Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C([Sn](CCCC)(CCCC)[C:19]1[CH:24]=[CH:23][N:22]=[N:21][CH:20]=1)CCC.[F-].[Cs+]>CN(C)C=O.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.[Cu]I>[N:21]1[CH:20]=[CH:19][C:24]([C:2]2[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=2[OH:13])=[CH:23][N:22]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Oc1ccc(OC(F)(F)F)cc1-c1ccnnc1
Temperature: 45 °C

Procedure:
2-Iodo-4-(trifluoromethoxy)phenol (Preparation 29, 3.30 g, 9.99 mmol) and 4-(tributylstannyl)pyridazine (4.06 g, 11.0 mmol) were taken up in dimethylformamide (40 mL). Cesium fluoride (3.03 g, 20.0 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol) and copper(I) iodide (380 mg, 2.0 mmol). The reaction mixture was evacuated and purged with argon (×5) then heated at 45° C. After 2 hours the reaction mixture was cooled and diluted with ethyl acetate and water. The mixture was filtered through a pad of diatomaceous earth and washed with ethyl acetate. The aqueous phase was separated and back extracted with ethyl acetate. The combined organic phase was concentrated in vacuo. The residue was purified by silica gel column chromatography (0% to 10% methanol in dichloromethane gradient elution) then triturated with ethyl ether. The solid was collected by filtration and dried in vacuo to afford the title compound product as a yellow solid (1.18 g, 46%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[N:7]([C:16](=[O:18])[CH3:17])[CH:6]=1.B(Br)(Br)Br>ClCCl>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[N:7]([C:16](=[O:18])[CH3:17])[CH:6]=1
Reactant: COC(=O)Cc1cn(C(C)=O)c2cc(OC)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)Cc1cn(C(C)=O)c2cc(O)ccc12
Reaction time: 18 h
Yield: 31.6 %

Procedure:
To a solution of methyl(1-acetyl-6-methoxy-1H-indol-3-yl)acetate (0.67 g, 2.56 mmol) (Example 13) in dichloromethane (10 mL) was added 1 M BBr3 in dichloromethane (10.3 mL, 10.3 mmol) at −78° C. under argon. Stirring was continued at −78° C. for 1 h, at 0° C. for 3 h and at rt for 18 h consecutively. The reaction mixture was quenched with water and dichloromethane was added. Solid NaHCO3 was added to adjust the pH of the mixture to 8. The mixture was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated to yield a yellow solid (200.0 mg, 32%). LC/MS m/z 248 (M+H)+; 1H NMR (400 MHz, DMSO-d6) 9.42 (s, 1H), 7.77 (d, 1H), 7.52 (s, 1H), 7.28 (d, 1H), 6.71 (dd, 1H), 3.71 (s, 2H), 3.61 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [NH3:1].[H][H].[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[C:6]1=[O:12]>[Pd].[Zn]>[CH3:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH3:11])[C:6]1=[O:12].[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[NH2:1]
Reactant: [H][H]
Reactant: N
Agent: [Pd]
Agent: CC1CCCC(C)C1=O
Agent: [Zn]
Product: Cc1cccc(C)c1N

Procedure:
A catalyst in extrudate form, containing 0.5% by weight of Pd, 0.11% by weight of Zn and 0.1% by weight of Cd on Al2O3 as the carrier is introduced into a tubular reactor having a capacity of one liter, corresponding to 1,000 parts by volume, and is brought to 210° C. Per hour, a gaseous mixture of 400,000 parts by volume of ammonia and 10,000 parts by volume of hydrogen, and, in co-current therewith, 100 parts of 2,6-dimethylcyclohexan-1-one in gaseous form, is passed over the catalyst bed at atmospheric pressure. The reaction product is cooled sufficiently to liquefy the high-boiling constituents, which can then be distilled, whilst the gaseous constituents are recycled. In this way, 100 parts of 2,6-dimethylcyclohexan-1-one give 92 parts of 2,6-dimethylaniline (xylidine) (boiling point 216° C. at atmospheric pressure), corresponding to a yield of 96% of theory.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]2[N:9]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:10]([CH2:12][C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].CO.[OH-].[Na+].Cl>C1COCC1>[CH2:19]([CH:18]([N:9]1[C:8]2[CH:23]=[CH:24][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[CH2:12][C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[CH2:21][CH3:22])[CH3:20]
