Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH:19](=[N:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)[O:8][C:4]=2[CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1CCN(c2nc3cc(Cl)c(N)cc3o2)CC1
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CN1CCN(c2nc3cc(Cl)c(N=Cc4ccccc4)cc3o2)CC1

Procedure:
A 30 mg portion of 6-amino-5-chloro-2-(4-methyl-1-piperazinyl)benzoxazole was dissolved in 20 ml of anhydrous toluene, and the solution was mixed with 1 ml of benzaldehyde and heated under reflux for 6 hours. The solvent was concentrated under a reduced pressure, the residual oily matter was mixed with hexane and then the thus formed precipitate was collected by filtration to obtain the title compound (24 mg) in white color.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[O:12])[CH:7]=[C:6]([CH2:19][CH3:20])[C:4]=1[NH2:5])[CH3:2].[C:21](Cl)(Cl)=[S:22].O.C(=O)([O-])[O-].[Ca+2]>ClCCl>[CH2:19]([C:6]1[CH:7]=[C:8]([N:10]([CH:11]=[O:12])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:3]([CH2:1][CH3:2])[C:4]=1[N:5]=[C:21]=[S:22])[CH3:20]
Reactant: S=C(Cl)Cl
Reactant: CCc1cc(N(C=O)c2ccccc2)cc(CC)c1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: O
Product: CCc1cc(N(C=O)c2ccccc2)cc(CC)c1N=C=S

Procedure:
With stirring, a solution of 24.0 g of 2,6-diethyl-4-(N-phenyl-N-formylamino)aniline in 80 ml of dichloromethane are added dropwise at 0° to 10° C. to 13.4 g of thiophosgene, 100 ml of dichloromethane, 60 ml of water and 19 g of calcium carbonate. The reaction mixture is stirred for 2 hours at room temperature and then filtered. The organic phase is separated, washed with 50 ml of water, dried over sodium sulfate and then concentrated by evaporation. The title compound of formula ##STR15## is obtained in the form of a crystalline powder which melts at 77°-78° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:9]=[C:8]([C:19]([O:21]C(C)(C)C)=[O:20])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[N:9]=[C:8]([C:19]([OH:21])=[O:20])[CH:7]=1
Reactant: COc1ccc(-n2nc(C(=O)OC(C)(C)C)cc2-c2ccco2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccco2)cc1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
Part C. To tert-butyl 5-(2-furyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (1.0 g, 3.0 mmol) was added dichloromethane (7 mL) and trifluoroacetic acid (7 mL). The resulting black solution was maintained at rt under nitrogen for 2 h and was then concentrated to dryness. The resulting mixture was triturated with chloroform, and the remaining solid was washed with 50% hexanes in chloroform to afford 5-(2-furyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylic acid (800 mg, 96%) as a light brown solid. 1H NMR (d6-DMSO) δ 7.75 (b m, 1H), 7.41 (d, 2H), 7.10 (d, 2H), 7.09 (s, 1H), 6.51 (br m, 1H), 6.09 (d, 1H), 3.84 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]([N:24]([CH3:26])[CH3:25])=O)[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.[B].O1CCCC1.[Cl-].[NH4+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:24]([CH3:26])[CH3:25])[C:17]=3[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: CN(C)C(=O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [B]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 13 h
Yield: 28.5 %

Procedure:
To a solution of 1-(2,4-dichlorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxamide (200 mg, 0.513 mmol) was added boron-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran, 2.6 mL, 2.6 mmol), and the mixture was stirred at 70° C. for 13 hr. To the mixture was added aqueous saturated ammonium chloride, and the mixture was stirred at 70° C. for 20 main. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with diisopropyl ether to give the title compound as a colorless powder (54.8 mg, 0.146 mmol, 28%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[N:8]([C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH2:28])=[CH:23][C:22]=2[CH3:30])[C:9](C2C=CC=CC=2[N+]([O-])=O)=[CH:10][CH:11]=1)[CH3:2].C([O-])=O.[NH4+:35]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[N:8]([C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[NH2:28])=[CH:23][C:22]=2[CH3:30])[C:9]([C:21]2[CH:26]=[CH:25][C:24]([NH2:35])=[CH:23][CH:22]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)CCc1ccc(-c2ccccc2[N+](=O)[O-])n1-c1ccc(C(N)=O)cc1C
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Product: CCOC(=O)CCc1ccc(-c2ccc(N)cc2)n1-c1ccc(C(N)=O)cc1C
Reaction time: 24 h

