Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[N:5]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14]>CN(C)C=O>[Br:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:14][CH2:13][C:12]([F:16])([F:15])[F:11])[N:5]=1
Reactant: OCC(F)(F)F
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1cccc(Br)n1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.93 g, 23 mmol) was added to a solution of 2,6-dibromopyridine (5 g, 21 mmol) in N,N-dimethylformamide (10 mL) and the mixture was allowed to stir for 10 minutes. 2,2,2-Trifluoroethanol (2.53 g, 25.2 mmol) was then added and the mixture was heated at 60° C. for 90 minutes. The reaction mixture was then partitioned between water and ethyl acetate and the layers were separated. The organic layer was washed with a further volume of water, dried over magnesium sulfate and concentrated in vacuo to give a liquid residue. Purification of the liquid by column chromatography on silica gel, eluting with petroleum ether (60-80):dichloromethane, 99:1, afforded the title compound as a white liquid in 80% yield, 4.3 g.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([OH:23])=O)=[CH:16][CH:15]=[CH:14]3)=[N:3][CH:2]=1.C(Cl)(C([Cl:28])=O)=O>C(Cl)Cl.CN(C=O)C>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([Cl:28])=[O:23])=[CH:16][CH:15]=[CH:14]3)=[N:3][CH:2]=1
Reactant: O=C(O)c1cccc2cc(Oc3ncnc4[nH]ccc34)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc2cc(Oc3ncnc4[nH]ccc34)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-1-naphthoic acid (357 mg, 1.17 mmol) in DCM (11.7 mL) under an N2 atmosphere, was added DMF (2 drops) followed by (COCl)2 (143 μL, 1.64 mmol) dropwise. After stirring at RT for 4 hours, the reaction mixture became a yellow slurry. An aliquot was removed and placed in a vial containing 500 μl of 1M MeNH2. After 5 min, the resulting solution was analyzed by LCMS to indicate complete conversion to the methylamine and that no acid was present in the reaction mixture. The slurry was concentrated to a yellow stable solid, which was taken directly to the next step of the reaction sequence.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([N:11]=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:7][C:6]=2[CH:19]=1.[NH4+].[Cl-].O.[CH3:23][C:24]([CH3:26])=O>[Zn]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([N:11]=[C:24]([CH3:26])[CH3:23])[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:7][C:6]=2[CH:19]=1
Reactant: Cc1ccc2c(c1)OC(c1ccccc1)CN2N=O
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: CC(C)=NN1CC(c2ccccc2)Oc2cc(C)ccc21
Temperature: 0 °C

Procedure:
7-Methyl-4-nitroso-2-phenyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.5 g) was dissolved in acetone (90 mL). To it was added saturated NH4Cl solution (4.6 mL) followed by water (4.6 mL) with constant stirring until a homogenous solution resulted. The reaction mixture was cooled to 0° C., and to it was added zinc dust (1.5 g) in small portions. After addition, the mixture was stirred at RT for 2 h. Reaction was monitored by TLC. After completion of reaction, the mixture was concentrated under reduced pressure, and water (100 mL) was added. The mixture was extracted with DCM (3×100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was dried under high vacuum (1.5 g), which was carried forward to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:39][OH:40])[C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:22])=[C:15](/[CH:18]=[CH:19]/[Cl:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.B(F)(F)F.CCOCC>C(O)(=O)C.C1(OC)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>[OH:40][N:39]=[C:7]([C:5]1[N:6]=[C:2]([NH2:1])[S:3][CH:4]=1)[C:8]([NH:10][CH:11]1[C:37](=[O:38])[N:13]2[C:14]([C:21]([OH:23])=[O:22])=[C:15](/[CH:18]=[CH:19]/[Cl:20])[CH2:16][S:17][C@H:12]12)=[O:9]
Reactant: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(/C=C/Cl)CS[C@H]23)cs1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: COc1ccccc1
Product: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)O)=C(/C=C/Cl)CS[C@H]23)cs1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 147 %