Reactant: CCC(CC)n1c(Cc2ccco2)nc2cc(C(=O)OC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)n1c(Cc2ccco2)nc2cc(C(=O)O)ccc21
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To 5.30 g of 1-(1-Ethyl-propyl)-2-furan-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 12 ml of methanol and 22 ml THF 22 ml of 1 M aqueous sodium hydroxide solution were added and the reaction was stirred for 16 h. The reaction mixture was adjusted to pH 5 by the addition of 2M aqueous hydrochloric acid and was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. 4.83 g (85%) of 1-(1-Ethyl-propyl)-2-furan-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid were obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[S:10][C:9]([CH2:11][NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)=[O:14])=[CH:8][CH:7]=1.C(OCC)(=O)C.O.[CH3:35][N:36](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:35]([C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[S:10][C:9]([CH2:11][NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)=[O:14])=[CH:8][CH:7]=1)#[N:36]
Reactant: CN(C)C=O
Reactant: O=C(NCc1ccc(Oc2cccc(Br)c2)s1)c1ccc2ncccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(Oc2ccc(CNC(=O)c3ccc4ncccc4c3)s2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
Next, to a solution of the mixture of quinoline-6-carboxylic acid (5-(3-bromophenoxy)-thiophene-2ylmethyl)-amide and debrominated compound (130 mg, 0.303 mmol) in N,N-dimethylformamide (5.0 mL) were added zinc cyanide (71 mg, 0.605 mmol) and tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmol) under nitrogen atmosphere, the solution was stirred at 100° C. for 1 hour, and the solution was stirred at 140° C. for 3 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and title compound (25 mg, 21%) was obtained as a colorless oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=O.CCOCC>ClCCl>[F:22][C:23]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:24]=1[C:25]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1ccc(-c2nc3ccccc3n2-c2ccccc2)c(F)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 59.7 %

Procedure:
N-phenyl-1,2-phenylenediamine (1.84 g, 10 mmol) and 40 ml of dichloromethane were charged in a 250 ml round bottle, 3 ml of triethylamine was then added, and the mixture was cooled to 0° C. 2,4-Difluoro-benzoyl chloride (1.94 g, 11 mmol) was dissolved in 40 ml of dichloromethane and then slowly added to the 250 ml round bottle. The reaction was conducted under a nitrogen atmosphere for 6 hours. After the reaction was complete, ether was added to form precipitation. The solid product was collected by filtration, washed with ether several times, and heated under reduced pressure to form 2-(2,4-difluoro-phenyl)-1-phenyl-1H-benzoimidazole (yield=1.83 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=1)=[O:4].ClCCCl.C(=O)(O)[O-].[Na+]>O>[O:14]=[C:12]1[C:8]2[NH:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=2[CH2:10][CH2:11]1
Reactant: COC(=O)c1cc(CCC(=O)O)c[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)c1cc2c([nH]1)C(=O)CC2
Temperature: 100 °C
Yield: 67.2 %

Procedure:
To a polyphosphoric acid (115%, 1.6 g) was added 3-(5-(methoxycarbonyl)-1H-pyrrol-3-yl)propanoic acid (174 mg, 0.88 mmol) and 1,2-dichloroethane (8 mL). The reaction mixture was heated for 1 h at 100° C. Water (20 mL) was added and the mixture was carefully poured into a 50 mL Erlenmeyer flask containing solid sodium bicarbonate and ice. The reaction was neutralized (pH 7) and was then extracted with EtOAc (5×50 mL). The combined organic extracts were washed with water, NaHCO3 and brine, dried (Na2SO4) filtered and concentrated. Purification by flash chromatography (0-40% EtOAc/Heptane) afforded methyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (106 mg, 67%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.91 (s, 4H), 3.92 (s, 3H), 6.78 (d, J=1.76 Hz, 1H), 9.33 (br s, 1H); LCMS-MS (ESI+) 180.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[CH3:18][CH:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20].N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([NH:15][S:21]([CH:19]([CH3:20])[CH3:18])(=[O:23])=[O:22])[C:9]=1[F:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc(N)c1F
Reactant: CC(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Nc1ccc(F)c(NC(=O)OC(C)(C)C)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
The tert-butyl-3-amino-2,6-difluorophenylcarbamate (100 mg, 0.41 mmol) prepared at Step 3 was added and dissolved into dichloromethane solvent. 2-propane sulfonyl chloride (50 uL, 0.45 mmol) and pyridine (36 uL, 0.045 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 94 mg of the target compound, tert-butyl-2,6-difluoro-3-(1-methylethylsulfonamido)phenylcarbamate (percentage yield: 65%), was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[C:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3]1.[NH4+].[Cl-].[CH3:21]COCC>[Cu]Cl>[CH3:21][C:4]1([CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3][C:2]([CH3:1])([CH3:18])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]1
Reactant: CCOCC
Reactant: CCOC(=O)C(C#N)=C1CC(C)(C)CC(C)(C)C1
Agent: Cl[Cu]
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(=O)C(C#N)C1(C)CC(C)(C)CC(C)(C)C1
Reaction time: 0.08 h
Yield: 47 %

Procedure:
Anhydrous copper (I) chloride (0.8 g, 8 mmol) was added to a cooled solution of alkylmagnesium iodide (prepared from magnesium (0.46 g, 19.2 mmol) and iodomethane (2.84 g, 20 mmol)) in ether (12 ml). The mixture was stirred in an inert atmosphere for 5 min and a solution of ethyl (3,3,5,5-tetramethylcyclohexylidene)cyanoacetate (16) (2 g, 8 mmol) in ether (10 ml), was added dropwise keeping the temperature below -15° C. After the addition of ketone was completed, the reaction mixture was stirred for 3 h and carefully neutralised with saturated aqueous NH4Cl solution. Traditional workup for Grignard reactions gave crude material which was separated on a silica gel column, eluting with a petroleum ether--ethyl acetate mixture (20:1) to give 1.0 g (47%) of 17 as an oil. 1H NMR (CDCl3, TMS) δ: 0.98 (9H, s, 3,5-CH3eq and 1-CH3); 1.06 (6H, s, 3,5-CH3ax); 1.31 (3H, t, J=7 Hz, ethyl-CH3); 1.2-1.5 (6H, m, ring protons); 3.41 (1H, s, α-CH) and 4.25 ppm (2H, q, J=7 Hz, CH2O).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH:6]=[CH2:7])[CH3:2].B1C2CCCC1CCC2.C([O-])([O-])=O.[Na+].[Na+].Br[C:27]1[CH:28]=[C:29]([CH:36]=[CH:37][C:38]=1[F:39])[C:30]([NH:32][CH:33]1[CH2:35][CH2:34]1)=[O:31]>C(OCC)(=O)C.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.CCO.C1C=CC=CC=1>[CH:33]1([NH:32][C:30](=[O:31])[C:29]2[CH:36]=[CH:37][C:38]([F:39])=[C:27]([CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])[CH:28]=2)[CH2:34][CH2:35]1
Reactant: O=C(NC1CC1)c1ccc(F)c(Br)c1
Reactant: C=CCC(OCC)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CCO
Product: CCOC(CCCc1cc(C(=O)NC2CC2)ccc1F)OCC
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A solution of 3-butenal diethyl acetal (144 mg, 1 mmol) and 9-BBN (0.5 M in THF, 2.2 mL, 1.1 mmol) was stirred at RT for 1 h. The mixture was concentrated and to the residue were added benzene (2 mL), EtOH (1 mL), aqueous Na2CO3 solution (2M, 1 mL), 3-bromo-4-fluoro-N-cyclopropylbenzamide (127 mg, 0.5 mmol) and Pd(Ph3P)4 (40 mg). The resulting mixture was stirred at 80° C. for 2 h. The mixture was then cooled to RT and diluted with ethyl acetate (10 mL) and washed with water. The organic layer was separated and concentrated. The residue was purified by column chromatography (SiO2; EtOAc/hexane 1:3) to afford N-cyclopropyl-3-(4,4-diethoxybutyl)-4-fluorobenzamide (151 mg, 93%). This material was dissolved in acetone (1 mL) and 3 N HCl solution (0.2 mL) and stirred at RT for 1 h. The mixture was neutralized with NaHCO3 solution and extracted with ethyl acetate (3×5 mL). The organic layer was dried and concentrated to afford N-cyclopropyl-4-fluoro-3-(4-oxo-butyl)-benzamide (110 mg, 94%). 1H NMR (CDCl3) δ 9.76 (s, 1H), 7.63 (dd, 1H, J=7.5 and 2.2 Hz,), 7.58 (m, 1H), 7.03 (t, 1H, J=9.0 Hz,), 6.47 (s, NH, 1H), 2.87 (m, 1H), 2.69 (t, 2H, J=7.5 Hz,), 2.48 (m, 2H), 1.95 (m, 2H), 0.86 (m, 2H) and 0.62 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCC(O)OC1CCCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCCCCCCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
The above-mentioned dodecanediol monotetrahydropyranyl ether (7.882 g) and 11.437 g of carbon tetrabromide were dissolved in 78 ml of dichloromethane. Triphenylphosphine (10.843 g) was added thereto under ice-cooling and the mixture was stirred at 0° C. for 5 minutes. The solvent was distilled away under reduced pressure and the residue was purified by silica gel column chromatography to give 4.029 g of 1-bromo-12-tetrahydropyranyloxydodecane.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[C:29]([N:31]2[CH:35]=[CH:34][C:33]([CH3:36])=[N:32]2)[CH:28]=[CH:27][C:3]=1[C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2/[C:10](=[CH:17]/[C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])/[C:9]([F:26])([F:25])[CH2:8][CH2:7]1)=[O:5].C1C=CC2N(O)N=[N:43][C:41]=2C=1.CCN=C=NCCCN(C)C.Cl.CN.C1COCC1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:30]=[C:29]([N:31]2[CH:35]=[CH:34][C:33]([CH3:36])=[N:32]2)[CH:28]=[CH:27][C:3]=1[C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2/[C:10](=[CH:17]/[C:18]([NH:20][CH2:21][C:22]([NH:43][CH3:41])=[O:23])=[O:19])/[C:9]([F:26])([F:25])[CH2:8][CH2:7]1)=[O:5]
Reactant: Cc1ccn(-c2ccc(C(=O)N3CCC(F)(F)/C(=C\C(=O)NCC(=O)O)c4ccccc43)c(Cl)c2)n1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)CNC(=O)/C=C1/c2ccccc2N(C(=O)c2ccc(-n3ccc(C)n3)cc2Cl)CCC1(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a solution of 258 mg of the compound of Example 10, 71 mg of HOBt and 101 mg of EDCI.HCl in 5 ml of THF, and 0.5 ml of 2.0 M methylamine-THF solution were added, and the mixture was stirred at room temperature overnight. The reaction solution was mixed with saturated NaHCO3 aq. and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by evaporation of the solvent was purified by silica gel column chromatography (chloroform-MeOH (30:1)). The residue obtained by concentration under reduced pressure was crystallized from a 2-propanol-hexane solvent mixture to obtain 51 mg of (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-[2-(methylamino)-2-oxoethyl]acetamide.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[CH:11]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:9]=[C:8]([C:19](O)=[O:20])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:32])[NH:26][C:27]([CH3:31])=[CH:28][C:29]=1[CH3:30].Cl>>[CH3:30][C:29]1[CH:28]=[C:27]([CH3:31])[NH:26][C:25](=[O:32])[C:24]=1[CH2:23][NH:22][C:19]([C:8]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:12]=2[CH:11]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:9]=1)=[O:20]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(N3CCOCC3)cc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: Cl
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCOCC3)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for example 39 from 1-(1-methylethyl)-6-(4-morpholinyl)-1H-indazole-4-carboxylic acid (55 mg, 0.19 mmol) and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone.HCl (53.8 mg, 0.29 mmol) The product was collected as an off-white solid (48 mg, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.44 (br. s., 1H) 8.49 (br. s., 1H) 8.18 (s, 1H) 7.35 (d, J=1.77 Hz, 1H) 7.10 (s, 1H) 5.88 (s, 1H) 4.95 (quin, J=6.57 Hz, 1H) 4.36 (br. s., 1H) 4.34 (br. s., 1H) 3.75-3.80 (m, 4H) 3.21-3.25 (m, 4H) 2.20 (s, 3H) 2.12 (s, 3H) 1.44 (s, 3H) 1.43 (s, 3H); LC-MS (ES) m/z=423.9
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][NH2:21])=[CH:14][CH:13]=1>>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][NH:21][CH2:9][CH:7]([OH:8])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(CCCN)cc1
