Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl>[CH2:33]([O:32][C:30]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1)=[O:31])[CH3:34]
Reactant: CCOC(=O)Cl
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
To an ice bath cooled solution containing 1.0 g 3.4mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole prepared as in Example 16 and 0.5 ml (3.6mmole) of triethylamine in 10 ml of methylene chloride is added 0.33 ml (3.5 mmole) of ethyl chloroformate. The reaction is allowed to warm to room temperature and stirred for several hours. Workup and chromatography in a manner analogous to that outlined in Example 18 affords the desired titled compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>C1(C)C=CC=CC=1>[C:7]([C:6]1[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][S:3][C:2]=1[NH:1][C:22]([NH:21][CH2:20][CH2:19][Cl:18])=[O:23])([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C=NCCCl
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)csc1NC(=O)NCCCl
Reaction time: 1 h

Procedure:
A solution of 2-amino-3-carboethoxy-4-phenylthiophene, prepared by the method of Gewald Chem. Ber. (1966), 99, 94, (2.47 g, 0.010 mol) in toluene (30 mL) was heated to reflux, treated with 2-chloroethylisocyanate (1.0 mL, 0.012 mol), stirred for 1 hour, treated with a second portion of 2-chloroethylisocyanate (1.0 mL, 0.012 mol), stirred for 1 hour, cooled, and concentrated. The product was crystallized from ethyl acetate/hexane to provide 2.93 g (83%) yield of the title compound.
Reaction SMILES: [C:1]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:23][CH2:24]I>CC#N>[C:1]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[C:14]([O:16][CH2:23][CH3:24])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: O=C(O)c1ccsc1C(=O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1ccsc1C(=O)c1ccncc1
Temperature: 30 °C
Reaction time: 48 h
Yield: 85.5 %

