Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH:14]=[CH2:15])=[CH:8][C:7]=1[CH3:16])[CH:2]1[O:4][CH2:3]1.C([O-])(=[O:19])C.[Na+].C(OO)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[C:7]([CH3:16])=[CH:8][C:9]([CH2:13][CH:14]2[O:19][CH2:15]2)=[CH:10][C:11]=1[CH3:12])[CH:2]1[O:4][CH2:3]1
Reactant: C=CCc1cc(C)c(OCC2CO2)c(C)c1
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(CC2CO2)cc(C)c1OCC1CO1
Reaction time: 4 h
Yield: 863.5 %

Procedure:
A 350 ml sulfurating flask equipped with thermometer, stirrer, cooler and drip funnel is charged with 46.30 g (0.21 mole) of 4-allyl-2,6-dimethylphenyl glycidyl ether, 1.93 g of sodium acetate and 160 ml of chloroform, and the batch is heated to 35°-40° C. At this temperature, 52.3 g (0.28 mole) of 40% peracetic acid are then added dropwise over about 1 hour. The reaction mixture is then held at this temperature for a further 4 hours until the educt is no longer discernible in the gas chromatograph. When the reaction is complete, the reaction mixture is diluted in chloroform and the resultant solution is washed with 3% NaOH until neutral, made peroxide-free with sodium sulfite, dried over sodium sulfate and filtered. The filtrate is concentrated by rotary evaporation, affording 47.6 g of 4-(2,3-epoxypropyl)-2,6-dimethylphenyl glycidyl ether in the form of a low viscous oil; epoxide content 8.1 equivalents/kg (95.13% of theory).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:14]1([C:20]2[O:24][N:23]=[CH:22][C:21]=2[CH2:25][CH2:26][C:27](O)=[O:28])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:13][C:4]1[S:3][C:2]([NH:1][C:27](=[O:28])[CH2:26][CH2:25][C:21]2[CH:22]=[N:23][O:24][C:20]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1sc(N)nc1-c1ccccc1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1sc(NC(=O)CCc2cnoc2-c2ccccc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A mixture of 2-amino-5-methyl-4-phenylthiazole (0.95 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (1.01 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.78 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.97 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(5-methyl-4-phenyl-2-thiazolyl)-3-(5-phenyl-4-isoxazolyl)propionamide (1.74 g, yield 96%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 150–151° C.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1.S(=O)(=O)(O)[OH:13].[N+]([O-])([O-])=O.[Na+]>O>[O:13]=[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[NH:3]1
Reactant: O=S(=O)(O)O
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1[nH]c(=O)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 97 %

Procedure:
To a suspension of 2-amino-5-nitro-6-methylpyridine (40.24 g, 260 mmol) was added concentrated sulfuric acid (48 mL). The homogeneous solution was cooled to 0° C., and sodium nitrate (26.97 g, 390 mmol) dissolved in 120 mL of water was added. The reaction mixture was warmed to room temperature over 4 hours, then cooled to 0° C. The resulting ivory precipitate was collected, washed with cold water, and dried at 40° C. in vacuo overnight to provide 39.05 g (97%) of the title compound. EA calculated for C6H6N2O3: C, 46.76; H, 3.92; N, 18.18. Found: C, 46.49; H, 3.94; N, 17.99.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.CC1C=CC(CN)=CC=1.[C:22]([NH:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][N:39]=1)[C:34](O)=[O:35])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([NH:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][N:39]=1)[C:34]([NH:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=1)=[O:35])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccnc(NC(=O)c2ccccc2)c1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: Cc1ccc(CN)cc1
Product: Cc1ccc(CNC(=O)c2ccnc(NC(=O)c3ccccc3)c2)cc1
Yield: 35 %

