Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.O>C1(C)C=CC=CC=1>[C:1](=[N:14][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Nc1cccc(O)c1
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1cccc(N=C(c2ccccc2)c2ccccc2)c1

Procedure:
3-(Benzhydrylidene-amino)-phenol was prepared as follows: A stirred solution of benzophenone imine (15.0 g, 82.8 mmol) and 3-aminophenol (9.03 g, 82.8 mmol) in 25 mL toluene was heated at reflux with removal of H2O with a Dean-Stark trap for 3.5 h. The crystals that formed from the cooled reaction mixture were collected by vacuum filtration, washed with hexanes and air dried. In this manner, 3-(benzhydrylidene-amino)phenol was obtained as a light yellow solid (17.3 g, 76%): 1H NMR (CDCl3) & 7.64 (d, 2H, J=7.1 Hz), 7.38 (d, 1H, J=7.1 Hz), 7.34-7.15 (m, 7H), 7.04 (d, 2H, J=7.2 Hz), 6.88 (t, 1H, J=8.1 Hz), 6.82 (d, 1H, J=8.2 Hz), 6.23 (s, 1H), 6.21 (d, 1H, J=7.8 Hz). Anal. Calc. for C19H15NO: C, 83.49; H, 5.53; N, 5.12. Found: C, 83.51; H, 5.65; N, 5.03.
Reaction SMILES: O1CCCC1.[S:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([S:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18]([Cl:27])=[CH:17][C:16]=1[F:28])C#N.[F:29][C:30]([Si](C)(C)C)([F:32])[F:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.CCCCCC>[F:29][C:30]([F:32])([F:31])[S:6][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([S:21][CH2:22][C:23]([F:26])([F:24])[F:25])[C:18]([Cl:27])=[CH:17][C:16]=1[F:28]
Reactant: N#CSCCCCCOc1cc(SCC(F)(F)F)c(Cl)cc1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Fc1cc(Cl)c(SCC(F)(F)F)cc1OCCCCCSC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To 60 ml of tetrahydrofuran were added 3.9 g (10.1 mmol) of 5-thiocyanatopentyl-[4-chloro-2-fluoro-5-(2,2,2-trifluoroethylthio)phenyl]ether and 4.5 g (31.6 mmol) of trifluoromethyltrimethylsilane. Thereto was added 1.0 ml (1.04 mmol) of tetrahydrofuran solution (1 mol/liter) of tetra-n-butylammonium fluoride at 0° C., and reaction was carried out. The mixture was stirred overnight at room temperature. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=20:1), to obtain 2.60 g (yield: 60%) of an intended product.
Reaction SMILES: CC(C)(C)C([C:5]12[O:14][CH:11]([CH:12]=[CH:13]1)[CH:10]1[CH:6]2[C:7](=[O:16])[O:8][C:9]1=[O:15])=O.OS(O)(=O)=O>>[OH:14][C:11]1[CH:12]=[CH:13][CH:5]=[C:6]2[C:7]([O:8][C:9](=[O:15])[C:10]=12)=[O:16]
Reactant: CC(C)(C)C(=O)C12C=CC(O1)C1C(=O)OC(=O)C12
Agent: O=S(=O)(O)O
Product: O=C1OC(=O)c2c(O)cccc21
Reaction time: 0.08 h
Yield: 73 %

