Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:26])([F:27])[F:1])[CH:4]=2)=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: O=C(O)/C=C/C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 105 %

Procedure:
As in Example 115, (E)-5,5-bis[3-(trifluoromethyl)phenyl]2,4-pentadienoic acid (5.8 g) and 4-nitrophenol (2.5 g) in dichloromethane (50 mL) was treated with 1,3-dicyclohexylcarbodiimide (3.1 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 2 hours. The usual work up furnished 8 g of (E)-5,5-bis[3-(trifluoromethyl)phenyl]-2,4-pentadienoic acid 4-nitrophenyl ester as an oil essentially homogeneous by tlc. This material was used without further purification in subsequent reactions.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:46]1[CH2:50][CH2:49][CH2:48][C@H:47]1[CH2:51][N:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1>CN(C=O)C.ClCCl>[N:52]1([CH2:51][C@@H:47]2[CH2:48][CH2:49][CH2:50][N:46]2[C:10]([C:9]2[CH:8]=[CH:7][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)=[O:12])[CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: O=C(O)c1ccc(-c2cccs2)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(-c2cccs2)cc1)N1CCC[C@H]1CN1CCCC1
Yield: 29.7 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 10 mL 10% DMF/dichloromethane using 4-(thiophen-2-yl)-benzoic acid (CAS 29886-62-2) (182 mg, 0.89 mmol), EDC-HCl (254 mg, 1.33 mmol), HOBt (180 mg, 1.33 mmol), DIEA (0.39 mL, 2.22 mmol) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (116 mg, 10.0 mmol) to give the title compound (90 mg, 35% yield). MS (ES+) 341.2 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:19])([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16](O)=[O:17])[CH:12]=[CH:13][CH:14]=1)[CH3:7])=[O:5])[CH3:2].[N:20]1C=CC=CC=1.C(=O)([O-])O.[NH4+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(#N)C>[NH2:20][C:16]([CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:6]([CH3:19])([CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:17]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CC(=O)O)c1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1cccc(CC(N)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-(1-Ethoxycarbonyl-1-methylethoxy)phenylacetic acid (532 mg, 0.2 mmol) was dissolved in acetonitrile (3 mL). Subsequently, pyridine (0.1 mL, 1.24 mmol) and ammonium hydrogencarbonate (206 mg, 2.6 mmol) were added thereto, and the mixture was stirred for 10 minutes at room temperature. Thereafter, di-tert-butyl dicarbonate [Boc2O (597.2 mL, 2.6 mmol)] was added thereto, and the mixture was stirred for 14 hours. The reaction mixture was concentrated under reduced pressure, and the resultant concentrate was added to water, followed by extraction with chloroform. Subsequently, washing was performed sequentially with 1M hydrochloric acid and saturated brine. The resultant mixture was subjected to drying over magnesium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=10/1), whereby the target compound was obtained (524 mg, 0.198 mmol, 98.8%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[N-:7]=[N+:8]=[N-:9].[Na+]>C1C=CC=CC=1.Cl>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]=[N+:8]=[N-:9])=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C=NCCCl
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Product: [N-]=[N+]=NC(=O)NCCCl
Temperature: 0 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A solution of 2-chloroethyl isocyanate (0.2 mole) in 100 ml of benzene was slowly added to a stirred solution of activated sodium azide (0.2 mole) in 100 ml of hydrochloric acid (13%) maintained at 0° C. The two-phase reaction mixture was stirred for 4 hours at 0° C. and the water phase was removed. 2-chloroethylcarbamoyl azide was crystallized from benzene/petroleum ether in the form of white needles. Yield: 88%. M.P. 49.6° to 50.2° C. NMR(CDCl3 -TMS) δ=3.4 to 3.9 ppm (unres., 4H,CH2 --CH2Cl); 6.12 ppm (br, s, iH, NH); MS(14 v): m/e 148 (M+), m/e 106(M-N3)+, m/e 105 (M-HN3)+=base peak. An intensity ratio of m/e 148 / m/e 150 is typical for a monochlorinated compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[O:19])=[CH:16][C:10]=3[CH:9]=2)=[CH:6][C:5]([C:32]2[N:36]([CH2:37][CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)[N:35]=[N:34][N:33]=2)=[CH:4][N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[O:19])=[CH:16][C:10]=3[CH:9]=2)=[CH:6][C:5]([C:32]2[N:36]([CH2:37][CH2:38][CH2:39][OH:40])[N:35]=[N:34][N:33]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCn1nnnc1-c1cnc(N)c(-c2cc3cc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)ccc3s2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ncc(-c2nnnn2CCCO)cc1-c1cc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 1-(2-(2-amino-5-(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-1H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (120 mg, 0.17 mmol, 1 eq) in anhydrous tetrahydrofuran (3 mL) under nitrogen atmosphere at 0° C. was added dropwise a solution of tetrabutylammonium fluoride (1.0 M in THF, 0.51 mL, 3 eq). After the reaction was stirred at room temperature for 2 hours, it was partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was isolated, further washed with saturated aqueous sodium bicarbonate, brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated and loaded onto silica. The mixture was subject to a gradient column chromatography (EtOAc-Hex 4:1 to MeOH-EtOAc 1:25) to yield 1-(2-{2-amino-5-[1-(3-hydroxypropyl)-1H-tetrazol-5-yl]pyridin-3-yl}-1-benzothien-5-yl)-3-[4-chloro-3-(trifluoromethyl)phenyl]urea as a white solid in the amount of 63 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[ClH:24].[C:25]([O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[Cl:41])(=[O:27])[CH3:26]>C(O)(C)C>[ClH:41].[ClH:24].[C:25]([O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[NH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8])(=[O:27])[CH3:26]
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)c2cc1OC(C)=O
Temperature: 85 °C
Yield: 79.8 %

