([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)c1ccc(C=CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Temperature: 72.5 °C

Procedure:
A mixture of the Wittig reagent (23, X═O) or the phosphonate (0.3 mmol), aldehyde (24) (0.33 mmol), and K2CO3 (0.9 mmol) in a mixture of THF (3 ml) and DMF (1 ml) was heated at 70-75° C. under TLC and HPLC monitoring. After completion of the reaction, THF was evaporated and the reaction mixture was quenched with water and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. After purification, the title compound (26) was recovered as white solid with 72% yield, mp 82-83° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26]
Reactant: Fc1ccc(NCc2cccnc2)c(F)c1
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N(Cc1cccnc1)c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
A 3.3 g. portion of 3-(2,4-difluorophenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and 2.8 g. of potassium carbonate and 3.6 g. of dimethylsulfamoyl chloride were added. The mixture was stirred at ambient temperature for several days, and was then stirred under reflux for 4 hours. The mixture was then cooled, and extracted with 20 ml. of aqueous sodium bicarbonate and with 20 ml. of water, and was dried and evaporated to an oil. The oil was dissolved in dichloromethane and chromatographed over silica gel, eluting with 9:1 dichloromethane:ethyl acetate to obtain 2.1 g. of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23]([O:25]C)=O.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:29]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cl
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cl
Yield: 38 %

Procedure:
A solution of the 9-[(2-chlorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (238 mg, 0.43 mM) in 20 mL THF and 25 mL concentrated aqueous ammonium hydroxide was sonicated for 20 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 86.9 mg (38%) of the 9-[(2-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.7 (m, 1H), 7.55 (d, 1H, J=8 Hz), 7.45 (m, 2H), 7.3 (m, 2H), 7.15 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.2 (d, 1H, J=8 Hz), 5.75 (s, 2H). IR (CHCl3, cm−1) 3500, 3400, 3200 (br), 1649, 1597, 1585, 1446, 1431, 1331, and 1269. MS (ES) m/e 349, 351, 353.
Reaction SMILES: C(O)=O.CC(C)(C)C([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[N:10]=1)=O.[ClH:32]>CO>[ClH:32].[ClH:32].[ClH:32].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)[N:10]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2cccc(NC(=O)C(C)(C)C)n2)CC1
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: Nc1cccc(CN2CCC(N)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirred solution of 2-(trimethylacetylamino)-6-[(4-t-butoxycarbonylamino-1-piperidinyl)methyl]pyridine formic acid salt (0.74 g, 3.0 mmol) in methanol (6 mL) was added 6 N HCl (2 mL) at room temperature. The resulting mixture was heated to reflux for 10 h. Then, the reaction was cooled to room temperature and concentrated under rotary evaporator. After azeotropic removal of water with 1-propanol twice (20 mL each), the resulting solid was treated with methanol (5 mL). After being stirred for 1 h in methanol, ethanol (12 mL) was added slowly and stirred for additional 1 h. After filtration, drying of the resulting crystalline solid gave the desired title compound (491 mg, 80% yield, 98 A % purity).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:31]#[N:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[C:31]([C:30]1[CH:33]=[CH:34][C:35]([CH3:36])=[C:28]([NH:27][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([NH:17][C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)=[CH:19][CH:20]=2)[CH:29]=1)#[N:32]
Reactant: Cc1ccc(C#N)cc1N
Reactant: O=C(O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C#N)cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 80 °C
Yield: 64.6 %

Procedure:
To a stirred mixture of 4-(4-phenylquinazolin-2-ylamino)benzoic acid (1.37 g, 4.02 mmol), 3-amino-4-methylbenzonitrile (529 mg, 4.01 mmol), and Hunig's base (2.1 mL, 12 mmol) in dimethylformamide (10 mL) was added HATU (3.04 g, 8.00 mmol). The stirred mixture was heated to 80° C. overnight, then cooled to rt. The reaction was diluted with ethyl acetate and extracted with water. The organic layer was washed with saturated sodium bicarbonate and concentrated on a rotary evaporator. The residue was sonicated with acetonitrile and filtered to give a light yellow solid, which was again washed with water, acetonitrile, and dried under reduced pressure to give N-(5-cyano-2-methylphenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (1.18 g, 65%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.36 (s, 1H), 9.87 (s, 1H), 8.19 (d, 2H), 8.00 (d, 2H), 7.91-7.78 (m, 6H), 7.66-7.62 (m, 4H), 7.51 (d, 1H), 7.42 (ddd, 1H), 2.36 (s, 3H). MS (EI) for C29H21N5O: 456.1 (MH+).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[C:4]([OH:12])[CH:3]=1.[F:13][C:14]1[C:21]([F:22])=[C:20]([C:23]([F:26])([F:25])[F:24])[C:19]([F:27])=[C:18]([F:28])[C:15]=1[CH2:16]Br.C[N:30](C=O)C>>[OH:12][C:4]1[CH:3]=[CH:2][C:7]([NH:30][CH2:16][C:15]2[C:14]([F:13])=[C:21]([F:22])[C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([F:27])[C:18]=2[F:28])=[CH:6][C:5]=1[S:8]([OH:11])(=[O:10])=[O:9]
Reactant: Nc1ccc(S(=O)(=O)O)c(O)c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Reactant: CN(C)C=O
Product: O=S(=O)(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1O
Yield: 28 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 4-amino-2-hydroxybenzene sulfonic acid (1.00 g, 5.30 mmole), DMF (10 ml), TEA (1.0 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (0.88 g, 5.30 mmole), 0.61 g (28.0% yield) of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzene sulfonic acid was obtained as a yellow solid.
Reaction SMILES: [C:1]([N:4]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]([OH:26])=O)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[NH2:27][C@@H:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([NH2:31])=[O:30].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(N(CC)CC)C>[NH3:4].[C:1]([N:4]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]2[C:24]([NH:27][C@@H:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([NH2:31])=[O:30])=[O:26])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1ccc([C@@H]2CCCC[C@H]2C(=O)O)cc1)c1ccccn1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1ccc([C@@H]2CCCC[C@H]2C(=O)N[C@H](C(N)=O)c2ccccc2)cc1)c1ccccn1
Product: N
Temperature: 25 °C
Reaction time: 48 h
Yield: 128.9 %

Procedure:
(1R,2R)-2-(4-{[Acetyl(2-pyridinyl)amino]methyl}phenyl)cyclohexanecarboxylic acid (0.44 g) is suspended in DMF (15 ml), (2S)-2-amino-2-phenylethanamide (0.37 g), triethylamine (0.68 ml), 1-hydroxybenzotriazole (0.18 g) and EDC hydrochloride (0.27 g) are admixed and the mixture is stirred at room temperature for 2 days. The suspension is diluted with water and extracted with dichloromethane and the organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. Chromatography (silica gel, dichloromethane:methanol:saturated aqueous ammonia solution=50:1:0.05 to 20:1:0.05 gives (1R,2R)-2-(4-{[acetyl(2-pyridinyl)amino]methyl}phenyl)-N-[(1S)-2-amino-2-oxo-1-phenylethyl]cyclohexanecarboxamide (0.39 g) as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[F:13][C:14]([F:19])([F:18])[C:15](Cl)=[O:16].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[NH2:25]>>[CH3:32][O:31][C:27]1[CH:26]=[C:24]([NH:25][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([NH:1][C:15](=[O:16])[C:14]([F:19])([F:18])[F:13])[CH:3]=2)[CH:23]=[C:22]([O:21][CH3:20])[C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: O=C(Cl)C(F)(F)F
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1ccc(C(=O)Nc2cc(OC)c(OC)c(OC)c2)cc1NC(=O)C(F)(F)F

Procedure:
Compound 263 is synthesized following a similar method as in Example 1 and using 3-amino-4-methoxy benzoic acid, trifluoroacetyl chloride and 3,4,5-trimethoxyaniline as materials. Total yield of the two steps: 50%.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH3:40])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)=[O:16])[C@H:9]([O:11][CH3:12])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>C(Cl)Cl>[NH2:7][C@@H:8]([C@H:9]([O:11][CH3:12])[CH3:10])[CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][CH3:40])=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)=[O:16]
Reactant: CCCc1ccc(-c2ccc(N(C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OC)C(=O)[C@@H]3C[C@H]3c3cnccn3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1ccc(-c2ccc(N(C[C@@H](N)[C@@H](C)OC)C(=O)[C@@H]3C[C@H]3c3cnccn3)cc2)cc1