Procedure:
To a solution of 2-isonicotinoylthiophene-3-carboxylic acid (2.2 g, 9.4 mmol) from example 2.1 and Cs2CO3 (6.2 g, 18.9 mmol) in CH3CN (500 mL) was added CH3CH2I (2.9 g, 18.9 mmol) dropwise. The mixture was stirred at 30° C. for 48 h. The mixture was filtered and concentrated to give the title compound as yellow oil (2.1 g, 85.5% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](O)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:38]1[C:43](C)=CC=C[C:39]=1C.Cl.CNC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:24])[N:38]([CH3:43])[CH3:39])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Agent: CNC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, dimethylamine hydrochloride (96 mg, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-dimethylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-propionamide (10 mg, 20%) as a white solid: ESI-LRMS m/e calcd for C23H31ClN4O4S [M+] 494.2, found 495.5 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.22 (m, 2H, CH2), 1.43-1.95 (m, 8H, 4×CH2), 2.16-2.31 (m, 1H, CH), 2.79 (t, J=6.6 Hz, 2H, COCH2), 2.92 (s, 3H, NCH3), 2.93 (s, 3H, NCH3), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.6 Hz, 1H, CH), 4.34 (t, J=6.6 Hz, 2H, NCH2), 6.59 (d, J=2.3 Hz, 1H, Ar), 7.36 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.8 Hz. 1H, Ar), 7.59 (d, Jm=1.8 Hz, 1H, Ar), 7.82 (s, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])([O-:3])=[O:2].Br[C:13]#[N:14].O>C(O)C>[N+:1]([C:4]1[C:5]2[NH:11][C:13]([NH2:14])=[N:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: N#CBr
Reactant: Nc1cccc([N+](=O)[O-])c1N
Solvent: O
Solvent: CCO
Product: Nc1nc2cccc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
To a solution of 1.53 g (10 mmol) of 3-nitro-benzene-1,2-diamine in ethanol (20 mL) was added 1.3 g (12.5 mmol) of BrCN and water (5 mL). The mixture was refluxed for 1.0 h. After cooling to room temperature, the solvent was concentrated, then the residue was dissolved in water, the pH was adjusted to 8.0 with sat. NaHCO3 solution. The resulting solid was filtered, washed with water and dried under vacuum to afford 1.42 g (80%) of the 7-nitro-1H-benzoimidazol-2-ylamine LCMS: 179 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][C:17]([CH3:33])([CH3:32])[C:18]([NH:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27](O)[C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19].N1C=CC=CC=1>C(Cl)Cl>[CH3:16][C:17]([CH3:33])([CH3:32])[C:18]([NH:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19]
Reactant: COC(=O)c1c(O)cccc1NC(=O)C(C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)C(C)(C)C)cccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Trifluoromethanesulphonic anhydride (6.2 g) was added dropwise to an ice cooled, stirred solution of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (Intermediate 40, 5.02 g) and pyridine (3.16 g) in DCM (70 mL) and the mixture was stirred for 1 hour. The resulting solution was washed with 2M hydrochloric acid, filtered through a phase separator and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give methyl 2-(2,2-dimethylpropionylamino)-6-trifluoromethanesulfonyloxybenzoate (7.09 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]=[CH:9][NH:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[H-].[Na+].Br[CH2:17][CH2:18][Cl:19].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]=[CH:9][N:8]([CH2:17][CH2:18][Cl:19])[C:7](=[O:12])[C:6]=2[CH:13]=1
Reactant: O=C1NC=COc2ccc(Cl)cc21
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2cc(Cl)ccc2OC=CN1CCCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
50 mg of 7-chloro-4,5-dihydro-1,4-benzoxazepin-5-one was dissolved in dimethylformamide (1 ml), then 12 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated for 30 minutes, then 54 mg (1.5 equivalents) of 1-bromo-2-chloroethane was added and the result was agitated at room temperature for 10 hours. Ice water was added to the reaction solution, and extraction was performed by ethyl acetate. This ethyl acetate extract was washed by saline and was dried with anhydrous magnesium sulfate. The solvent was distilled off and the resultant crude product was refined with silica gel column chromatography (hexane: ethyl acetate=4:1) to obtain the above-referenced compound in an amount of 28 mg (yield of 42%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]2([CH2:20][O:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([Mg]Br)[CH:37]=[CH:38][CH:39]=1>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C:13]2([CH2:20][O:21][S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:24])=[O:23])[CH2:18][CH2:17][C:16]([OH:19])([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([O:33][CH3:32])[CH:39]=3)[CH2:15][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CCC(=O)CC2)cc1
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C2(O)CCC(COS(=O)(=O)c3ccc(C)cc3)(COS(=O)(=O)c3ccc(C)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a solution of (4-oxocyclohexane-1,1-diyl)bis(methylene) bis(4-methylbenzenesulfonate) (417 mg, 0.894 mmol) in THF (5 mL) at 0° C. was added 3-methoxyphenylmagnesium bromide (1.073 mL, 1.073 mmol) dropwise over a period of 5 min. The reaction was stirred at 0° C. for 2 h and quenched with sat′d aqueous NH4Cl (1 mL). The mixture was diluted with EtOAc (10 mL) and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residual crude oil was purified by flash chromatography on SiO2 (0-50% EtOAc:hexanes) to afford the title compound (372 mg, 72% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.76 (dd, J=10.9, 8.3 Hz, 4H), 7.37 (d, J=7.7 Hz, 4H), 7.23 (t, J=8.0 Hz, 1H), 6.93-6.88 (m, 1H), 6.88-6.82 (m, 1H), 6.78 (dd, J=8.1, 2.3 Hz, 1H), 4.00 (s, 2H), 3.81-3.78 (m, 5H), 2.47 (s, 3H), 2.43 (s, 3H), 1.79 (s, 1H), 1.73-1.60 (m, 2H), 1.61-1.53 (m, 4H), 1.53-1.45 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[O-:7].[Na+].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]2=[O:7])=[CH:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: [O-]c1cnccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cnccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 35 °C

Procedure:
A mixture of 632 mg Sodium pyrazin-2-olate and 720 mg 1-Fluoro-4-nitro-benzene and 3.3 g Cs2CO3 in 13 mL DMF was heated to 35° C. for 6 h. This solution was poured on to 300 mL of water and the resulting precipitate was collected by filtration to yield a bright yellow crystalline product, which was dried under reduced pressure. Yield: 545 mg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[CH3:11][N:12]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:10][O:9][C:4]1[N:3]=[C:2]([N:26]2[CH2:25][CH2:24][CH:23]([N:12]([CH3:11])[C:13](=[O:22])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:28][CH2:27]2)[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: CN(C(=O)OCc1ccccc1)C1CCNCC1
Reactant: COc1nc(C)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1nc(C)cc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)n1
Yield: 71 %

Procedure:
A mixture of 4-chloro-2-methoxy-6-methylpyrimidine (300 mg, 1.8987 mmol, 1 eq), benzyl methyl(piperidin-4-yl)carbamate (stage 3 AMN-52) (470 mg, 1.8987 mmol, 1 eq) and K2CO3 (523 mg, 3.796 mmol, 2 eq) in acetone (10 ml) was refluxed for 16 h. When the reaction was complete according to TLC monitoring, filtration over Celite was carried out and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 2% methanol/dichloromethane). The desired product was in the form of a light-yellow solid. Yield: 71% (500 mg, 1.3513 mmol)
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([O:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1.[ClH:21]>C(#N)C.[Cu](Cl)Cl>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([Cl:21])=[C:11]([O:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: FC(F)(F)Oc1cc(Br)ccc1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of tert-butyl nitrite (1.78 mL, 15.0 mmol), copper (II) chloride (1.61 g, 12.0 mmol) and 4-bromo-2-(trifluoromethoxy)aniline (2.56 g, 10.0 mmol) in acetonitrile (40 mL) was heated to 70° C., stirred for 3 hours, cooled to room temperature, poured into 0.5M HCl, and extracted with diethyl ether. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 275 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13]O)=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(F)cc2)c1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of [3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (5.0 g, 24 mmol) in THF (290 mL) was added phthalimide (4.7 g, 32 mmol) and triphenylphosphine (8.4 g, 32 mmol) at ambient temperature under an argon atmosphere. Then a solution of diethyl azodicarboxylate (40% in toluene, 12.5 mL, 32 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. Concentration and repeated trituration and then purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (6.0 g, 74%) as a white solid. MS: m/e=337.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH:15]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:23])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=4[C:11]([F:14])([F:13])[F:12])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)=[O:23])[CH2:17][CH2:16]1
Reactant: O=C(NCCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Product: O=C(NCCCC1CC1)c1ccc(N2CCN(C(=O)c3ccc(F)cc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 4-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide, the title compound was obtained as a white powder (49% yield). 1H NM R (300 MHz, CDCl3) δ 8.04, 7.87, 7.45-7.3, 6.99, 4.09-3.98, 3.89-3.67, 3.49, 3.33, 1.75-1.66, 1.28, 0.69-0.62, 0.43-0.37, 0.04-0.03.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:15]=[C:16]([NH2:18])[N:17]=2)[C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:15]=[C:16]([NH:18][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)[N:17]=2)[C:7]=1[NH:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc2ccc(Br)c(NC3CCCCC3)n2n1
Agent: Cl
Product: O=C(Nc1nc2ccc(Br)c(NC3CCCCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 6-bromo-N5-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A14), 616 mg; 1.99 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (424 mg; 2.38 mmol; 1.2 eq.) as a beige powder (99 mg, 12%). HPLC, Rt: 3.41 min. (purity 94.6%). LC/MS, M+(ESI): 416.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[S:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19].ClC1C=C(C=CC=1)C(OO)=[O:26]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:10]1[S:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19])=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Solvent: ClCCl
Product: CC(=O)c1cc([N+](=O)[O-])c(S(=O)c2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 66.3 %

Procedure:
To a solution of 1-[5-(2,4-Dichlorophenylsulfanyl)-4-nitro-2-thienyl]ethanone (200 mg, 0.58 mmol) as prepared in example 2 in dichloromethane (5 mL), m-chloroperoxybenzoic acid (198 mg, 1.14 mmol) was added slowly at 0° C. The mixture was stirred at ambient temperature for 10 hours. After this time the mixture was diluted with dichloromethane (25 mL) and washed with aqueous sodium bicarbonate solution (10 mL×3), then water (10 mL×2) and brine (5 mL). The organic phase was dried (Na2SO4), concentrated under vacuum to afford a yellow solid as the title product (0.14 g, 67% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.65 (1H, s), 7.96 (1H, d), 7.63 (2H, m), 2.66 (3H, s). MS m/z: 362.10 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([N:9]1[CH2:22][CH2:21][N:20](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N+:44]([O-:46])=[O:45])(=[O:37])=[O:36])[CH2:11][CH2:10]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C=O)C>[CH2:7]([O:6][P:4]([N:9]1[CH2:10][CH2:11][N:12]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N+:44]([O-:46])=[O:45])(=[O:37])=[O:36])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(OCC)N1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCCCCCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)N1CCNCCCCCCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Reaction time: 3 h
Yield: 18.3 %