Procedure:
A mixture of N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide (178 mg), 6-acetoxy-4-chloro-7-methoxyquinazoline hydrochloride (150 mg) and isopropanol (5 ml) was stirred and heated to 85° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature and the solid was isolated and washed in turn with isopropanol (5 ml) and isohexane (2×5 ml). There was thus obtained the title compound (249 mg, 80%); NMR: 2.17 (s, 3H), 2.38 (s, 3H), 3.56 (m, 4H), 3.72 (m, 4H), 4.0 (s, 3H), 7.16 (m, 1H), 7.37 (m, 2H), 7.52 (s, 1H), 7.68 (m, 1H), 7.87 (m, 1H), 8.24 (m, 1H), 8.67 (s, 1H), 8.8 (s, 1H), 10.6 (s, 1H), 11.50 (s, 1H); m/s: M+H+ 529.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([S:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([S:16][C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[CH:15]=1)[C:9]([O:11]C)=[O:10])=[O:4].[OH-].[Na+]>>[CH3:1][N:2]([CH3:22])[C:3]([S:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([S:16][C:17](=[O:21])[N:18]([CH3:20])[CH3:19])[CH:15]=1)[C:9]([OH:11])=[O:10])=[O:4]
Reactant: COC(=O)c1cc(SC(=O)N(C)C)cc(SC(=O)N(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: CN(C)C(=O)Sc1cc(SC(=O)N(C)C)cc(C(=O)O)c1
Temperature: 0 °C
Yield: 87.1 %