Procedure:
To a solution of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (syn isomer) (2.5 g) in a mixture of acetic acid (2.5 ml) and anisole (9.6 ml) was dropwise added boron trifluoride etherate (2.5 ml) at 3° C. and the mixture was stirred for 30 minutes at the same temperature for 30 minutes. The reaction mixture was dissolved in 20% aqueous solution of potassium carbonate, washed with ethyl acetate, concentrated to remove the organic solvent under reduced pressure, cooled to 5° C. and adjusted to pH 2.3 with 10% hydrochloric acid. The resultant precipitates were collected by filtration, washed with water and dried in vacuo to give 7-[2-hydroxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylic acid (syn isomer) (2.65 g)
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[C:15]([NH:27][NH2:28])=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1>C1COCC1>[Cl:13][C:14]1[C:15]2[N:16]([C:2](=[O:4])[NH:28][N:27]=2)[CH:17]=[CH:18][C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: Cc1ccc(-c2ccnc(NN)c2Cl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccn3c(=O)[nH]nc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
To a stirred solution of triphosgene (2.64 g, 8.9 mmol) in THF (25 mL) at room temperature under argon was added 1-(3-chloro-4-p-tolylpyridin-2-yl)hydrazine (0.692 g, 3.0 mmol). The reaction mixture was stirred at room temperature for 16 h. Analysis by HPLC/MS indicated that starting material had been consumed. Water (25 mL) was added while stirring. The resulting suspension was heated at 100° C. for 40 h. Upon cooling to room temperature, the desired product was filtered and further washed with water (15 mL×2). After drying in a vacuum oven under reduced pressure overnight, 562 mg of the title compound was obtained as a white solid. HPLC/MS: retention time=2.98 min, [M+H]+=260.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.Br[C:15]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([N:27](CC3C=CC(OC)=CC=3OC)[C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[N:17]([CH3:44])[CH:16]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:15]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([NH:27][C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:25])=[O:26])=[CH:21][CH:22]=2)[N:17]([CH3:44])[CH:16]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: COc1ccc(-c2cn(C)c3cc(S(=O)(=O)Nc4ncns4)ccc23)c(OC)c1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (2,4-dimethoxyphenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(2,4-dimethoxyphenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.76 (s, 3H) 3.80 (s, 3H) 3.87 (s, 3H) 6.59-6.68 (m, 2 H) 7.35 (d, J=8.25 Hz, 1 H) 7.43 (dd, J=8.42, 1.43 Hz, 1 H) 7.52-7.60 (m, 1 H) 7.85 (s, 1 H) 7.94 (br. s., 1 H). m/z (ESI) 430.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[NH2:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([NH2:21])=[CH:18][CH:19]=2)[NH:14][N:13]=1>>[NH2:21][C:17]1[CH:16]=[C:15]2[C:20]([C:12]([NH:11][C:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:9])=[N:13][NH:14]2)=[CH:19][CH:18]=1
Reactant: Nc1ccc2c(N)n[nH]c2c1
Reactant: CN1CCC(C(=O)Cl)CC1
Product: CN1CCC(C(=O)Nc2n[nH]c3cc(N)ccc23)CC1

Procedure:
1-Methylpiperidine-4-carbonyl chloride (1 mmol), prepared from its corresponding carboxylic acid using general procedure E, was reacted with 3,6-diaminoindazole (1 mmol) (see Example 69) employing general procedure E to yield 1-methylpiperidine-4-carboxylic acid (6-amino-1H-indazol-3-yl)-amide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.Cl[C:19]1[CH:29]=[C:23]2[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:16][O:17][C:19]1[CH:29]=[C:23]2[N:24]([CH3:28])[CH2:25][CH2:26][CH2:27][N:22]2[C:21](=[O:30])[N:20]=1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(F)cc2)c(F)c1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(F)cc3)c(F)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3-fluoro-4-(4-fluorophenoxyl)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]1([C:14]2([S:17][CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15]2)[CH2:13][O:12]1.[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.CC(C)([O-])C.[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:14]1([S:17][CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15]1)([OH:12])[CH2:13][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1
Reactant: c1nc[nH]n1
Reactant: CCCSC1(C2(C=Cc3ccc(Cl)cc3Cl)CO2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSC1(C(O)(/C=C/c2ccc(Cl)cc2Cl)Cn2cncn2)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 25.3 %