Procedure:
Compound 6 (1 mmol, 266 mg) was added in small portions to 98% H2SO4 (2 ml) at 15° C. The cream colored mixture was stirred for 5 min and then poured over crushed ice. The precipitated product was filtered off, washed with ice-cold water and dried in a desiccator to afford product 7 (73%). 1H NMR (CD3OD): δ 7.40 (d, 1H, J=8.1) 7.62 (d, 1H, J=6.9), 7.85 (t, 1H, J=7.8).
Reaction SMILES: [C:1]([C:6]1[CH:22]=[C:21]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:7]=1[O:8][C:9]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:10]=1[C:11](O)=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCCCCCC>ClCCl.C(OCC)(=O)C>[C:1]([C:6]1[CH:22]=[C:21]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:7]=1[O:8][C:9]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:10]=1[C:11]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1ccc(Oc2ccc(O)cc2C(=O)O)c(C(C)(C)CC)c1
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(C)(C)c1ccc(Oc2ccc(O)cc2C(=O)Nc2ccccc2)c(C(C)(C)CC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(2,4-di-tert-pentylphenoxy)-5-hydroxybenzoic acid (3.3 g, 8.9 mmol) and oxalyl chloride (1.25 g, 9.8 mmol) in dichloromethane (75 mL) was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue triturated with toluene (25 mL) followed by distillation of the solvent. The crystalline residue was taken up in dichloromethane (80 mL) and aniline (1.66 g, 17.9 mmol) was added. The reaction mixture was allowed to stir at room temperature for 8 hours, then submitted to aqueous, acidic workup. Flash column chromatography on silica gel with 90:10 heptane:ethyl acetate yielded the addition product. Recrystallization from heptane/ethyl acetate yielded analytically pure product in 79% overall yield.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@H:12]1[CH2:14][C@@H:13]1[CH2:15][NH:16]C(=O)OC(C)(C)C.[ClH:24].CO>CO>[ClH:24].[ClH:24].[F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[C@H:12]1[CH2:14][C@@H:13]1[CH2:15][NH2:16]
Reactant: Cn1cc2c([C@H]3C[C@@H]3CNC(=O)OC(C)(C)C)c(F)ccc2n1
Agent: Cl
Solvent: CO
Product: Cn1cc2c([C@H]3C[C@@H]3CN)c(F)ccc2n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of tert-butyl {[(1S,2S)-2-(5-fluoro-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}carbamate (315 mg, 0.986 mmol) in methanol (1 mL) was added hydrochloric acid-methanol reagent (manufactured by TCI, 3 mL) solution, and the mixture was stirred at room temperature for 14 hr. The solvent was concentrated under reduced pressure and the obtained crystals were washed with ethyl acetate to give the title compound (297 mg, yield 100%).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH:8]1[C:12]2=[C:13]([S:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:14]3[C:15]([Br:21])=[CH:16][C:17]([F:20])=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9]1)([F:7])[F:6])C.[Li+].[OH-]>O1CCOCC1>[Br:21][C:15]1[C:14]2[C:13]([S:22][C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[C:12]3[CH:8]([C:5]([F:6])([F:7])[C:4]([OH:30])=[O:3])[CH2:9][CH2:10][N:11]3[C:19]=2[CH:18]=[C:17]([F:20])[CH:16]=1
Reactant: CCOC(=O)C(F)(F)C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C(F)(F)C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
The ethyl ester (65 mg) from Step 1 was dissolved in 2 mL of old (peroxide containing) 1,4-dioxane. 1 N LiOH was added (0.25 mL) and the mixture was stirred at room temperature for 2 h. Excess 1 N NaH2PO4 was added and the mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography on preparative plates eluting with 25% EtOH/CH2CL2+3% AcOH gave the desired compound (32 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[N:7]([CH3:14])[C:8]([CH2:12]Cl)=[N:9]2)=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[N:7]([CH3:14])[C:8]([CH2:12][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cn1c(CCl)nc2cc(Br)ccc2c1=O
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(CN2CCCC2)nc2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
The mixture of 7-bromo-2-(chloromethyl)-3-methylquinazolin-4(3H)-one (125 mg, 0.43 mmol), pyrrolidine (65 mg, 0.91 mmol), K2CO3 (244 mg, 1.768 mmol) and DMF (10 mL) was stirred at room temperature for 30 min. Then water was added and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over Na2SO4, filtered and evaporated to give 100 mg of the desired product. MS (ESI): 322, 324 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.O.O.Cl[Sn]Cl>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[C:6]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(-n2cccc2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(-n2cccc2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
A mixture of 1-(3,5-dinitrophenyl)pyrrole (1.52 g, 6.52 mmol) and SnCl2.2H2O (4.4 g, 19.57 mmol) in 30 mL of ethyl acetate was stirred over weekend at RT. The solvent was removed and the residue was taken in water. The aqueous layer was basified with 1 N NaOH to dissolve the tin salts, and the product was extracted into ethyl acetate. Chromatography (silica gel, hexane:ethyl acetate, 4:1) of the crude product provided 440 mg of 1-(3-amino-5-nitrophenyl)pyrrole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[CH:19](O)=[O:20]>C1(C)C=CC=CC=1>[NH:18]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:19]=[O:20])=[CH:3][CH:4]=1)[CH2:9][CH2:10][N:11]([CH3:12])[CH3:13]
Reactant: CN(C)CCC(c1ccc(N)cc1)c1ncc[nH]1
Reactant: O=CO
Solvent: Cc1ccccc1
Product: CN(C)CCC(c1ccc(NC=O)cc1)c1ncc[nH]1

