Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=1)[C:16]([O:18]CC)=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][N:23]=1)[C:16]([OH:18])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccnc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1cc(C(=O)O)ccn1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of ethyl 2-(N-(tert-butoxycarbonyl)methylsulfonamido)isonicotinate (0.920 g, 2.67 mmol) in THF (15 ml), aqueous 1M LiOH (2.94 ml, 2.94 mmol) was added, and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and acidified with aqueous 2N HCl. The organic layer was separated, washed with brine and dried over Na2SO4. The solvent was removed under vacuum and the solid residue was purified by trituration with iPr2O affording after filtration 2-(N-(tert-butoxycarbonyl)methylsulfonamido) isonicotinic acid as a white solid (0.625 g, 1.976 mmol, 74.0% yield, MS/ESI+ 339.2 [MNa]+).
Reaction SMILES: [C:1]1([CH:7]([C:18]([O-:20])=O)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:22]1([C:28]2([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:36]3[CH:32]([CH2:33][NH:34][CH2:35]3)[C:31](=[O:37])[CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:10][C:8]([CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:18]([N:34]1[CH2:33][CH:32]2[CH:36]([C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30][C:31]2=[O:37])[CH2:35]1)=[O:20])=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C([O-])C(C(=O)OCc1ccccc1)c1ccccc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)C(C(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1)c1ccccc1
Reaction time: 0.42 h
Yield: 2 %

Procedure:
N,N'-Carbonyldiimidazole (24.3 g) is added to a solution of monobenzyl phenylmalonate (40.5 g) in dry dichloromethane (810 cc), cooled to +5° C. The mixture is stirred for 25 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (49.1 g) and triethylamine (21 cc) in dichloromethane (1,000 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with distilled water (3×1,000 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 5.8 cm, height 63 cm), eluting with a mixture of ethyl acetate and cyclohexane (90/10 by volume) and collecting 200 cc fractions. Fractions 14 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from isopropyl ether (400 cc); the crystals obtained are drained, washed with isopropyl ether (40 cc) and dried. The crystals obtained (5 g of the 35.6 g) are chromatographed on a silica gel column (0.2-0.063 mm, diameter 4.6 cm, height 30 cm), eluting with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 100 cc fractions. Fractions 4 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa); the residue is recrystallized from acetonitrile (5 cc). The crystals obtained are drained, washed with isopropyl ether (5 cc) and dried. (3aRS,7aRS)-2-(2-benzyloxycarbonyl-2-phenylacetyl)-7,7-diphenyl-4-perhydroisoindolone (1.6 g) melting at 210° C. is obtained.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[CH2:25]2)[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH2:11][CH2:10]1)(C)(C)C>O1CCOCC1>[ClH:36].[ClH:1].[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[CH2:25]2)[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH2:13][CH2:14]1
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CN1CCC(NC(=O)OC(C)(C)C)CC1)C3
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CN1CCC(N)CC1)C3
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A 4N solution of HCl in dioxane (1.0 mL, 4 mmol) was added to a solution of {1-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-benzyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (136 mg, 0.24 mmol) in dioxane (1.0 mL). After 3 hours of stirring at RT, the precipitate was filtered off and washed with dioxane (2×). The solid was dissolved in water (2 ml) and lyophilized to give the title compound as an off-white powder (82 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ 10.97-10.60 (m, 1H), 8.63-8.24 (m, 3H), 8.15-7.98 (m, 1H), 7.76-7.41 (m, 3H), 5.08-4.86 (m, 2H), 4.73-4.48 (m, 2H), 4.44-4.17 (m, 2H), 3.60-2.96 (m, 5H), 2.85 (s, 1.5H), 2.81 (s, 1.5H), 2.63 (s, 1.5H), 2.56 (s, 1.5H), 2.23-1.78 (m, 4H). HPLC (max plot) 96.1%, Rt 2.23 min. UPLC/MS: (MS+) 439.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.Cl[CH:10]([C:15](=O)[CH2:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11]([C:10]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:8][C:15]=1[CH2:16][CH3:17])=[O:12]