Procedure:
A solution of 38.2 g (0.12 mol) of 2-(2,4-dichlorophenylethenyl)-2-(1-propylmercaptocyclopropyl) oxirane in 30 ml of dimethylformamide is added dropwise under a nitrogen atmosphere and with stirring at 80° C. to a mixture of 24 g (0.35 mol) of 1,2,4-triazole, 2.7 g (0.02 mol) of potassium tert.-butoxide and 50 ml of dimethylformamide. The mixture is stirred at 80° C. for 6 hours, then the solvent is removed under reduced pressure, and the residue is taken up in ethyl acetate/toluene, washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue which remains is chromatographed on silica gel using chloroform as the eluant. In this manner, 12.1 g (26% of theory) of trans-4-(2,4-dichlorophenyl)-2-(1-propylmercaptocyclopropyl)1-(1,2,4-triazol-1-yl)-but-3-en-2-ol are obtained in the form of an oily product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[I:18]I.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CN(C=O)C.O>[I:18][C:3]1[C:4]2[C:9](=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: O=Cc1ccc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(I)n[nH]c2c1
Reaction time: 2 h

Procedure:
To a solution of 1H-indazole-6-carbaldehyde (2.00 g, 13.7 mmol), K2CO3 (3.79 g, 27.4 mmol) in DMF (15 mL) was added dropwise a solution of I2 (5.91 g, 23.3 mmol) in DMF (15 mL) and the reaction allowed to stir for two h. An aqueous solution consisting of Na2S2O4 (3.30 g)/K2CO3 (0.20 g)/H2O (30 mL) was then added and the solution stirred for one h. The product was then precipitated by pouring the solution over ice-water (300 mL) and collected by vacuum filtration to give after drying 3.02 g, 81% of a beige powder. 1H NMR (400 MHz, CD3OD) δ 10.11 (s, 1H), 8.11 (s, 1H), 7.74 (d, J=8.34 Hz, 1H), 7.62 (d, J=8.34 Hz, 1H); MS ESI 272.9 [M+H]+, calcd for [C8H5IN2O+H]+ 272.95.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:14]([C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH2:31][CH2:32][C:33]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:40])[CH3:15])=[CH:9][C:8]=1[CH3:41])C.[Li+].[OH-].Cl>C1COCC1>[Cl:40][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([F:39])[C:33]=1[CH2:32][CH2:31][C:17]1[N:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=2)[S:20][C:16]=1[CH:14]([S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:42])=[O:3])=[C:8]([CH3:41])[CH:9]=1)[CH3:15]
Reactant: CCOC(=O)COc1ccc(SC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2CCc2c(F)cccc2Cl)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(SC(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2CCc2c(F)cccc2Cl)ccc1OCC(=O)O

Procedure:
(4-{1-[4-[2-(2-Chloro-6-fluoro-phenyl)-ethyl]-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethylsulfan yl}-2-methyl-phenoxy)-acetic acid ethyl ester (30 mg) is taken into THF (0.5 mL and treated with LiOH (1.0 N, 0.5 mL for 2 hrs. The reaction mixture is acidified with 5 N HCl, extracted with ethyl ether, dried over sodium sulfate. Concentration gave the title compound. MS (ES): 610.1 (M++1, 35Cl), 612.1 (M++1, 37Cl), the structure is also confirmed by proton NMR.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:22](=O)[CH3:23])=[CH:7][NH:8][NH:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=1[Cl:21])=[O:5])[CH3:2].S(=O)(=O)(O)O>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[Cl:21])[C:22]=1[CH3:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(=CNNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Yield: 85.9 %