Procedure:
A mixture of 3-(4-aminophenyl)-N,N-dimethyl-3-(imidazol-2-yl)propanamine (0.8 g), formic acid (2 ml) and toluene (50 ml) was boiled under reflux for 2 days in a Dean and Stark apparatus. Solvent was removed and the residue partitioned between 2 N sodium carbonate (25 ml) and ethyl acetate (3×50 ml). The extracts were dried (Na2SO4) and concentrated to a white solid. Recrystallisation from ethyl acetate gave the title compound, m.p. 142°-144°, (0.46 g). ν max (CHBr3) 3445, 3420,3390 (NH), 1690(CO), 1500, 2780 and 2820 cm-1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([S:7]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.Cl[C:21]1[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=1>>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[CH:19][C:10]=1[S:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:21]2[N:22]=[CH:23][CH:24]=[CH:25][C:26]=2[C:27]#[N:28])[CH2:2][CH2:3]1)(=[O:9])=[O:8]
Reactant: N#Cc1cccnc1Cl
Reactant: O=S(=O)(c1ccc2ccccc2n1)C1CCNCC1
Product: N#Cc1cccnc1N1CCC(S(=O)(=O)c2ccc3ccccc3n2)CC1
Yield: 86 %

Procedure:
Using the procedure from Example 7A, Step 7E, 2-(piperidin-4-ylsulfonyl)quinoline (Example 1T, Step 3, 150 mg, 0.51 mmol) was reacted with 2-chloro-3-cyanopyridine (139 mg, 1.0 mmol) to afford the title compound (166 mg), an off-white solid, in 86% yield.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1.Br[CH2:24][CH2:25][CH2:26][CH3:27]>C(#N)C>[CH2:24]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCn1nc(C(=O)NC2CCNCC2)c2ccccc21
Reactant: CCCCBr
Agent: Cl
Solvent: CC#N
Product: CCCCN1CCC(NC(=O)c2nn(CCC)c3ccccc23)CC1
Yield: 69 %

Procedure:
To a suspension of N-(4-piperidyl)-1-n-propylindazole-3-carboxamide hydrochloride (0.52 g) obtained in Example 20 in acetonitrile were successively added 50% potassium fluoride-Celite (1.10 g) and 1-bromobutane (0.22 ml), and the mixture was heated under reflux for 11 hours. The reaction solution was filtered off, distilled off under reduced pressure, and to the residue was added chloroform and saturated aqueous sodium hydrogencarbonate. After extraction with chloroform, the chloroform layer was dried over anhydrous potassium carbonate, and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the title compound (0.42 g) as a yellow oily substance. Yield=69%.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([C@@H:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=2)[O:2]1.C(N(CC)CC)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C(OCC)(=O)C>[O:28]([C:26]([NH:12][CH2:11][C@@H:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]=12)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:27])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCC[C@@H](CN)c1cccc2c1OCO2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](CNC(=O)Oc1ccccc1)c1cccc2c1OCO2
Yield: 98.9 %