Reactant: Nc1nccnc1Cl
Reactant: CCC(=O)C(Cl)C(=O)OC
Product: CCc1nc2c(Cl)nccn2c1C(=O)OC
Temperature: 170 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
3-Chloro-2-aminopyrazine (2.1 g, 16.2 mmol) and methyl 2-chloro-3-oxopentanoate (6.7 mL, 48.6 mmol) were mixed, and heated under stirring at 170° C. for 2 hours. After being allowed to cool, the unnecessary materials were filtered off and washed with ethyl acetate, and then filtrates were combined and evaporated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (0.99 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([Cl:28])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[C:12](=[CH:17][N:18](C)C)[CH2:11]2)[C:6]1=[O:21].O.[NH2:30]N>C(O)C>[Cl:28][C:22]1[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=[C:2]([Cl:1])[C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][C:13]3[C:12](=[CH:17][NH:18][N:30]=3)[CH2:11]2)[C:6]1=[O:21]
Reactant: COc1cc(Cl)c(CC2CCN(C3CCC(=O)C(=CN(C)C)C3)C2=O)c(Cl)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc(Cl)c(CC2CCN(C3CCc4n[nH]cc4C3)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Dissolve 3-(2,6-Dichloro-4-methoxy-benzyl)-1-(3-dimethylaminomethylene-4-oxo-cyclohexyl)-pyrrolidin-2-one in ethanol (Preparation 24) (50 mL), and hydrazine hydrate (2.6 mL, 54 mmol) stir the resulting orange solution for 3 days at room temp. Concentrate the mixture to dryness, dilute with ethanol (15 mL) and ether (20 mL), cooled to 0° C. and filter to give 3.6 g, 68%, as a tan solid. MS (m/z): 394 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH:25](=O)[CH:26]([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH2:25]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1)[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C=O
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccncc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)CN1CC=C(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL scintillation vial were mixed N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide (100 mg, 0.312 mmol), isobutyraldehyde (0.343 mmol), and sodium triacetoxyborohydride (0.43 mmol) in anhydrous dichloroethane (4 ml). The reaction mixture was stirred overnight at room temperature. This mixture was diluted with water and the resulting suspension was stirred again overnight at room temperature. The solid was filtered through a 30 mL plastic disposable Buchner funnel, and the collected solid was washed with water, dried for 2 hours, washed with ether, and dried again to provide the title compound. 1H NMR (400 MHz, DMSO-d6, Temp=90° C.) δ ppm 8.58 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.18 (m, 1H), 7.50 (m, 2H), 7.38 (d, J=5.1 Hz, 1H), 7.30 (m, 2H), 6.03 (m, 1H), 4.80 (m, 4H), 3.06 (m, 2H), 2.61 (t, J=5.6 Hz, 2H), 2.44 (m, 2H), 2.17 (d, J=7.2 Hz, 2H), 1.82 (m, 1H), 0.89 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 377 (M+H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[CH2:23](O)[CH2:24][OH:25].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH3:19][C:18]1([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:1])([F:21])[F:22])=[N:4][N:5]=4)[CH:8]=3)=[CH:13][CH:14]=2)[O:25][CH2:24][CH2:23][O:20]1
Reactant: CC(=O)c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Reactant: OCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CC1(c2ccc(-c3ccc4nnc(C(F)(F)F)n4c3)cc2)OCCO1
Reaction time: 8 h

Procedure:
In a 50-mL round-bottom flask equipped with a magnetic stir bar 1-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)ethanone (50 mg) was dissolved in dry toluene (1 mL), ethylene glycol (0.1 mL) and camphorsulfonic acid (a few crystals) were added. The reaction mixture was stirred overnight at reflux temperature. Extracted with concentrated NaHCO3 and EtOAc, organic layer dried over MgSO4, concentrated, and purified by chromatography (1:1 hexanes/EtOAc). The desired 6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine was isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([N:34]2[CH2:38][CH2:37][CH2:36][C@H:35]2[CH2:39][OH:40])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[OH:40][CH2:39][C@@H:35]1[CH2:36][CH2:37][CH2:38][N:34]1[S:31]([C:27]1[CH:26]=[C:25]([NH:24][C:21]([C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:15])([F:16])[F:17])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:30]=[CH:29][CH:28]=1)(=[O:33])=[O:32]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)N2CCC[C@H]2CO)c1