Procedure:
A solution of ((1R,2R)-2-methoxy-1-{[(4′-propyl-biphenyl-4-yl)-(trans-2-pyrazin-2-yl-cyclopropanecarbonyl)-amino]-methyl}-propyl)-carbamic acid tert butyl ester (55 mg) in DCM (1 mL) was treated with TFA/DCM (2/2 mL) for 1 h. The mixture was concentrated to give the titled compound as di-TFA salts (65.5 mg). 1H NMR (400 MHz, MeOD) δ ppm 8.5 (d, J=5.3 Hz, 1H), 8.1-8.2 (m, 2H), 7.5 (t, J=8.0 Hz, 2H), 7.4 (dd, J=8.3, 4.5 Hz, 2H), 7.3 (dd, J=8.2, 3.4 Hz, 2H), 7.2 (dd, J=8.1, 1.5 Hz, 2H), 4.2 (ddd, J=14.8, 8.5, 8.3 Hz, 1H), 3.8 (ddd, J=14.7, 7.9, 4.2 Hz, 1H), 3.4 (qd, J=6.1, 5.9 Hz, 1H), 3.2 (s, 3H), 3.2-3.2 (m, 1H), 2.6 (dddd, J=14.8, 6.1, 5.7, 4.2 Hz, 1H), 2.5 (t, J=7.6 Hz, 2H), 2.0 (q, J=8.3 Hz, 1H), 1.7 (dddd, J=8.9, 7.1, 5.6, 3.7 Hz, 1H), 1.6 (d, J=7.6 Hz, 2H), 1.3-1.4 (m, J=8.5, 5.8, 2.9, 2.9 Hz, 1H), 1.1 (dd, J=6.1, 3.0 Hz, 3H), 0.9 (t, J=7.3 Hz, 3H). LRMS (ESI)=459.3, [(M+H)+, Calcd for C28H35N4O2 459.6].
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([CH2:11][OH:12])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[CH:11]([C@@H:8]([NH:7][C:6](=[O:13])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][CH3:10])=[O:12]
Reactant: CC[C@@H](CO)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC[C@@H](C=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
A solution of tert-butyl[(1S)-1-(hydroxymethyl)propyl]carbamate (30.0 g) in dimethyl sulfoxide (300 mL) was ice-cooled under a nitrogen atmosphere, and triethylamine (64.4 mL) and a solution of sulfur trioxide pyridine complex (80.7 g) in dimethyl sulfoxide (300 mL) were successively added. The mixture was stirred at the same temperature for 30 min and then at room temperature for 3 hr, 1 mol/L aqueous citric acid solution (500 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%) to give the title compound as a white powder (yield: 24.3 g, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][N:7]=[C:8]([C:16]1[CH:21]=[CH:20][C:19]([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].[H][H].Cl[C:35]([N:38]([S:46]N(C(Cl)(C)C)CCC(OCC)=O)[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])([CH3:37])[CH3:36]>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]([S:46][N:38]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:35]([CH3:36])[CH3:37])[N:7]=[C:8]([C:16]1[CH:21]=[CH:20][C:19]([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NN=C(c1ccc(Cl)cc1)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)CCN(SN(CCC(=O)OCC)C(C)(C)Cl)C(C)(C)Cl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCN(SN(N=C(c1ccc(Cl)cc1)c1ccc(OS(=O)(=O)C(F)(F)F)cc1)C(=O)OCC)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.5 %

Procedure:
A solution of 4-chloro-4'-trifiuoromethyls ulfonyloxybenzophenone-N-ethoxycarbonylhydrazone (0.5 g) in tetrahydrofuran (6 ml) was stirred at room temperature under a nitrogen atmosphere, during which an oily mixture (50 mg) of sodium hydride containing 60% (w/w) sodium hydride was added to the solution at a time. After stirring at room temperature for 15 minutes and finding no evolution of hydrogen gas, the mixture was cooled to -78° C., and chloro-{N-(2-ethoxycarbonylethyl)-N-isopropylamino }sulfide (0.3 g) was added dropwise over 3 minutes. The reaction mixture was warmed to room temperature over 4 hours, and then poured into ice-water. Further, a saturated saline solution was added thereto. The aqueous layer was extracted with ethyl acetate, and the extract was combined with the organic layer. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel chromatography, which afforded 0.2 g of 4-chloro-4'-trifluoromethylsulfonyloxybenzo- phenone-N-ethoxycarbonyl-N-{N'-(2-ethoxycarbonylethyl)-N'-isopropylaminosulfenyl }-hydrazone (compound 28).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)=[N:7]2.[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:19]=1[C:33]1[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]4[S:13][CH:14]=[CH:15][N:16]=4)=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:20][C:19]=1[C:33]1[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Reactant: Clc1ccnc2nc(-c3nccs3)ccc12
Product: N#Cc1ccccc1-c1cc(-c2ccnc3nc(-c4nccs4)ccc23)ccc1F
Yield: 59 %

Procedure:
This was prepared in 59% yield from 5-chloro-2-(thiazol-2-yl)-[1,8]naphthyridine (from step a) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (from Example 2, step e) using a similar procedure to that described in Example 55, step a. δH (400 MHz, CDCl3) 7.45 (1H, t, J 9.0), 7.51 (1H, d, J 4.3), 7.54 (1H, td, J 7.4, 1.2), 7.58 (1H, d, J 3.1), 7.60-7.63 (3H, m), 7.71 (1H, td, J 7.4, 1.2), 7.84 (1H, dd, J 7.4, 1.2), 8.02 (1H, d, J 3.1), 8.48 (1H, d, J 8.6), 8.54 (1H, d, J 8.6), 9.46 (1H, d, J 4.7). m/z (ES+) 409 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(I)ccc1F
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1ccc(F)c(C#N)c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, step 3 starting from 2-Fluoro-5-iodo-benzonitrile (1.0 g, 4.14 mmol), and Ethynyl-trimethyl-silane (0.487 g, 4.97 mmol), and was obtained as a waxy brown solid, (0.90 g, 99%), identified by NMR and mass spectral analyses. MS (EI+): 216 (M+).
Reaction SMILES: [O:1]=[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])[CH3:3].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:3][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:13])[CH3:12])=[O:1]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Nc1ccccc1C(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccccc1C(=O)C=CN(C)C
Yield: 63.6 %

Procedure:
A suspension of 48 g of N-[2-(1-oxo-1-ethanyl)-phenyl]acetamide and 38 g of N,N-dimethylformamide dimethyl acetal in 150 ml of toluene was heated at reflux for about 16 hours, then concentrated in vacuo to a solid. The solid was recrystallized from 1-chlorobutane to yield 40 g of the title compound; m.p. 90°-95° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:13].[C:14]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=2B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=[CH:27][C:22]=2[O:21][CH2:20][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:3]([CH3:13])[CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: CCS(=O)(=O)c1ccc(Br)c(C)c1
Product: CCS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)ccc2OCc2ccccc2)c(C)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and (ii), yield 2.72 g.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=2[N:6]=1.[CH3:15][CH:16]([CH3:27])[CH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20]>COCCO>[ClH:1].[CH3:12][O:11][C:9]1[C:8]([O:13][CH3:14])=[CH:7][C:5]2[N:6]=[C:2]([N:24]3[CH2:25][CH2:26][N:21]([C:19](=[O:20])[CH2:18][CH2:17][CH:16]([CH3:15])[CH3:27])[CH2:22][CH2:23]3)[NH:3][C:4]=2[CH:10]=1
Reactant: COc1cc2nc(Cl)[nH]c2cc1OC
Reactant: CC(C)CCC(=O)N1CCNCC1
Solvent: COCCO
Product: COc1cc2nc(N3CCN(C(=O)CCC(C)C)CC3)[nH]c2cc1OC
Product: Cl

Procedure:
By the method of Example I, 2.00 g 2-chloro-5,6-dimethoxy benzimidazole and 4.00 g N-(4-methyl valeroyl) piperazine were reacted in 15 ml. 2-methoxy ethanol to give the desired product as a base; which was converted to the hydrochloride with HCl in isopropyl alcohol. Yield: 3.31 g (89%) mp 255°-257° C.