Procedure:
Following the procedure as described in Example 1, making variations as required to replace (4-(trifluoromethyl)phenyl)methanamine with p-tolylmethanamine to react with 2-benzamidoisonicotinic acid, 2-benzamido-N-(4-methylbenzyl)-isonicotinamide was obtained as a colorless solid in 35% yield: mp 135-138° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.33-9.30 (m, 1H), 8.60-8.51 (m, 2H), 8.06-8.03 (m, 2H), 7.63-7.50 (m, 4H), 6.25-7.03 (m, 4H), 4.45 (d, J=6.0 Hz, 2H), 2.28 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.0, 164.7, 152.8, 148.4, 143.6, 136.1, 135.9, 133.8, 131.9, 128.8, 128.3, 127.9, 127.3, 117.2, 112.7, 42.4, 20.6; MS (ES+) m/z 346.5 (M+1).
Reaction SMILES: Cl[C:2]([Cl:12])(OC(=O)OC(Cl)(Cl)Cl)Cl.C[N:14](C)[NH:15][C:16]([NH:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:22][C:21]=1[CH3:32])=[O:17].[C:34](OCC)(=O)C>C(Cl)Cl>[Cl:12][C:2]1[N:18]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][C:21]=2[CH3:32])[C:16](=[O:17])[N:15]([CH3:34])[N:14]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(-c2ccccc2)cc1CNC(=O)NN(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2ccccc2)cc1Cn1c(Cl)nn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 9.24 g (31.1 mmol) of triphosgene in 50 ml of methylene chloride was added dropwise a solution of 4.41 g (15.6 mmol) of 1,1-dimethyl-4-(2-methyl-5-phenylbenzyl)semicarbazide (produced in the following Reference Production Example 15) in 35 ml of methylene chloride with ice-cooling. The mixture was removed from an ice bath, allowed to warm to room temperature, and heated under reflux for 6 hours. After allowing to cool to room temperature, the reaction mixture was poured into 300 ml of an about 5% aqueous solution of sodium bicarbonate, and the mixture was stirred for 1 hour. The organic layer was washed with water, dried and concentrated. The residue was subjected to silica gel column chromatography (developed with n-hexane:ethyl acetate=2:1and then 1:1) to obtain 2.01 g (6.4 mmol) of 5-chloro-2-methyl-4-(2-methyl-5-phenylbenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 7 of the present invention) having a melting point of 115.7° C.
Reaction SMILES: Cl[C:2]1[C:3]([F:21])=[CH:4][C:5]2[C:6]([CH:20]=1)=[N:7][C:8]1[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH2:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:23]>N1C=CC=CC=1>[N:9]1[C:8]2[N:7]=[C:6]3[CH:20]=[CH:2][CH:3]=[CH:4][C:5]3=[CH:14][C:13]=2[CH:12]=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=1.[CH2:22]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[C:3]([F:21])=[CH:4][C:5]3[C:6]([CH:20]=2)=[N:7][C:8]2[N:9]([CH3:19])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=2[CH:14]=3)[CH2:26][CH2:25]1)[CH3:23]
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CCN1CCNCC1
Solvent: c1ccncc1
Product: CCN1CCN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CC1
Product: O=C(O)c1cnc2nc3ccccc3cc2c1
Yield: 112.1 %

Procedure:
8-(4-Ethyl-1-piperazinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydro=benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions described below in Example 5 but starting from 1.85 g of 8-chloro-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 2.75 g of 1-ethylpiperazine in 20 cm3 of pyridine. 1.3 g of 8-(4-ethyl-1-piperazinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 285°-286° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.I[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)Cc1cccc(OC)c1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1cccc(OC)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 89.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.3 1M stock solution, 7.13 mmol) cooled to −78° C. was treated with (3-methoxy-phenyl)-acetic acid methyl ester (1.07 g, 5.94 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (14.8 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (1.37 g, 6.53 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.16 mL). The reaction mixture was stirred at −78° C. for 3 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. At this time, the reaction was quenched by the dropwise addition of a saturated aqueous ammonium chloride solution. This solution was diluted with water (100 mL) and extracted into ethyl acetate (3×50 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (1×75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-methoxy-phenyl)-propionic acid methyl ester (1.39 g, 89.1%) as a clear oil: EI-HRMS m/e calcd for C16H22O3 (M+) 262.1568, found 262.1561.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[CH:18]2>>[Cl:1][C:2]1[N:11]=[C:10]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([O:14][CH3:13])=[CH:23][CH:22]=3)[CH:18]=[CH:19]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: COc1ccc2[nH]ccc2c1
Product: COc1ccc2c(ccn2-c2nc(Cl)nc3ccccc23)c1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 5-methoxyindole (40 mg, 0.302 mmol) similar to Example 1b and was isolated as white powder (14 mg, 28%). 1H NMR (CDCl3): 8.91 (s, 1H), 8.70 (ddd, J=8.4, 2.8 and 1.5 Hz, 1H), 8.01 (ddd, J=8.4, 2.8 and 1.5 Hz, 1H), 7.92 (dd, J=6.9 and 1.5 Hz, 1H), 7.87 (m, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.61 (ddd, J=8.4, 6.9 and 1.2 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 6.97 (dd, J=9.0 and 2.4 Hz, 1H), 3.88 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH:31]1([CH2:30][N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:33][CH2:32]1
Reactant: BrCC1CC1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), (bromomethyl)cyclopropane (0.16 mL), potassium carbonate (0.38 g) and N,N-dimethylacetamide (10 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.54 g, 93%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: Brc1cc(Br)cc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Brc1cc(Br)cc(-c2ccc(OCc3ccccc3)cc2)c1

Procedure:
9.0 g (32 mmol) of sodium metaborate octahydrate and 1.3 g (1.82 mmol) of bis(triphenylphosphine)palladium(II) chloride are initially introduced in 200 ml of water and 40 ml of THF, a solution of 55 g (171 mmol) of 1,3,5-tribromobenzene in 80 ml of THF is added, and a solution of 10 g (45.5 mmol) of 4-benzyloxybenzeneboronic acid is added dropwise under reflux. The batch is heated under reflux for 16 h, added to water and extracted three times with MTB ether. The combined org. phases are washed with sat. sodium chloride soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is chromatographed on silica gel with heptane/ethyl acetate (19:1) and recrystallised from ethanol, giving 4′-benzyloxy-3,5-dibromobiphenyl as colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH2:25]1[O:33][C:32]2[CH:31]=[CH:30][C:29]([CH2:34][C:35](Cl)=[O:36])=[CH:28][C:27]=2[O:26]1.C(=O)([O-])O.[Na+]>ClCCl>[NH2:1][C:2]1[N:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:35](=[O:36])[CH2:34][C:29]3[CH:30]=[CH:31][C:32]4[O:33][CH2:25][O:26][C:27]=4[CH:28]=3)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=C(Cl)Cc1ccc2c(c1)OCO2
Reactant: Nc1nc(C2CCNCC2)c2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1nc(C2CCN(C(=O)Cc3ccc4c(c3)OCO4)CC2)c2ccccc2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 3,4-methylenedioxyphenylacetic acid (569 mg, 3.16 mmol) in chloroform (6 ml) was added thionyl chloride (1.2 ml). The mixture was refluxed for about 3 hours, and was evaporated. Toluene was added to the residue and the mixture was evaporated to remove the excess of thionyl chloride. To the residue was added dichloromethane (3 ml) to give a dichloromethane solution of 3,4-methylenedioxyphenylacetyl chloride. To an ice-cold mixture of 2-amino-4-(4-piperidinyl)quinazoline (600 mg, 2.63 mmol) and triethylamine (319 mg, 3.16 mmol) in dichloromethane (16 ml) was added dropwise the solution of 3,4-methylenedioxyphenylacetyl chloride prepared above under a nitrogen atmosphere. The mixture was stirred for about two hours and to the reaction mixture was added dichloromethane and saturated sodium hydrogencarbonate aqueous solution followed by extraction. The organic layer was washed with water, and then dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1). Crystallization from methanol gave the titled compound (617 mg).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:11][N:10]=2)[CH2:5][CH2:4]1.[CH3:20][N:21]1[CH:30]=[CH:29][C:28]2[N:27]=[C:26]([C:31]3[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=3)[C:25]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:24][C:23]=2[C:22]1=[O:45].C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[CH3:20][N:21]1[CH:30]=[CH:29][C:28]2[N:27]=[C:26]([C:31]3[CH:38]=[CH:37][C:34]([CH2:35][N:3]4[CH2:8][CH2:7][CH:6]([C:9]5[N:13]=[C:12]([C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=6)[NH:11][N:10]=5)[CH2:5][CH2:4]4)=[CH:33][CH:32]=3)[C:25]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:24][C:23]=2[C:22]1=[O:45]
Reactant: Cn1ccc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cc2c1=O
Reactant: c1ccc(-c2nc(C3CCNCC3)n[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cn1ccc2nc(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)c(-c3ccccc3)cc2c1=O
Temperature: 25 °C