Procedure:
To a mixture of 2.35 g of (R)-2-(2, 3-methylenedioxyphenyl) heptylamine, 1.20 g of triethylamine and 20 ml of ethyl acetate was dropwise added 1.72 g of phenyl chloroformate with ice cooling and stirring, and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and saturated saline in this order, dried over anhydrous sodium sulfate and the solvent evaporated to give 3.51 g of N-phenoxycarbonyl-(R)-2-(2, 3-methylenedioxyphenyl) heptylamine.
Reaction SMILES: C(N(CC)CC)C.[Si:8]([O:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)[OH:18])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:18][C@H:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:16][O:15][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])(=[O:30])=[O:29]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(F)c(Cl)c1
Reaction time: 1 h
Yield: 98.7 %

Procedure:
Triethylamine (0.480 mL, 3.44 mmol) was added to (R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethanol (0.70 g, 2.30 mmol) in DCM (10 mL) cooled in ice, and then methanesulfonyl chloride (0.213 mL, 2.76 mmol) was added. After 1 hour, the reaction mixture was diluted with DCM, washed with aqueous NaHCO3, dried over MgSO4, filtered, and evaporated to yield (R)-2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl methanesulfonate (0.87 g, 2.27 mmol, 98.9% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.47-7.44 (m, 1H), 7.29-7.24 (m, 1H), 7.16 (t, 1H), 5.51-5.47 (m, 1H), 3.94-3.89 (m, 1H), 3.81-3.76 (m, 1H), 2.97 (s, 3H), 0.88 (s, 9H), 0.04 (d, 6H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)C2
Reactant: N#Cc1ccc(Br)cc1
Product: Cc1c(C)c(N2CCN(c3ccc(C#N)cc3)CC2)c(C)c2c1OC(C)C2
Yield: 39.3 %

Procedure:
By using 1-(2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (130 mg, 0.50 mmol) synthesized in Reference example 56 and 4-bromobenzonitrile (182 mg, 1.0 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 71 mg (yield 39%).
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:10][C:11]=1[CH2:12][CH2:13][CH3:14].CSC(=S)NN=CC1N=C(CC2C=CC=CC=2)NC=1C>>[CH2:15]([C:9]1[N:8]2[C:3](=[S:2])[NH:4][N:5]=[CH:6][C:7]2=[C:11]([CH2:12][CH2:13][CH3:14])[N:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1[nH]c(Cc2ccccc2)nc1C=NNC(=S)SC
Agent: CSC(=S)NN=Cc1nc(Cc2ccccc2)[nH]c1C
Product: CCCc1nc(Cc2ccccc2)n2c(=S)[nH]ncc12