Procedure:
5 g (0.013 mole) of N-[2-ethoxycarbonyl-2-acetylvinyl]-N'-(2,6-dichloro-4-trifluoromethyl-phenyl)-hydrazine are dissolved in 50 ml of ethanol, 1 ml of concentrated sulphuric acid is added and the mixture is heated for 1 hour under reflux. The reaction mixture is concentrated in vacuo, taken up in methylene chloride, washed with saturated sodium hydrogen carbonate solution, the methylene chloride phase is dried over magnesium sulphate and concentrated in vacuo. 4.1 g (86% of theory) of 4-ethoxycarbonyl-5-methyl-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-pyrazole with a melting point of 61°-62° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH:20]=1)[CH:18]=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[CH:18]([C:17]1[CH:20]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:14]=[N:15][CH:16]=1)=[O:19]
Reactant: O=Cc1cncc(Br)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cncc(C=O)c2)cc1
Temperature: 120 °C
Yield: 52.8 %

Procedure:
A mixture of 4-cyanophenylboronic acid (735 mg, 5.00 mmol), 5-bromonicotinaldehyde (930 mg, 5.000 mmol), sodium carbonate (5000 μl, 10.00 mmol), bis(triphenylphosphine)palladium(II) chloride (88 mg, 0.125 mmol) in DMF (15 mL, dry) was heated to 120° C. for 3 h. After concentration, the residue was dissolved into CH2Cl2-MeOH, mixed with silica gel and concentrated. Purification by flash column (MeOH—CH2Cl2, v/v, 0%-1%) yielded 4-(5-formylpyridin-3-yl)benzonitrile as colorless solid (550 mg) 1H NMR (400 MHz, CDCl3): δ 7.55 (d, J=8.57 Hz, 2H), 7.82 (d, J=8.57 Hz, 2H), 8.36 (s, 1H), 9.08 (d, J=2 Hz, 1H), 9.12 (d, J=2 Hz, 1H), 10.21 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:8][C:7]1[C:2]([O:22][C:19]2[CH:20]=[CH:21][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
2,3-Dichloro-5-trifluoromethylpyridine (2.16 g, 0.01M) and 4-nitrophenol (1.53 g, 0.011M) were mixed in methyl ethyl ketone (10 ml) containing anhydrous potassium carbonate (2.0 g) and heated at the reflux temperature for 10 hours. The cooled mixture was filtered to remove the solid matter and the filtrate concentrated by evaporation of the solvent under reduced pressure. The residue was triturated with diethyl ether and 3-chloro-5-trifluoromethyl-2-(4-nitrophenoxy)pyridine collected as a buff coloured solid (0.75 g), m.p. 98°-100° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[C:37]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4ccncc4)cc3)cc21
Yield: 72.3 %

Procedure:
In a similar manner to that described in Example 47, a reaction was carried out using 5-{4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride (400 mg), isonicotinoylchloride (142 mg), triethylamine (232 mg) and anhydrous N,N-dimethylformamide (8 ml) and the reaction mixture was purified to give the title compound (306 mg).
Reaction SMILES: [OH-].[Na+].O.[Br:4][C:5]1[C:6]2[N:7]([C:24]([CH3:27])=[N:25][N:26]=2)[C:8]2[CH:13]=[C:12]([CH3:14])[N:11](S(C3C=CC=CC=3)(=O)=O)[C:9]=2[CH:10]=1>C1COCC1.CCO.CCOCC>[Br:4][C:5]1[C:6]2[N:7]([C:24]([CH3:27])=[N:25][N:26]=2)[C:8]2[CH:13]=[C:12]([CH3:14])[NH:11][C:9]=2[CH:10]=1
Reactant: Cc1cc2c(cc(Br)c3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: Cc1cc2c(cc(Br)c3nnc(C)n32)[nH]1
Reaction time: 1 h