Procedure:
To a solution of 2-(3-piperidin-4-yl-1H-1,2,4-triazol-5-yl)pyridine dihydrochloride (142 mg, 10.47 mmol) and 4-(6-methyl-5-oxo-3-phenyl-5,6-dihydro-1,6-naphthyridin-2-yl)benzaldehyde (5141 mg, 0.415 mmol) in dry DMF (1.5 mL) was added triethylamine (0.21 mL, 1.5 mmol). After stirring for 10 minutes acetic acid (0.26 mL, 4.5 mmol) was added and the mixture was stirred at room temperature over night. Then sodium triacetoxy borohydride (110 mg, 0.52 mmol) was added in one portion and stirred for eight hours. After monitoring by LC/MS determined the reaction was not complete additional sodium triacetoxy borohydride (46 mg, 0.21 mmol)) were added and the reaction was stirred over night. This reaction mixture was adsorbed on silica gel and purified by column chromatography eluting with 1-7% methanol/ethyl acetate (sat'd NH3). The appropriate fractions were combined, the solvents removed in vacuo, and the residue digested in acetonitrile containing a little methanol to give pure title compound. 1H NMR (500 MHz, CDCl3): δ 8.69 (1H, s), 8.65 (1H, d, J=4.4 Hz), 8.15 (1H, d, J=7.8 Hz), 7.83 (1H, t, J=7.6 Hz), 7.31-7.39 (5H, m), 7.22-7.25 (6H, m), 6.86 (1H, d, J=6.5 Hz), 3.66 (3H, s), 3.53 (2H, s), 2.95 (2H, br d, J=10.7 Hz), 2.85 (1H, m), 2.06-2.15 (4H, m), 1.92-2.01 (2H, m). m/e (m+1): 554.3, 277.9 [(m+2)/2].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[CH2:25].C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:29]1([S:26](/[CH:24]=[CH:25]/[C:13]2[CH:12]=[CH:11][C:10]([N:16]3[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]3)=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]=2)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CN(c2ccc(/C=C/S(=O)(=O)c3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 120 °C

Procedure:
A mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (80 mg, 0.18 mmol), ethenesulfonylbenzene (37 mg, 0.22 mmol), Pd(OAc)2 (2 mg) and triethylamine (186 mg, 1.84 mmol) in MeCN (2 mL) is heated at 120° C. in a microwave apparatus for 15 min. The mixture is filtered, poured into EtOAc and is washed with 1N HCl and brine then dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound: (M−1)−=483.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:8]=1)=[O:2].[NH2:28][C:29]1[CH:30]=[C:31]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=1[NH2:35].C(C1C(NC(=O)C(C)(C)C)=NC=C(C2C=CC=CC=2)C=1)=O.COC1C=C(B(O)O)C=C(OC)C=1OC>>[NH2:21][C:4]1[C:3]([C:1]2[NH:28][C:29]3[CH:30]=[C:31]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:32]=[CH:33][C:34]=3[N:35]=2)=[CH:8][C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:6][N:5]=1.[CH:1]([C:3]1[C:4]([NH:21][C:22](=[O:27])[C:23]([CH3:25])([CH3:24])[CH3:26])=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:8]=1)=[O:2]
Reactant: Nc1ccc(S(N)(=O)=O)cc1N
Agent: CC(C)(C)C(=O)Nc1ncc(-c2ccccc2)cc1C=O
Agent: COc1cc(-c2cnc(NC(=O)C(C)(C)C)c(C=O)c2)cc(OC)c1OC
Agent: COc1cc(B(O)O)cc(OC)c1OC
Product: COc1cc(-c2cnc(N)c(-c3nc4ccc(S(N)(=O)=O)cc4[nH]3)c2)cc(OC)c1OC

Procedure:
The title compound was synthesized using the procedure recited in Example 2, except that N-(3-formyl-5-(3,4,5-trimethoxyphenyl)pyridin-2-yl)-2,2-dimethylpropanamide and 3,4-diaminobenzene-1-sulfonamide were utilized. N-(3-formyl-5-(3,4,5-trimethoxyphenyl)pyridin-2-yl)-2,2-dimethylpropanamide was synthesized using the sequence of steps (a), (b), and (c) of Example 1, utilizing 3,4,5-trimethoxyphenylboronic acid in step (a).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.[NH2:26][C:27]1[CH:28]=[C:29]([C:33]2[N:38]=[C:37]([NH:39][C:40]3[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH3:49])=[C:42]([O:50][CH3:51])[CH:41]=3)[C:36]3=[C:52]([CH3:56])[N:53]=[C:54]([CH3:55])[N:35]3[N:34]=2)[CH:30]=[CH:31][CH:32]=1>>[CH3:56][C:52]1[N:53]=[C:54]([CH3:55])[N:35]2[C:36]=1[C:37]([NH:39][C:40]1[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([O:46][CH3:47])[CH:45]=1)=[N:38][C:33]([C:29]1[CH:28]=[C:27]([NH:26][C:1](=[O:4])[CH3:2])[CH:32]=[CH:31][CH:30]=1)=[N:34]2
Reactant: CC(=O)O
Reactant: COc1cc(Nc2nc(-c3cccc(N)c3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COc1cc(Nc2nc(-c3cccc(NC(C)=O)c3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
14 mg (0.21 mmol) of acetic acid, 31 mg (0.23 mmol) of HOBt, 63 mg (0.62 mmol) of 4-methylmorpholine, 44 mg (0.23 mmol) of EDC and 87 mg (0.21 mmol) of 3-[5,7-dimethyl-4-(3,4,5-trimethoxyphenoxy)imidazo[5,1-f][1,2,4]triazin-2-yl]-aniline from example 7 are reacted analogously to example 2.
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[C:5]=1[C:6]#[N:7]>[Fe](Cl)Cl.CO>[F:3][C:4]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([C:13]([F:16])([F:14])[F:15])[C:5]=1[C:6](=[N:1][OH:2])[NH2:7].[F:3][C:4]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([C:13]([F:16])([F:14])[F:15])[C:5]=1[C:6]([NH2:7])=[O:2]
Reactant: N#Cc1c(C(F)(F)F)ccc(F)c1F
Reactant: NO
Agent: Cl[Fe]Cl
Solvent: CO
Product: NC(=NO)c1c(C(F)(F)F)ccc(F)c1F
Product: NC(=O)c1c(C(F)(F)F)ccc(F)c1F
Reaction time: 6 h

Procedure:
In a colorless, transparent glass reaction vessel was placed a mixed solvent of 150 ml of methanol-distilled water (volume ratio 1:2) into which were dissolved beforehand 9.91 g (150 mmol) of 50% hydroxylamine aqueous solution and on purpose 86 μg (0.00068 mmol) of iron(II) chloride. Into the mixed solvent was added 10.36 g (50.0 mmol) of 2,3-difluoro-6-trifluoromethylbenzonitrile (I″). The reaction temperature stood at 60° C. for 6 hours and was returned to room temperature. In HPLC analysis of the reaction solution, it was shown that (I″) disappeared, 2,3-difluoro-6-trifluoromethylbenzamidoxime (II′) was mainly produced (yield 62.4%) and 2,3-difluoro-6-trifluoromethylbenzamide (III′) was noticeably produced as a byproduct (yield 22.8%).