Product: O=C(Nc1cccc(S(=O)(=O)N2CCC[C@H]2CO)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and (S)-[1-(3-amino-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (example B.14) according to general procedure II. Pale-yellow solid. MS (ISP) 580.3 [(M+H)+]; mp 227-229° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[C:23]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][NH:14][C:13]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:11]([O:10][CH3:9])[CH:12]=1
Reactant: COc1ccc(N)cc1OC
Reactant: BrCc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(NCc2ccccc2-c2ccccc2)cc1OC
Temperature: 80 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
Potassium carbonate (1.38 g, 10 mmol), catalytic amount of potassium iodide, and 3,4-dimethoxyaniline (1.53 g 10 mmol) were added to a solution of 2-(bromomethyl)biphenyl (1.83 mL, 10 mmol) in acetonitrile (200 mL). The reaction mixture was heated and stirred at 80° C. for 18 hours, then was cooled to room temperature. The solid was filtered and the filtrate concentrated to dryness. Purification by silica gel column chromatography using 20% ethyl acetate in hexanes as the eluant afforded the pure product (1.04 g). MH+320: 1H (CDCl3) δ 3.77 (3H, s), 3.78 (3H, s), 4.21 (2H, s), 6.05 (1H, dd, J=8, 3), 6.14 (1H, m) 6.67 (1H, d, J=8), 7.28-7.42 (8H, m), 7.54 (1H, m).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](O)=[O:16])[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29]>>[CH3:25][O:26][C:27](=[O:31])[CH:28]([NH:29][C:15]([C:13]1[N:14]=[C:10]([NH:9][C:8]([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:18])[S:11][CH:12]=1)=[O:16])[CH3:30]
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Product: COC(=O)C(C)NC(=O)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Yield: 17 %

Procedure:
Prepared in 17% yield (44 mg) as described in general procedure (K) from 2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid (210 mg, 0.60 mmol) and (S)-alanine methyl ester (HCl salt, 84 mg, 0.6 mmol).
Reaction SMILES: [CH2:1]=[O:2].[CH:3]1([OH:10])[NH:8][C:6](=[O:7])[NH:5][CH:4]1[OH:9]>O>[CH2:1]([N:5]1[CH:4]([OH:9])[CH:3]([OH:10])[NH:8][C:6]1=[O:7])[OH:2]
Reactant: O=C1NC(O)C(O)N1
Reactant: C=O
Solvent: O
Product: O=C1NC(O)C(O)N1CO
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
Formaldehyde (8.85 parts of 37.3 percent solution; 0.11 mole), adjusted to pH 7-8.5, is diluted with water (20 parts). While stirring, 11.8 parts (0.1 mole) of dihydroxyethyleneurea powder are added. The temperature is raised to 55° C., held at 55° C. for 30 minutes, cooled to room temperature, and refrigerated. The sample is recovered as an 80 percent aqueous solution.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[N:20]=[C:19]([F:21])[C:18]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[F:21][C:19]1[C:18]([O:22][CH2:23][CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]2)=[CH:17][CH:16]=[C:15]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[N:20]=1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)nc2F)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2F)CC1

Procedure:
The title compound (197 mg, 70%) was prepared as a light gray solid from [4-(methylsulfonyl)phenyl]boronic acid (160 mg, 0.75 mmol), 1-methylethyl 4-{[(6-bromo-2-fluoro-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (235 mg, 0.63 mmol), Pd(PPh3)2Cl2 (45 mg, 0.06 mmol), 2M Na2CO3 (4 mL) and DME (4 mL) in a manner similar to Example 21, Step 3. The crude product was triturated with MeOH to give the title compound as a light gray solid. 1H NMR (400 MHz, CDCl3): δ 8.12 (d, 2H, J=8.3 Hz), 7.99 (d, 2H, J=8.6 Hz), 7.63 (d, 1H, J=8.3 Hz), 7.40-7.30 (m, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.30-4.15 (m, 2H), 3.92 (d, 2H, J=6.4 Hz), 3.07 (s, 3H), 2.85-2.70 (m, 2H), 2.15-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (ESI), m/z 451 (M+H).