Reactant: O=CC(=O)c1ccccc1
Product: Cc1ccc(CCCNCC(O)c2ccccc2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9 using phenylglyoxal and 3-(4-Methylphenyl)propanamine. Recrystallization of the chromatographed material from benzene-hexane gave the title compound m.p. 114-116. τ(CDCL3) 8.15 (2H, m), 7.7 (3H, s), 6.9-7.5 (6H, m+2H, disappears with D2O), 5.3 (1H, m), 2.9 (4H, s), 2.7 (5H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[O:22])[C@@H:17]([CH3:30])[CH2:16]1)(=[O:14])=[O:13].[C:31](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.[ClH:46]>O1CCOCC1.C(Cl)Cl.CCOCC.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>[ClH:46].[CH3:30][C@H:17]1[CH2:16][N:15]([S:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[CH3:31])(=[O:14])=[O:13])[CH2:20][CH2:19][N:18]1[C:21]([C:23]1[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=1)=[O:22]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)C[C@@H]2C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3C)C[C@@H]2C)cn1
Temperature: 100 °C

Procedure:
(2S)-4-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-2-methyl-1-[(6-methyl-3-pyridinyl)carbonyl]piperazine (may be prepared as described in Description 31) (216 mg, 0.427 mmol), potassium carbonate (153 mg, 1.109 mmol) in 1,4-dioxane (9 ml) were stirred for 5 min then trimethylboroxin (0.154 ml, 1.109 mmol) and Pd(PPh3)4 (84 mg, 0.073 mmol) were added and the reaction mixture heated at 100° C. for 1 h. The reaction mixture was concentrated under vacuum, dissolved in MeOH and filtered through a 5 g SCX column. LCMS showed still some triphenylphosphine oxide and another small impurity so the product was dissolved in EtOAc (40 ml) and extracted with HCl 2N (40 ml). 2 N NaOH was added to the aqueous layer until pH12 and product extracted with EtOAc (100 ml). The organic phase was dried on a phase separation cartridge and concentrated under vacuum. LCMS of the first EtOAc layer showed it contained some of the product so was extracted again with 2 N HCl (40 ml). 2 N NaOH was added to the aqueous layer until pH12 and product extracted with EtOAc (100 ml). The organic layer was dried on a phase separation cartridge and the two batches were combined and concentrated under vacuum to give the free base of the product. The product was suspended in DCM, 0.5 ml of 1 N HCl in ether was added and the solvent was evaporated to give the title compound (193 mg).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][NH2:21])[CH3:17].B(F)(F)F.CCOCC.C(N(CCCC)CCCC)CCC>O.C1(C)C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:22])[CH2:20][N:21]=[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:17]
Reactant: CCOC(=O)CN
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 20 °C

Procedure:
To a 250 mL round bottom flask, was added 5.52 g of benzophenone (1 eq), 8.46 g of glycine ethyl ester hydrochloride (1, 2 eq), 67 mL of toluene, and a trace amount of BF3.Et2O. The slurry was heated to reflux (112˜113° C.). Tributylamine (11.2 g) was then added dropwise over 120 min. The reaction mixture was stirred at reflux (114–116° C.) until the area percent (AP) of benzophenone <9.0% by HPLC (22–29 h). The reaction mixture was cooled to 15–25° C. and water (35 mL) was added. After phase separation, the organic phase was concentrated to 50% (w/w) under reduced pressure at <40°. The concentrated solution was then cooled to 20° C., followed by addition of methanol (3 mL). The slurry was cooled to 10° C. and stirred for 30 min. The resultant slurry was filtered. The wet cake was washed with cold water/methanol (5:1 v/v, 2×20 mL), and dried under vacuum at 20° C. for 24 h to give N-(diphenylmethylene)glycine ethyl ester (2) as an off-white to yellow solid (5.5 g, 95% pure by HPLC, 65.6% isolated yield). 1H NMR (CDCl3): δ 1.27 (t, J=7.25 Hz, 3H), 4.20 (s, 2H), 4.20 (q, J=7.07, 2H), 7.17–7.67 (m, 10H). Preparation of Ethyl 2-(diphenylmethylene)amino-2-difluoromethyl-4-cyanobutanoate from N-(Diphenylmethylene)glycine Ethyl Ester (R1=CH3CH2, R2=Ph)