Procedure:
1.0 M NaOH in water (15 mL, 15 mmol) was added to 4-bromo-1,7-dimethyl-6-(phenylsulfonyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (1.57 g, 3.87 mmol, from Step 1) in THF (15 mL) and EtOH (15 mL). The reaction was continued for 1 hour, and a precipitate formed. The solid product was isolated by filtration. The solid was then suspended in Et2O, filtered and air dried. Yield: (0.86 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]3[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[O:18][C:17]([CH3:25])([CH3:24])[C:16]3=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:30])(=O)=O>C(Cl)(Cl)Cl>[Cl:30][C:15]1([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[CH:12][C:11]=2[CH3:14])[C:20](=[O:21])[C:19]([CH3:22])([CH3:23])[O:18][C:17]([CH3:25])([CH3:24])[C:16]1=[O:26]
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1(Cl)C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4′-chloro-4-methylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione in anhydrous chloroform (3 ml) at 0° C. is added a second solution of sulfuryl chloride (0.025 ml, 0.315 mmol) in anhydrous chloroform (0.3 ml) dropwise. The reaction mixture is stirred for 30 minutes at 0° C. then for a further 1 hour at room temperature. Additional sulfuryl chloride (0.025 ml, 0.315 mmol) is next added, followed by warming to 60° C. for 2 hours, followed by addition of further sulfuryl chloride (0.20 ml, 2.52 mmol). The reaction mixture is finally stirred at room temperature overnight then quenched with saturated aqueous sodium bicarbonate, and extracted with ethylacetate. Purification by flash column chromatography (20% ethylacetate in hexane eluant) afforded 4-chloro-4-(4′-chloro-4-methylbiphenyl-3-yl)-2,2,6,6-tetramethyl-pyran-3,5-dione (0.033 g) as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][OH:9])=[N:2]1.[H-].[Na+].Cl[C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=1.Cl>CN(C=O)C>[NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=2)=[N:2]1
Reactant: OCCSc1nc[nH]n1
Reactant: N#Cc1ccnc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccnc(OCCSc2nc[nH]n2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
A solution of 2-(1H-1,2,4-triazol-3-ylthio)ethanol obtained in Reference Example 16 (7.34 g, 50.6 mmol) in DMF (50 mL) was added to a solution of 60% sodium hydride (oil dispersion, 4.91 g, 123 mmol) in DMF (50 mL) at 0° C. The mixture was stirred at 0° C. for 15 min, and then at room temperature for 30 min. A solution of 2-chloropyridine-4-carbonitrile (6.80 g, 49.1 mmol) in DMF (50 mL) was added at 0° C., and the mixture was stirred at 0° C. for 15 min, and then at room temperature for 2 hr. The mixture was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give the title compound as a white powder (4.01 g, 33%).
Reaction SMILES: N[C:2]1[N+:7]([O-:8])=[C:6]([CH2:9][C:10](CC(C)C)([CH3:12])[CH3:11])[C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][C:3]=1[CH2:25][OH:26].[CH3:27][S:28]SC.N(OCCC(C)C)=O.C(OCC)C>CC#N>[CH2:18]([O:17][C:5]1[C:6]([CH2:9][CH:10]([CH3:12])[CH3:11])=[N+:7]([O-:8])[C:2]([S:28][CH3:27])=[C:3]([CH2:25][OH:26])[N:4]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)CC(C)(C)Cc1c(OCc2ccccc2)nc(CO)c(N)[n+]1[O-]
Reactant: CSSC
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CCOCC
Product: CSc1c(CO)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Temperature: 25 °C

Procedure:
4.55 Grams of 6-amino-5-hydroxymethyl-3-benzyloxy-2-isobutyl isobutylpyrazine 1-oxide and 6.75 ml of dimethyl disulfide were dissolved in 50 ml of CH3CN, and thereto was added 3.02 ml of isoamyl nitrite. The mixture was subjected to a reaction for 20 minutes at 70°-80° C., and the reaction mixture was cooled to room temperature, and mixed with 150 ml of diethyl ether. The resulting mixture was washed with water (100 ml×3), and the ether layer was dried over MgSO4. The solvent was removed by evaporation. The residue was purified by a silica gel chromatography (30% EtOAc-hexane), followed by recrystallization from isopropyl ether-n-hexane to obtain 2.17 g of colorless needle-like crystals (Compound E-52c) having a melting point of 88.5°-86.5° C.