Procedure:
Methyl 3,5-bis(dimethylcarbamoylthio)benzoate (3.42 g, 10 mmol) was made to react with 5% aqueous sodium hydroxide solution (10 ml. 12.5 mmol) for 3 hours at 22-25° C. with stirring. After cooling by the addition of 50 ml of ice-water, the reaction mixture was extracted with ethyl acetate (300 ml×3) and the extract was dried over magnesium sulfate. The ethyl acetate was evaporated under reduced pressure and the colorless crystals thus obtained was recrystallized from ethanol to give 2.86 g (87.2%) of 3,5-bis(dimethylcarbamoylthio)benzoic acid as colorless needles. The melting point is 196-198° C. (with decomposition).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:27][C:23]=1[C:24](O)=[O:25].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:27][C:23]=1[C:24]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[O:8][CH:5]1[CH2:4][CH2:3][C:2]([CH3:20])([CH3:1])[CH2:7][CH2:6]1)=[O:25]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: CC1(C)CCC(Oc2ncnc3c(N)cccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CCC(Oc2ncnc3c(NC(=O)c4cc(CNC(=O)C(C)(C)C)ccc4Cl)cccc23)CC1
Yield: 51.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-((4,4-dimethylcyclohexyl)oxy)quinazolin-8-amine (Intermediate-10, 50 mg, 0.185 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 99 mg, 0.369 mmol), oxalyl chloride (70 mg, 0.55 mmol), DMF (1 drop) and DIPEA (72 mg, 0.56 mmol) in CH2Cl2 (3 mL) to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.24 (s, 1H), 8.80 (s, 2H), 8.18 (m, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.73-7.71 (m, 1H), 7.59-7.54 (m, 2H), 7.39 (d, J=7.8 Hz, 1H), 5.38 (m, 1H), 4.30 (d, J=6.0 Hz, 2H), 1.95 (m, 2H), 1.81 (m, 2H), 1.51 (m, 2H), 1.34 (m, 2H), 1.12 (s, 9H), 1.00 (s, 3H), 0.97 (s, 3H); MS (m/z): 523.07 (M+H)+.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[C:18]([CH:20]=O)[S:19][C:13]=2[CH2:12][CH2:11]1)=[O:9])[CH3:6].[N:22]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N+:23]=[N-:24]>C(O)C>[CH2:5]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[C:18]([CH:20]=[C:25]([N:22]=[N+:23]=[N-:24])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[S:19][C:13]=2[CH2:12][CH2:11]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)N1CCc2cc(C=O)sc2CC1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cc2c(s1)CCN(C(=O)OCC)CC2)N=[N+]=[N-]
Temperature: 0 °C
Yield: 44.8 %

Procedure:
A solution of sodium ethoxide in ethanol (21 wt % in EtOH, 8 ml, 21.4 mmol) was diluted with additional ethanol (˜5 ml) and cooled to 0° C. To this solution was added the product from step (c) (4.50 g, 17.76 mmol) and ethyl azidoacetate (25% wt % in EtOH, 11 ml, 21.4 mmol). The reaction mixture was stirred and allowed to warm to RT over 16 hrs. The reaction mixture was then quenched by pouring into saturated aqueous NH4Cl. The aqueous mixture was extracted with Et2O (3×). The combined Et2O extracts were washed with brine, dried (MgSO4), filtered, and solvent evaporated in vacuo to give an orange oil. The crude oil was purified by flash silica-gel chromatography (gradient elution: 0 to 45% EtOAc in hexanes) to give the subtitled compound as a yellow oil (2.9 g). MS: ESI (positive): 365 (M+H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][CH2:36][O:37][CH2:38][CH3:39]>>[CH2:36]([O:37][C@@H:38]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=2)[C@H:35]([CH2:12][O:11][C:10](=[O:13])[CH3:9])[C@@H:15]([CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:25][C@@H:39]1[O:25][C@@H:15]1[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:13][C@H:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:16]1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:35]1[CH:31]=[CH:30][CH:29]=[CH:34][CH:33]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CCOCC
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](COC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Ethereal silver perchloride (0.08M, 9.58 mL, 7.67 mmol) was added with stirring at -30° C. to a solution of methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside (2.592 g, 5.59 mmol), 2,3,6-tri-O-benzyl-1,4-dideoxy-4-acetyloxymethyl-D-gluco-pyranosyl chloride (3.661 g, 6.98 mmol) in ether (20 mL). The mixture was stirred 15 min at -30° C. and silver chloride precipitated. The mixture was filtered through a celite pad, the solids were washed with ether, the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride and the organic layer was washed successively with aqueous sodium thiosulfate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a foam. Flash chromatography on silica gel and elution with a graded mixture of hexane and ethyl acetate afforded mehyl 4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethyl-α-D-glucopyranosyl) -2,3,6-tri-O-benzyl-α-D-glucopyranoside (3.19 g, 60%) as a foam.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[Na].[NH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([NH:17][NH2:18])=O)=[CH:13][CH:12]=1>CO>[NH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]2[N:2]=[C:1]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)[NH:18][N:17]=2)=[CH:13][CH:12]=1
Reactant: NNC(=O)c1ccc(N)cc1
Reactant: N#Cc1ccncc1
Agent: [Na]
Solvent: CO
Product: Nc1ccc(-c2n[nH]c(-c3ccncc3)n2)cc1
Temperature: 245 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
To 4-cyanopyridine (4.2 g.) in methanol (60 ml.) is added sodium (0.2 g.). The solution is allowed to stand for 0.5 hour at room temperature and is then added to a suspension of p-aminobenzhydrazide (6.4 g.) in 150 ml. of methanol. The resulting solution is heated 20 hours at reflux during which time a solid separates. The solid is filtered and heated to 245° C. over one hour and maintained at that temperature for an additional 15 minutes. After cooling the solid is recrystallized from a mixture of acetonitrile and water to yield 3-(p-aminophenyl)-5-(4-pyridyl)-1,2,4-triazole (2 g.) m.p. 251°-252.5° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[C:14]([CH:15]=[O:16])=[C:13]([CH3:17])[C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=1.[Cl:27][C:28]1[N:33]=[C:32](Cl)[CH:31]=[CH:30][N:29]=1.O>C(COC)OC>[Cl:27][C:28]1[N:33]=[C:32]([C:12]2[C:13]([CH3:17])=[C:14]([C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)[CH:15]=[O:16])[CH:31]=[CH:30][N:29]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccnc(Cl)n2)c(C)c1C=O
Temperature: 80 °C
Reaction time: 10 h
Yield: 87.9 %

Procedure:
A 2 M aqueous solution of sodium carbonate (2.72 mL, 5.43 mol) and tetrakistriphenylphosphine palladium(0) (209 mg, 0.181 mmol) were added to a suspension of the 6-methoxy-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde obtained in Example 4-1 (500 mg, 1.81 mmol) and 2,4-dichloropyrimidine (405 mg, 2.72 mmol) in dimethoxyethane (5.4 mL) at room temperature. The mixture thus obtained was stirred at 80° C. for 10 hours. Thereafter, the resulting solution was cooled to room temperature. Water was added to the reaction solution, and the precipitated crude product was collected by filtration and was then washed with water and diisopropyl ether to obtain the title compound (418 mg, yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH:10]2[CH2:23][NH:24][S:25](=[O:28])(=[O:27])[NH2:26])[CH:5]=[CH:6][C:7]=1[Cl:8].C(OCC)(=O)C.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[CH2:23][NH:24][S:25]([NH2:26])(=[O:27])=[O:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CNS(N)(=O)=O)C1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)NCC1CNCCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 118.6 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-[(sulfamoylamino)methyl]-1,4-oxazepane-4-carboxylate (202 mg) in ethanol (1 mL) was added 4 N hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 18 hr. The crystals obtained by concentration under reduced pressure were recrystallized from ethanol-water to give the title compound (103 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH:12]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[N:9]2[C:10](=[O:18])[CH2:11][CH2:12][CH2:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C1CC=C[C@@H]2CCC[C@H](c3cccc(F)c3)N12
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@@H]2CCC[C@H](c3cccc(F)c3)N12
Yield: 82.6 %

Procedure:
Platinum oxide (20 mg) was added to a solution of (6R*,9aS*)-6-(3-fluorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (460 mg) in methanol (10 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for three hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 383 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][C:7]3[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=3[C:5](=O)[C:4]=2[CH:3]=[CH:2]1.[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:18]=1[CH2:19][Mg]Cl>C1COCC1>[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:18]=1[CH:19]=[C:5]1[C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[CH2:8][CH2:9][C:10]2[S:1][CH:2]=[CH:3][C:4]1=2
Reactant: O=C1c2ccccc2CCc2sccc21
Reactant: Cl[Mg]Cc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: Clc1ccc(C=C2c3ccccc3CCc3sccc32)c(Cl)c1
Yield: 44.2 %