Procedure:
The procedure of Example 65 is repeated substituting an equimolecular amount of 3-[(2-benzyl-5-n-propylimidazolyl)-methylene]dithiocarbazic acid methyl ester for the 3-[(2-benzyl-5-methylimidazolyl)methylene]dithiocarbazic acid methyl ester employed in that example. There is thus obtained the title compound in equally good yield.
Reaction SMILES: Br[C:2]1[C:3]([CH3:18])=[N:4][O:5][C:6]=1[C:7]1([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]1.[CH3:19][C:20]1([CH3:27])[C:24]([CH3:26])([CH3:25])[O:23][BH:22][O:21]1.C(N(CC)CC)C>CC#N.CC#N.Cl[Pd]Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O1CCOCC1>[CH3:18][C:3]1[C:2]([B:22]2[O:23][C:24]([CH3:26])([CH3:25])[C:20]([CH3:27])([CH3:19])[O:21]2)=[C:6]([C:7]2([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]2)[O:5][N:4]=1
Reactant: CC1(C)OBOC1(C)C
Reactant: Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)c1Br
Agent: Cl[Pd]Cl
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)c1B1OC(C)(C)C(C)(C)O1
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a 50 mL round bottom flask containing tert-butyl 1-(4-bromo-3-methylisoxazol-5-yl)cyclopropylcarbamate (0.219 g, 0.621 mmol) was added dichlorobis(acetonitrile)palladium(II) (0.0025 g, 9.64 μmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.0134 g, 0.033 mmol), followed by anhydrous 1,4-dioxane (0.40 mL). The reaction vessel was evacuated and purged with N2 (g) (3×). To the flask was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.153 mL, 1.056 mmol) and triethylamine (0.294 mL, 2.113 mmol) sequentially. The reaction vessel was evacuated and purged with N2 (g) again, then heated to 100° C. The reaction mixture became heterogeneous and was judged complete within 1 h by LC-MS. The heterogeneous mixture was cooled to room temperature, dilute with EtOAc and the mixture was filtered over a plug of Celite. The filter cake was rinsed with EtOAc (3×) and the filtrate was concentrated to give a yellow oil, that crystallized upon standing under vacuum. The product tert-butyl 1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)cyclopropylcarbamate (0.226 g, 0.620 mmol, 100% yield) was used without further purification. LC/MS m/z 365 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9](N)[N:10]=2)[CH:7]=1.N([O-])=O.[Na+].C(Br)(Br)[Br:17].ClC(Cl)C(O)=O>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O.ClCCl>[Br:17][C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]2[N:8]=1
Reactant: BrC(Br)Br
Reactant: Nc1nc2ccc(Br)cn2n1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C(O)C(Cl)Cl
Agent: O=N[O-]
Solvent: ClCCl
Solvent: O
Product: Brc1ccc2nc(Br)nn2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
A mixture of 6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine (20.86 g, 97.9 mmol), sodium nitrite (67.6 g, 979 mmol) and benzyltriethylammonium bromide (53.3 g, 196 mmol) in bromoform (1.47 kg, 508 ml, 5.81 mol) was stirred for 30 minutes at 25° C. Then dichloroacetic acid (25.3 g, 16.2 ml, 196 mmol) was added and the mixture was stirred for 20 hours at 25° C. under exclusion of light. 600 ml of water were added to the mixture and stirred for 30 minutes. The mixture was diluted with water and dichloromethane, filtrated over dicalite and the filtrate extracted 3 times with dichloromethane. The organic layers were combined, washed with water, dried over magnesium sulfate, filtrated and evaporated to dryness under reduced pressure. The crude material was purified by flash chromatography in 2 portions over 2×70 g silica columns using dichloromethane/methanol 5% as eluent, affording 2,6-dibromo-[1,2,4]triazolo[1,5-a]pyridine (7 g, 26%) as light brown solid. Mp.: 201° C. MS: m/z=277.7/279.9 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)(=[O:20])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester (2.11 g, 4.1 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.11 g (56%); white solid; mp 201° C.; MS: 485.9 (M+H)+
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([Cl:16])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccccc2s1
Yield: 23 %

Procedure:
Benzothiophene-2-carboxylic acid was treated with 1.5 equivalents of oxalyl chloride in dichloromethane in the presence of a catalytic amount of DMF to form benzothiophene-2-carbonyl chloride. Following procedures described for Example 1 and substituting this acyl chloride for 3-trifluoromethylbenzoyl chloride, compound 77 was prepared in 23% yield.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:25])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2cc(F)ccc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3cc(F)ccc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a mixture of 4-{[cyclohexyl(6-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}benzoic acid (350 mg) synthesized above, β-alanine ethyl ester hydrochloride (212 mg), 1-hydroxybenzotriazole monohydrate (211 mg), triethylamine (383 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (403 mg, 91%) as a pale-yellow oil.