Procedure:
3-[1-(4-carbamoyl-2-methyl-phenyl)-5-(nitro-phenyl)-1H-pyrrole-2-yl]-propanoic acid ethyl ester (83 mg, 0.2 mmol) was dissolved in 2 mL methanol under an inert atmosphere of nitrogen. To this solution was added ammonium formate (117 mg, 1.8 mmol) and 10% Pd/C (10 mg). After 24 hrs, the reaction mixture was filtered using celite, rinsed with MeOH and concentrated in vacuo. The residue was diluted with acetone, filtered and the filtrate concentrated in vacuo to give the crude product, which was purified using preparative TLC (solvent: 5% IPA/CH2Cl2). The band corresponding to 3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propanoic acid ethyl ester (Rf=0.6) was isolated and dried under high vacuum (36 mg, 77%, light orange hydroscopic powder).
Reaction SMILES: [N:1]1([CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]([O-:9])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:30][C:31]1([O:44][CH3:45])[C:38](=[O:39])[N:37]2[CH:32]1[S:33][CH2:34][C:35]([CH3:43])=[C:36]2[C:40]([OH:42])=[O:41]>O1CCCC1>[C:10]([CH:6]([N:1]1[CH:2]=[CH:3][CH:4]=[CH:5]1)[C:7]([NH:30][C:31]1([O:44][CH3:45])[C:38](=[O:39])[N:37]2[CH:32]1[S:33][CH2:34][C:35]([CH3:43])=[C:36]2[C:40]([OH:42])=[O:41])=[O:9])([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C(=O)[O-])n1cccc1
Reactant: COC1(N)C(=O)N2C(C(=O)O)=C(C)CSC21
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)NC1(OC)C(=O)N2C(C(=O)O)=C(C)CSC21)n1cccc1
Temperature: 0 °C

Procedure:
2-(1-Pyrryl)propanedioic acid, 3-ethyl ester, 1 equivalent and 1 equivalent of triethylamine is added to tetrahydrofuran (THF) which is cooled to 0° C. While stirring, iso-butyl chloroformate, 1 equivalent, is added and the temperature is maintained at 0° C. for about 15 minutes. A cold solution of 7-amino-7-methoxy-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1 equivalent, and triethylamine, 1 equivalent, in 50% aqueous THF is added with stirring to the previous solution.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=2[CH3:15])[C:6](=[S:16])[N:5]([CH3:17])[N:4]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(#N)C.C(N(CC)CC)C.C(Cl)(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:1][C:2]([F:19])([F:18])[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:10][C:9]=2[CH3:15])[C:6](=[S:16])[N:5]([CH3:17])[N:4]=1
Reactant: Cc1cc(I)ccc1-n1c(C(F)(F)F)nn(C)c1=S
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C#C[Si](C)(C)C)ccc1-n1c(C(F)(F)F)nn(C)c1=S
Yield: 101.8 %

Procedure:
To a stirred mixture of 5.00 g (0.0125 mole) of 3-trifluoromethyl-4,5-dihydro-4-(4-iodo-2-methylphenyl)-1-methyl-1,2,4-triazol-5(1H)-thione and 2.46 g (0.0250 mole) of trimethylsilylacetylene in 20 ml of acetonitrile and 100 ml of triethylamine was added 0.0880 g (0.000125 mole) of bis(triphenylphosphine)palladium (II) chloride and 0.048 g (0.00025 mole) of copper (I) iodide. The reaction mixture was heated at reflux for approximately 18 hours. The solvents were removed from the reaction mixture by evaporation under reduced pressure, leaving a residue. This residue was dissolved in chloroform, and the organic solution was washed in succession with an aqueous, saturated sodium chloride solution and an aqueous, 20% ammonium chloride solution. The washed organic phase was evaporated under reduced pressure, leaving a dark oil. This oil was purified by column chromatography on silica gel, eluting with chloroform, to yield 4.7 g of 3-trifluoromethyl-4,5-dihydro-1-methyl-4-(2-methyl-4-trimethylsilylethynylphenyl)-1,2,4-triazol-5(1H)-thione as a solid, mp 90°-93° C., Compound 113 of Table 1. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[C:10]=1[F:18])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:19]C(OC(C)=O)=O.C(OCC)(OCC)OCC.[NH2:36][C:37]1([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][CH2:39][CH2:38]1>C1(C)C=CC=CC=1>[OH:44][CH2:43][CH2:42][C:37]1([NH:36][CH:19]=[C:3]([C:2](=[O:1])[C:9]2[CH:14]=[C:13]([F:15])[C:12]([F:16])=[C:11]([F:17])[C:10]=2[F:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CC(=O)OC(C)=O
Reactant: NC1(CCO)CCCC1
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC1(CCO)CCCC1)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
A stirred solution of ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (20.3 g, 76.8 mmol), Ac2O (44.0 mL, 0.465 mol) and triethyl orthoformate (25.6 mL, 0.154 mol) was heated at 120° C. for 3 hours. The mixture was concentrated in vacuo and dried under high vacuum. 1-amino-1-(2-hydroxyethyl)cyclopentane (9.94 g, 76.9 mmol) in anhydrous toluene (50 mL) was slowly added to a solution of the mixture in anhydrous toluene (200 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation. Flash chromatography (AcOEt:Hexane=2:1) of the residue gave the title compound as a colorless solid (23.2 g, 75%). 1H-NMR (400 MHz, CDCl3) δ 0.96 (0.6H, t, J=7.3 Hz), 1.09 (2.4H, t, J=7.3 Hz), 1.48-1.54 (1H, m), 1.74-1.90 (6H, m), 1.97-2.06 (4H, m), 3.78-3.85 (2H, m), 3.98-4.10 (2H, m), 6.95-7.12 (1H, m), 8.17-8.24 (1H, m), 9.81-9.94 (0.3H, m), 11.20-11.35 (0.7H, m).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[F:6][C:7]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[F:6][C:7]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:8]=1[C:9]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1F
Reaction time: 1 h