Procedure:
Following the procedures essentially as described in Example 238 and using 9,10-dihydro-1-thia-benzo[f]azulene-4-one (40.8 mg, 0.19 mmol) and 2,4-dichlorobenzyl magnesium chloride (0.575 mmol) in THF:diethyl provides, after dehydration, 30.0 mg (44%) of the title compound as a 3:1 mixture of E- and Z-isomers. 1H NMR (CDCl3) δ 2.88-3.40 (m, 4 H), 6.26 (d, J=4.8 Hz, 1/4 H), 6.50 (d, J=8.2 Hz, 3/4 H); 6.63 (s, 1/4 H, Z), 6.74 (s, 3/4 H), 6.76 (td, J=8.6 Hz, 2.0 Hz, 3/4 H), 6.88 (td, J=8.2 Hz, 1.2 Hz, 3/4 H), 6.96 (s, 3/4 H), 6.95-6.98 (m, 1/4 H), 7.06 (d, J=4.8 Hz, 3/4 H), 7.08-7.20 (m, 14/4 H), 7.28 (d, J=2.0 Hz, 3/4 H), 7.34 (d, J=2.4 Hz, 1/4 H), 7.35-7.38 (m, 1/4 H); TLC shows 0.95% purity: Rf=0.20 (hexanes).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23](C)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:7]=1.C([Mg]Cl)CCC.C(B(CC)CC)C.C([O-])(=O)C.[Na+].[NH2:45]OS(O)(=O)=O>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:45])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:5]=[N:4][CH:3]=1
Reactant: NOS(=O)(=O)O
Reactant: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)c1
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: CCCC[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 9.6 %

Procedure:
To a solution of 3-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (Example 39) (1.9 mmol) in 25 mL of dry THF was added n-BuMgCl (3.8 mL of 2.0 M THF solution, 7.5 mmol) slowly at 0° C. After stirring for additional 15 minutes, the solution was stirred at room temperature for 2 hours. The reaction mixture was re-cooled to 0° C. and triethylborane (9.5 mL of 1.0 M THF solution, 9.5 mmol) was added. After stirring at for 2 hours, the mixture was heated to reflux for 72 hours. The reaction mixture was cooled to room temperature and treated with a solution of sodium acetate (2.3 g) in 10 mL of water. After stirring for 5 minutes, hydroxylamine-O-sulfonic acid (2.3 g) was added and the mixture was stirred for 20 hours. The reaction mixture was extracted with ether (2×100 mL). The ethereal layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (isopropanol/toluene, 5:95) to give 0.07 g of 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide as a colorless solid (8%): mp 242-243° C. Anal. Calc'd. For C16H13F3N4O2S: C, 50.26, H, 3.43, N, 14.65, S, 8.39. Found: C, 50.02, H, 3.63, N, 14.26, S, 8.41.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:5][C:6](=[O:8])[CH3:7].[CH2:15]([NH2:17])[CH3:16]>>[CH2:15]([NH:17][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:5][C:6](=[O:8])[CH3:7])[CH3:16]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(F)c1
Reactant: CCN
Product: CCNc1cc(NC(C)=O)ccc1[N+](=O)[O-]

Procedure:
In a manner similar to Example 31, the title compound was prepared from 3′-fluoro-4′-nitroacetanilide and ethylamine. 1H-NMR (CDCl3): δ 8.17 (1H, br s), 8.13 (1H, d), 7.57 (1H, br d), 7.33 (1H, br s), 6.38 (1H, dd), 3.36 (2H, m), 2.22 (3H, s), 1.37 (3H, t).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:5][CH:4]=1.C1(NC(N)=S)C=CC=CC=1>C(Cl)Cl.CO>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[S:11][C:10]([NH:9][C:6]3[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=3)=[N:14][CH:13]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(Nc2ncc(-c3ccc(OC)cc3)s2)cc1
Agent: NC(=S)Nc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2cnc(Nc3ccccc3)s2)cc1

Procedure:
The title compound is prepared as described in Example 4 for (4-methoxy-phenyl)-[5-(4-methoxy-phenyl)thiazol-2-yl]-amine but using phenylthiourea. Title compound: ES-MS: 283.0 [M+H]+; single peak at tR=7.89 min (System 1); Rf=0.50 (CH2Cl2/MeOH, 98/2).