Procedure:
To a stirred solution of 4-diethoxyphosphoryl-1,7-bis(2-nitrobenzenesulfonyl)-1,4,7-triazacyclotetradecane (1.32 g, 1.87 mmol) and K2CO3 (654 mg, 4.73 mmol) in DMF (11 mL) under nitrogen was added dropwise a solution of thiophenol (0.15 mL, 1.46 mmol) in DMF (8 mL) over 1 h. The mixture was stirred for an additional 3 h and then concentrated in vacuo. The residue was partitioned between CHCl3 (50 mL) and H2O (25 mL). The aqueous phase was separated and extracted with CHCl3 (3×20 mL) and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on basic alumina (CHCl3 then 3% MeOH/CHCl3) to give the title compound as a yellow oil (178 mg, 23%): 1H NMR (CDCl3) δ 1.31 (t, 6H, J=7.0 Hz), 1.40-1.67 (m, 10H), 2.65 (m, 2H), 2.78 (m, 2H), 3.12 (m, 2H), 3.26-3.37 (m, 4H), 3.48 (m, 2H), 3.97-4.09 (m, 4H), 7.61 (m, 1H), 7.68 (m, 2H), 8.06 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[CH:14]=O.Cl.[NH2:17][OH:18].Cl>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@H:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[C:4](=[O:13])[C:3]=1[CH:14]=[N:17][OH:18]
Reactant: NO
Reactant: CC(C)[C@H](C)n1ccc(Cl)c(C=O)c1=O
Agent: Cl
Solvent: CC(C)O
Product: CC(C)[C@H](C)n1ccc(Cl)c(C=NO)c1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 4-chloro-1-((2S)-3-methylbutan-2-yl)-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step C (31.8 g) in 2-propanol (300 mL) were added hydroxylamine hydrochloride (14.6 g) and conc. hydrochloric acid (0.43 mL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was crystallized from (2-propanol/diisopropyl ether), and the resulting solid was collected by filtration, and washed with 2-propanol/diisopropyl ether to give the title compound (23.2 g).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:9])=[CH:22][CH:21]=1
Reactant: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1
Yield: 85 %

Procedure:
A mixture of 3-cyclopentyl-2-(4-nitro-phenyl)-N-pyridin-2-yl-propionamide (130 mg, 0.38 mmol) in ethyl acetate (50 mL) and methanol (5 mL) was treated with a catalytic amount of 10% palladium on activated carbon (50 mg). The resulting mixture was shaken at 25° C. under 60 psi of hydrogen gas in a Parr apparatus for 24 h. At this time, the catalyst was removed by filtration through a plug of celite. The filtrate was concentrated in vacuo to afford 2-(4-amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (99.9 mg, 84.3%) as a tan oil: EI-HRMS m/e calcd for C19H23N3O (M+) 309.1834, found 309.1849.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[S:21](Cl)(=[O:23])=[O:22]>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[S:21]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1F
Reactant: Nc1ccccc1S(N)(=O)=O
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccccc1F
Yield: 31 %

Procedure:
The title compound was synthesized as described for Example 178 in 31% yield, starting from 2-aminobenzenesulfonamide and (E)-2-(2-fluorophenyl)ethenesulfonyl chloride.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][C:11]#[CH:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O)(=O)/C=C/C(O)=O>>[CH2:10]([O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1[N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)[C:11]#[CH:12]
Reactant: CN1CCNCC1
Reactant: C#CCOCCn1c(Cl)nc2ccccc21
Agent: O=C(O)/C=C/C(=O)O
Product: C#CCOCCn1c(N2CCN(C)CC2)nc2ccccc21

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(propargyloxy)ethyl]benzimidazole (3.00 g), N-methylpiperazine (2.70 g) and fumaric acid (1.52 g), there are obtained crude crystals, which are recrystallized from ethyl acetate-ethanol to give 1-[2-(propargyloxy)ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole.3/2 fumarate (2.80 g) as colorless plates, m.p. 145°-146.5° C.