Reaction SMILES: N1C=CC=CC=1NC1C=CC=CC=1N.C1(/C=C/C(Cl)=O)CCCCC1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1/[CH:41]=[CH:42]/[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH:43]1(/[CH:42]=[CH:41]/[C:33]2[N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[N:34]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Nc1ccccc1Nc1ccccn1
Agent: O=C(Cl)/C=C/C1CCCCC1
Product: C(=C/C1CCCCC1)\c1nc2ccccc2n1-c1ccccn1

Procedure:
The titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-Cyclohexylacryloyl chloride (Amino, Y.; Kawada, K.; Toi, K.; Kumashiro, I.; Fukushima, K. Chem. Pharm. Bull., 1988, 36, 4426) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 303.41; mp: 105.0-106.0° C.; 1H-NMR (CDCl3) δ: 8.78-8.73 (1H, m), 7.96 (1H, ddd, J=7.7, 7.7, 1.8 Hz), 7.81-7.76 (1H, m), 7.49-7.39 (3H, m), 7.33-7.18 (2H, m), 7.11 (1H, dd, J=15.8, 7.3 Hz), 6.42 (1H, dd, J=15.8, 1.5 Hz), 2.26-2.12 (1H, m), 1.98-1.60 (5H, m), 1.39-1.10 (5H, m).
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[CH3:14][O:15][C:16]1[CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:28][C:29]2[CH:40]=[CH:39][CH:38]=[CH:37][C:30]=2[C:31]([NH:33][CH2:34][C:35]#[CH:36])=[O:32])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].[N:41]([CH2:44][C:45]([NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:46])=[N+:42]=[N-:43]>CS(C)=O.O.S([O-])([O-])(=O)=O.[Cu+2].C(C(N(C(C1N=NNC=1)CC1C=CC=CC=1)C(C1N=NNC=1)CC1C=CC=CC=1)C1N=NNC=1)C1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:28][C:29]2[CH:40]=[CH:39][CH:38]=[CH:37][C:30]=2[C:31]([NH:33][CH2:34][C:35]2[N:43]=[N:42][N:41]([CH2:44][C:45](=[O:46])[NH:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH:36]=2)=[O:32])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: C#CCNC(=O)c1ccccc1NC(=O)/C=C/c1ccc(OC)c(OC)c1
Reactant: [N-]=[N+]=NCC(=O)Nc1ccccc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)NCc2cn(CC(=O)Nc3ccccc3)nn2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
Sodium ascorbate (5.4 mg, 27 μmol), tris-(benzyltriazolylmethyl)amine (2.9 mg, 5.5 μmol) and copper sulfate (0.88 mg, 5.5 μmol) were added to a solution of (E)-2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]-N-(prop-2-ynyl)benzamide (100 mg, 0.27 mmol) and 2-azido-N-phenylacetamide (48 mg, 0.27 mmol) in DMSO (4.0 mL) and water (1.0 mL). The solution was stirred at rt for 16 h and diluted with water. The suspension was filtered and the filter cake was washed with water and dried. The product was recrystallised from acetonitrile and (E)-2-(3-(3,4-dimethoxyphenyl)acrylamido)-N-((1-(2-oxo-2-(phenylamino)ethyl)-1H-1,2,3-triazol-4-yl)methyl)benzamide (127 mg, 86%) was obtained as a colourless solid; mp 189-191° C.; δH (400 MHz, DMSO-d6) 3.77 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.59 (d, J=6.8 Hz, 2H, CH2NH), 5.30 (s, 2H, CH2N), 6.79 (d, J=15.6 Hz, 1H, CH═CHCO), 6.96 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.06 (t, J3″,4″=J4″,5″=8.0 Hz, 1H, H4″), 7.15 (t, J3,4=J4,5=8.4 Hz, 1H, H4), 7.23 (dd, J5′,6′=8.4, J2′,6′=1.6 Hz, 1H, H6′), 7.28 (t, J2″,3″=J3″,4″=J4″,5″=J5″,6″=8.0 Hz, 2H, H3″, H5″), 7.37 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.50-7.56 (m, 4H, CH═CHCO, H5, H2″, H6″), 7.78 (d, J3,4=8.0 Hz, 1H, H3), 8.08 (s, 1H, C═CH), 8.57 (d, J5,6=8.0 Hz, 1H, H6), 9.37 (t, J=5.6 Hz, 1H, CH2NH), 10.43 (s, 1H, NHPh), 11.40 (s, 1H, NH); δC (100 MHz, DMSO-d6) 34.9, 40.4, 52.2, 55.5, 55.6, 110.4, 111.5, 119.2, 119.9, 120.7, 120.8, 122.6, 122.7, 123.7, 124.6, 127.3, 128.1, 128.9, 131.9, 138.4, 139.2, 141.5, 144.5, 148.9, 150.6, 164.0, 164.2, 168.3; HRMS (ESI) calculated for C29H28N6O5 [M+Na]+ 563.2013. found 516.2015; vmax 755, 1023, 1259, 1516, 1671, 3262 cm−1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:15])[C:10]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25]>CC(C)=O>[CH2:22]([NH:26][C:27]([NH:14][S:11]([C:10]1[N:9]([CH3:15])[N:8]=[CH:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:13])=[O:12])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: CCOC(=O)c1cnn(C)c1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1c(C(=O)OCC)cnn1C
Yield: 71.6 %

Procedure:
To a mixture of 5.0 g of4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide(Reference example 25), 4.45 g of dry potassium carbonate and 50 ml of acetone was added 2.13 g of n-butyl isocyanate at room temperature, and the mixture was stirred under reflux for 3 hours. After the reaction, acetone was evaporated under reduced pressure, and ice-water was added to the residue, followed by filtration of the insolubles. The filtrate was made acidic with hydrochloric acid and the crystals precipitated were filtered, washed with water and dried to give 5.1 g of N-(n-butylcarbamoyl)-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide melting at 117°-119° C. Then, this product was added into 120 ml of dry toluene, and 9.1 g of phosgene was passed into the mixture under reflux, followed further by refluxing for 1.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain crude sulfonyl isocyanate.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]([CH3:22])[CH2:20][C:19](=[O:23])[NH:18][N:17]=3)=[CH:12][C:11]=2O)=[O:8])=[CH:5][CH:4]=1)#[N:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C>O>[CH3:22][CH:21]1[CH2:20][C:19](=[O:23])[NH:18][N:17]=[C:16]1[C:13]1[CH:14]=[CH:15][C:10]2[N:9]=[C:7]([C:6]3[CH:25]=[CH:26][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[O:8][C:11]=2[CH:12]=1
Reactant: CC1CC(=O)NN=C1c1ccc(NC(=O)c2ccc(C#N)cc2)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(C#N)cc3)oc2c1

Procedure:
250 mg (718 μmol) 4-cyano-N-[2-hydroxy-4-(4-methyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenyl]-benzamide and 126 mg (718 μmol) para-toluenesulphonic acid monohydrate are refluxed with 10 ml glacial acetic acid for 3 h. Then the solv. is eliminated by rotary evaporation i.V., water is added to the residue and the product is filtered off.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C@@H:10]([CH3:26])[CH2:11][N:12]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[CH:18]=3)=[N:13]2)=[O:8])[N:6]=1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[N:33]1[C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:35]=[N:34]1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][N:12]([CH2:11][C@@H:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([C:37]4[N:33]([CH:28]5[CH2:29][CH2:30][CH2:31][CH2:32][O:27]5)[N:34]=[CH:35][CH:36]=4)[S:3][CH:4]=3)=[O:8])[CH3:26])[N:13]=2)[CH:22]=[CH:21][C:20]=1[C:23]#[N:24]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(Br)n1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(-c2ccnn2C2CCCCO2)n1
Temperature: 120 °C
Yield: 3.7 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)thiazole-4-carboxamide (300 mg, 0.666 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (222 mg, 0.799 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.020 mmol), THF and 2M Na2CO3 solution were added in a microwave flask and heated in microwave at 120° C. for 2 h. 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (37 mg) and tetrakis(triphenylphosphine)palladium (8 mg) were added and the reaction mixture was heated in 120° C. for 1 h. The reaction mixture was diluted with DCM and washed twice with Na2CO3 solution. Organic phase was dried and evaporated to dryness. The product was purified by Flash-chromatography. Yield 3.7%. m/z [522.0+1].