Procedure:
At 0° C., 0.258 ml (2.7 mmol, 1.0 eq.) of tert-butanol was added to a solution of 500 mg (2.7 mmol) of 2-fluoro-4-nitrobenzoic acid and 1.03 g (5.4 mmol, 2.0 eq.) of para-toluenesulphonyl chloride in 5.4 ml of pyridine, the mixture was stirred for 60 min and a further 0.258 ml (2.7 mmol, 1.0 eq.) of tert-butanol was added. The reaction mixture was stirred for another 18 h and concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the residue. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was then purified by normal phase chromatography (mobile phase: cyclohexane/ethyl acetate 14%-20% mixtures). Yield: 524 mg (75% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[O:15][CH2:16][C:17](=[O:24])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][N:32]=2)[C:27]([CH:34]=O)=[CH:26]1.[OH-].[Na+]>C(O)C.Cl>[NH:25]1[C:33]2=[N:32][CH:31]=[CH:30][CH:29]=[C:28]2[C:27]([CH:34]=[C:16]2[O:15][C:14]([NH:13][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:7][C:2]=3[F:1])=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2=[O:24])=[CH:26]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(OCCOC)cc2F)OCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(OCCOC)cc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 35.2 %

Procedure:
To a solution of ethyl 2-{[2-fluoro-4-(2-methoxyethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.011 g, 0.032 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0045 g, 0.031 mmol) in ethanol (0.2 mL), 2M hydrochloric acid in ethanol (0.016 mL, 0.032 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. Cooled with ice bath, 2M sodium hydroxide solution (0.015 mL, 0.029 mmol) was added dropwise to neutralize, and ethanol (1.5 mL) was added. The mixture was refluxed for further 30 min. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.0051 g, y. 32%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2.[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]Cl.O>CN(C)C=O>[F:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(O)ccc3c2)cc1-c1ccccc1
Reactant: Fc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4ccccc4F)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
Sodium hydride (60%, oily, 36.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propionate (360 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 2-Fluorobenzyl chloride (0.119 ml) was added to this mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[1-[6-(2-fluorobenzyloxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (404 mg, yield: 88%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:54][C:55]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][C:56]=1[C:62]1[CH:67]=[CH:66][C:65]([C:68](O)=[O:69])=[CH:64][CH:63]=1>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:68]([C:65]1[CH:66]=[CH:67][C:62]([C:56]2[CH:57]=[C:58]([F:61])[CH:59]=[CH:60][C:55]=2[F:54])=[CH:63][CH:64]=1)=[O:69]
Reactant: O=C(O)c1ccc(-c2cc(F)ccc2F)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2cc(F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 19.9 %

Procedure:
DIPEA (211 mg, 0.28 mL, 1.6 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (140.5 mg, 0.399 mmol) in DMF (3 mL). HOBT (53.9 mg, 0.39 mmol) and EDCI (139.2 mg, 0.72 mmol) were then added at room temperature. After 2 minutes, 2′,5′-difluoro-biphenyl-4-carboxylic acid (85 mg, 0.36 mmol) (prepared by the method as described above) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 38 mg (19.79% yield) of 2′,5′-difluoro-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.02%. 1H NMR (DMSO-d6): δ 8.7 (s, 1H), 8.0 (d, 2H), 7.9-7.65 (m, 5H), 7.6-7.46 (m, 2H), 7.44-7.25 (m, 2H), 4.3-4.1 (d, 2H), 3.6-3.4 (m, 4H), 3.26-3.04 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH3:11])[N:8]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:5]2=[N:6][CH:7]=1.[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[C:9]([CH3:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc2cc(Br)cnc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2cc(Br)cnc2n1COCC[Si](C)(C)C
Product: Cc1nc2ncc(Br)cc2n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To 5.06 g of 5-bromo-2,3-diaminopyridine 46 (Ryabukhin et al (2006) Synthesis 21:3715-3726; Oguchi et al (2000) J. Med. Chem. 43(16):3052-3066; Seki et al (1995) J. Hetero. Chem. 32(3):1071-73; Fray et al (1995) J. Med. Chem. 38(18):3524-35) was added 50 mL acetic acid under N2 and the reaction was heated to reflux overnight. Complete reaction was confirmed by LCMS. The solution was concentrated in vacuo and purified by flash chromatography (DCM/MeOH) to give 4.68 g of 6-bromo-2-methyl-3H-imidazo[4,5-b]pyridine 51 (82% yield), which may also be prepared by the methods of Cee et al (2007) J. Med. Chem. 50(4):627-40; Itoh et al (1982) J. Hetero. Chem. 19(3):513-17. 6-Bromo-2-methyl-3H-imidazo[4,5-b]pyridine (4.68 g) in 150 mL THF was added to 0.63 g (1.1 eq) NaH in 10 mL THF under N2 at −78° C. The reaction was stirred at −78° C. for 30 minutes followed by the addition of 3.86 g of SEM-Cl (1.05 eq) and allowed to warm up to room temperature. The reaction was stirred at room temperature 4.5 hours and complete reaction was confirmed by LCMS. The reaction was quenched with water followed by the addition of NaCl (not saturated) and the two products extracted with EtOAc and concentrated in vacuo. The two regioisomers were separated by flash chromatography (EtOAc/Hexanes) to give 2.84 g 6-bromo-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 52 and 1.94 g 6-bromo-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine 53 (63% overall yield). 6-Bromo-2-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 52 (2.08 g) was dissolved in 50 mL toluene followed by the addition of 2.32 g (1.5 eq) of bis(pinacolato)diboron, 0.24 g (0.05 eq) of PdCl2(dppf), and 1.79 g (3.0 eq) of KOAc. The reaction mixture was heated to 95° C. under N2 and let stir overnight. Complete reaction confirmed by LCMS. The mixture was cooled to room temperature, rotovapped and purified by flash chromatography (EtOAc/Hexanes) to give 1.83 g of 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine 54 (77% yield). MS (Q1) 390.2 (M)+
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=O)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].Cl.[NH2:30][OH:31].N1C=CC=CC=1>C(O)C.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([C:19](=[N:30][OH:31])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: NO
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(=NO)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 68.2 %

Procedure:
Compound 1 (0.300 g, 0.812 mmol) was dissolved in ethanol (10 mL), and hydroxylamine monohydrochloride (0.113 g, 1.63 mmol) and pyridine (0.145 mL, 1.79 mmol) was added to the solution, followed by stirring at 60° C. for 3.5 hours. The reaction mixture was diluted with chloroform, and sequentially washed with water, 0.5 mol/L hydrochloric acid, and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude crystals were recrystallized from ethanol to obtain Compound 3 (0.213 g, yield 68%).
Reaction SMILES: N1CCCCC1.[C:7]([O:11][C:12]([NH:14][CH2:15][CH2:16][NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27]C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[CH:23][CH:22]=1)=[O:19])=[O:13])([CH3:10])([CH3:9])[CH3:8].O>CN(C=O)C>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:18]([NH:17][CH2:16][CH2:15][NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])=[O:19])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NCCNC(=O)Nc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.3 %

Procedure:
Piperidine (9.68 mL, 97.75 mmol, 5.0 eq) was added at room temperature to a stirred solution of N-(4-[({2-[(tert-butoxy)carbonylamino]ethyl)amino)carbonylamino]phenyl}(fluoren-9-ylmethoxy)carboxamide (10.10 g, 19.55 mmol, 1.0 eq) in DMF (140 mL). After 2 hours stirring at room temperature, water was added to the reaction mixture and precipitation occurred. The resulting mixture was filtered, and the liquid phase was concentrated to afford 6.75 g of the expected product as an orange oil: