Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[NH:10][C:9]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:22]([O:26][C:27](=[O:36])[CH:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=2[N:10]([CH:28]([C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:36])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(C#N)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
To a chilled solution of 5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (808 mg, 3.1 mmol) in dry DMF (15 mL) was added NaH (60% dispersion mineral oil, 131 mg, 3.3 mmol) under N2 atmosphere. The reaction was stirred at room temperature for 15 min. Then at 0° C., a solution of bromophenylacetic acid tert-butyl ester (887 mg, 3.3 mmol) in DMF (5 mL) was added. The reaction was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with water, with a saturated NH4Cl aqueous solution, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel using 15% ethyl acetate in n-heptane as eluent to afford 3-(tert-butoxycarbonyl-phenyl methyl)-5-cyano-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (VIIc) (1.1 g, 78%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1ccccc1Cl
Product: Clc1ccccc1-c1cncc(Br)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 3,5-dibromo-pyridine and 2-chlorophenylboronic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29]>>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: COc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Product: COc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 73.5 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(methyloxy)benzonitrile (0.30 mmol) and 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.083 g, 0.30 mmol) were employed in a similar process described herein to prepare the title compound (0.096 g, 74%) as a white solid after deprotection and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.74 (s, 1H) 7.29-7.46 (m, 2H) 7.04 (s, 1H) 6.69-6.83 (m, 2H) 4.65 (s, 2H) 3.83 (s, 3H). ES-LCMS: m/z 435.8, 437.7 (M+1).
Reaction SMILES: [CH:1]([SiH:4]([CH:10]([CH3:12])[CH3:11])CC(C)(C)C)([CH3:3])[CH3:2].Br[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17]>>[CH3:17][CH:16]([CH3:18])[CH2:15][CH2:14][SiH:4]([CH:10]([CH3:12])[CH3:11])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)CCBr
Reactant: CC(C)[SiH](CC(C)(C)C)C(C)C
Product: CC(C)CC[SiH](C(C)C)C(C)C

Procedure:
The procedure of synthesizing Compound 51a was repeated, except that 1-bromo-3-methylbutane (12.6 mL, 100 mmol) was employed, whereby the Compound 53a was obtained as a colorless liquid (12.6 g, 73%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17]([N:20]2[CH2:36][CH2:35][C:23]3([N:27]=[C:26]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[NH:25][C:24]3=[O:34])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:28]1([C:26]2[NH:25][C:24](=[O:34])[C:23]3([CH2:22][CH2:21][N:20]([S:17]([CH2:16][CH2:15][C:12]4[CH:13]=[CH:14][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[CH:10][CH:11]=4)(=[O:18])=[O:19])[CH2:36][CH2:35]3)[N:27]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(C2CCCCC2)NC3=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(C2CCCCC2)NC3=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Acetic anhydride (45 mg, 0.44 mmol) was added to a solution of 8-[2-(4-amino-phenyl)-ethanesulfonyl]-2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (92 mg, 0.22 mmol) in CH2Cl2 (5 mL). Triethylamine (55 mg, 0.5 mmol) was then added on an ice bath, and the mixture was stirred at room temperature for one hour. The reaction mixture was diluted with dichloromethane, and the organic layer was then sequentially washed with water and saturated brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure, and the resulting residue was then purified by P-TLC to give N-{4-[2-(2-cyclohexyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl)-ethyl]-phenyl}-acetamide (55 mg, 54.3%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[CH:17](OC)(OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.CO>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:17][N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: COC(OC)OC
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nccc(-n2cnc3ccc(Br)cc32)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (750 mg, 2.68 mmol) in mixture of methanol (7 mL) and THF (30 mL) was added trimethyl orthoformate (8.81 ml, 80.32 mmol) and TsOH (0.04 ml, 0.27 mmol). The reaction mixture was stirred at 70° C. for 1 h. Then another portion of trimethyl orthoformate (4.4 ml, 40.16 mmol) was added. Stirring at 70° C. was continued for another 6 hr. The reaction mixture was allowed to cool down to RT then a saturated aqueous solution of NaHCO3 was added. The product was extracted into DCM (×3) and the combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated in vacuo to give the title compound; 1H NMR (500 MHz, DMSO) δ 7.08-7.24 (3H, m), 7.50 (1H, dd, J=8.51, 1.89 Hz), 7.71 (1H, d, J=8.51 Hz), 8.37 (1H, d, J=5.52 Hz), 8.83 (1H, d, J=1.73 Hz), 9.08 (1 H, s); LC-MS (Method B): m/z=+289.9, 291.8 (M+H)+. This compound, with LC-MS purity=70%, was used in the next step without further purification.
Reaction SMILES: [OH-].[Li+].O1CCCC1.C[O:9][C:10](=[O:38])[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([CH2:22][C:23]2[S:27][CH:26]=[N:25][C:24]=2[S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[C:13]1[CH3:37]>O>[C:31]1([S:28]([C:24]2[N:25]=[CH:26][S:27][C:23]=2[CH2:22][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)[N:12]([CH2:11][C:10]([OH:38])=[O:9])[C:13]=2[CH3:37])(=[O:29])=[O:30])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC(=O)Cn1c(C)c(Cc2scnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cc2scnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A mixture of lithium hydroxide (0.10 g), tetrahydrofuran (1.0 mL) and water (1.0 mL) was treated [3-(4-benzenesulfonylthiazol-5-ylmethyl)-5-fluoro-2-methylindol-1-yl]acetic acid methyl ester (0.20 g), and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water, concentrated to low bulk under reduced pressure and acidified by the addition of 1.0 M aqueous hydrochloric acid solution. The resulting precipitate was collected by filtration, washed with water and dried to afford the title compound as a white solid (0.19 g).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[CH:29]=[C:30]([O:34][CH3:35])[CH:31]=[CH:32][CH:33]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(Br)c1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4cccc(F)c4OC)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12h and 3-bromoanisole
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH2:20]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCN(Cc3ccccc3)CC2)cc1

Procedure:
To a solution of 48.67 g (0.35 mol) of 1-fluoro-4-nitrobenzene and 67.15 g (0.38 mol) of 1-benzylpiperazine in 600 mL of acetonitrile, add 52.65 g (0.381 mol) of anhydrous potassium carbonate. Heat the reaction mixture to reflux for 20h under nitrogen. After this time, add 300 mL of water and concentrate mixture to 500 mL volume. Extract the mixture with 3×500 mL of methylene chloride. Remove the solvent of the combined organic layers in vacuo. Triturate the resulting crystalline residue with 1000 mL of diethyl ether and filter to obtain title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:15]([CH2:24][CH:25](OC)OC)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH:25]=[CH:24][N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:13](=[O:14])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN(Cc1ccc(F)cc1)C(=O)CNC(=O)OCc1ccccc1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CN(C(=O)OCc2ccccc2)C=CN1Cc1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of N2-benzyloxycarbonyl-N1-(2,2-dimethoxyethyl)-N1-(4-fluorobenzyl)glycinamide (61.5 g, 152 mmol) and p-toluenesulfonic acid monohydrate (3 g) in toluene (450 mL) was stirred at 75° C. for 5 days. Each day an additional 3 g of toluenesulfonic acid was added. The resultant reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue dissolved in dichloromethane. The organic solution was washed successively with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residual solid was subjected to column chromatography on silica gel eluted first with dichloromethane and then 5% ethyl acetate in dichloromethane. Appropriate fractions were collected and concentrated under vacuum. Residual ethyl acetate and dichloromethane was removed by co-evaporation with toluene 3 times for subsequent hydrogenation. The residue was triturated with hexane, and filtered to provide the cyclization product as an off-white solid.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4].[CH2:16]([S:20](Cl)(=[O:22])=[O:21])[CH2:17][CH2:18][CH3:19]>N1C=CC=CC=1>[CH2:16]([S:20]([O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([OH:5])=[O:4])(=[O:22])=[O:21])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CCCCCCCCCCC(O)C(=O)O
Solvent: c1ccncc1
Product: CCCCCCCCCCC(OS(=O)(=O)CCCC)C(=O)O
Reaction time: 8 h

Procedure:
2-Hydroxydodecanoic acid (1 g) dissolved in a 10% methanolic hydrochloric acid solution was stirred at room temperature for 1 hour. The mixture was then concentrated and distributed into chloroform and water, and the chloroform layer was washed with a 1% aqueous sodium hydrogen carbonate solution and water, dried with anhydrous sodium sulfate and concentrated to give the methyl ester of 2-hydroxydodecanoic acid (1.02 g). To the methyl ester of 2-hydroxydodecanoic acid dissolved in pyridine (20 ml) was added butanesulfonyl chloride (0.80 g), and the mixture was stirred for 8 hours. Then, the pyridine was removed by distillation, and the residue was distributed into chloroform and water. The chloroform layer was dried with anhydrous sodium sulfate, concentrated and subjected-to chromatography on a silica gel column with an eluent system of n-hexane-ethyl acetate (50:1) to give the methyl ester of 2-butanesulfonyloxydodecanoic acid (1.21 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](O)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=1.S(Cl)([Cl:39])=O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([Cl:39])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=1
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(C(Cl)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc(NC(=O)c2ccccc2)c1
Yield: 75 %

Procedure:
At room temperature, 8.0 g of N-[2,6-dimethyl-4-{1-hydroxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl}phenyl]3-(benzoylamino)benzamide and 1.0 g of pyridine were introduced to 40 ml of thionyl chloride. Then, the temperature was elevated, and the mixture was stirred under reflux conditions. After the loss of the starting material was confirmed through TLC, the reaction solution was cooled and was concentrated under reduce pressure. Thus obtained residue was purified by silica gel chromatography (eluent:hexane:ethyl acetate=3:1) to give 6.2 g (yield 75%) of the title compound as a powder form.
Reaction SMILES: [C:1]([CH2:9][N:10]1[C:15]2[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:18][C:14]=2[C:13](=[O:26])[N:12]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:29]=[C:11]12)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:37][OH:38].N1C=CC=CC=1>C(O)C>[CH:19]1([N:17]2[CH2:18][C:14]3[C:13](=[O:26])[N:12]4[N:27]=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:29]=[C:11]4[N:10]([CH2:9][C:1](=[N:37][OH:38])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:15]=3[C:16]2=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cn1c2c(c(=O)n3nc(-c4ccccc4)cc13)CN(C1CCCCC1)C2=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1c2c(c(=O)n3nc(-c4ccccc4)cc3n2CC(=NO)c2ccccc2)CN1C1CCCCC1
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 4-(benzoylmethyl)-6-cyclohexyl-6,7-dihydro-2-phenyl-4H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-dione (see Example 4), (1.00 g.; 2.15 mmoles) and hydroxylamine hydrochloride (225 mg.; 3.23 mmole), in 4.5 ml of absolute ethanol and 1.5 of pyridine was heated to reflux, becoming homogenous. The solution deposited a precipitate with time, so another 2 ml. of ethanol was added to aid stirring. After a total of eight hours at reflux, the mixture was cooled and diluted with 15 ml. of ethanol. The mixture was suction filtered through a medium glass frit and the collected solid was washed with ethanol and dried in vacuo. The crude solid was suspended in boiling 95% ethanol (400 ml.), and chloroform was added until dissolution was achieved (70 ml.). About 50 ml. of the resulting solvent mixture was then boiled off before cooling to room temperature. This procedure afforded 624 mg. (60% yield) of the titled compound, m.p. >280° C. The NMR spectral analysis of a sample of this material indicated that a 1:1 mixture of the titled oxime isomers had been obtained. 1H NMR (DMSO d6, δ) (mixture of oxime isomers) 12.14 (s, 1H, OH), 11.12 (s, 1H, OH), 8.01 [d, 2H, J=7 Hz, 2-phenyl-H (ortho)], 7.89 (d, 2H, J=7 Hz, oxime-phenyl-H (ortho)], 7.2-7.7 (m, 17H, phenyl-H and pyrazole-H of one isomer), 6.76 (s, 1H, pyrazole-H), 6.12 (bs, 2H, (C(NOH)CH2), 5.72 (bs, 2H, C(NOH)CH2), 4.41 (s, 2H, NCH2), 4.30 (s, 2H, NCH2), 4.0 (m, 2H, cyclohexyl CH of both isomers), 1.1-1.9 (m, 20H, cyclohexyl CH2 of both isomers).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][C:13]=1[CH3:27])=O)C1C=CC=CC=1>[Pd].CO>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[N:22]=2)=[CH:14][C:13]=1[CH3:27]
Reactant: COC(=O)c1coc(-c2ccc(NC(=O)OCc3ccccc3)c(C)c2)n1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1coc(-c2ccc(N)c(C)c2)n1
Yield: 102.7 %

Procedure:
The same operation as in Example (95b) was performed using methyl 2-(4-{[(benzyloxy)carbonyl]amino}-3-methylphenyl)-1,3-oxazole-4-carboxylate obtained in Example (109d) (0.4 g, 1.09 mmol), 10% Pd/C (0.2 g) and methanol (10 mL), to obtain 0.26 g of the title compound as a colorless oily substance (100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:45])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([O:43][CH3:44])[CH:17]=2)[CH:10]([O:46][CH3:47])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH:10]5[O:46][CH3:47])=[O:45])=[CH:17][C:18]=4[O:43][CH3:44])=[N:42][C:27]2=3)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2OC)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCNCC2OC)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1.5 h
Yield: 37.2 %

Procedure:
To a mixture of 0.050 g (0.075 mmole) of rac-(3S,4R)-4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester (I-56) and 1 mL of dichloromethane was added 1 mL of trifluoroacetic acid-dichloromethane (25:75). The mixture was stirred for 1.5 hours, and then concentrated under reduced pressure. The residue was dissolved in methanol, and the mixture neutralized by the addition of 1M sodium hydroxide at 0 degrees. The mixture was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 1:99-90:10) to give 0.0156 g of rac-(3S,4R)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(3-methoxy-piperidin-4-yl)-benzamide (I-57).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[Cl:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21])=[O:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:27]=[CH:26][CH:25]=[CH:24][C:9]=1[C:10]([NH:12][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:21])([F:22])[F:23])[C:2]([O:4][CH2:5][CH3:6])=[O:3])=[O:11]
Reactant: O=C(NNc1ccccc1C(F)(F)F)c1ccccc1Cl
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)N(NC(=O)c1ccccc1Cl)c1ccccc1C(F)(F)F

Procedure:
1.8 ml (19 mmol) of ethyl chloroformate are added dropwise while cooling to a mixture of 4.28 g (14 mmol) of 2-chloro-N'-(α,α,α-trifluoro-o-tolyl)-benzhydrazide and 2.7 ml (19 mmol) of triethylamine in 30 ml of toluene. The reaction mixture is heated at the reflux temperature for a further 4 hours and then extracted with diethyl ether against water and sodium bicarbonate solution. The organic phase is dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residual oil is then purified by chromatography using ethyl acetate/n-hexane (1:4) as the eluent. In this manner there is obtained ethyl 3-(2-chlorobenzoyl)-2-(α,α,α-trifluoro-o-tolyl)-carbazate as an almost colourless oil, IR spectrum (CHCl3): 3405, 1735, 1710 cm-1 ; 1H-NMR (CDCl3): 4.28 (q,OCH2CH3).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:19][C:18]=1[C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: OB(O)c1ccc(F)c(-c2ncccc2F)c1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1ncccc1F
Yield: 49.2 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (100 mg, 0.43 mmol) was coupled to 4-fluoro-3-(3-fluoropyridin-2-yl)phenylboronic acid (131 mg, 0.56 mmol) as described in Example 3 part g), affording 5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-2-trifluoromethyl[1,8]-naphthyridine (82 mg, 49%). δH (360 MHz, CDCl3) 7.39-7.44 (2H, m), 7.55-7.63 (3H, m), 7.79 (1H, dd, J 2.3 and 6.5), 7.85 (1H, d, J 8.4), 8.55-8.60 (2H, m), 9.28 (1H, d, J 4.6). m/z (ES+) 388 [MH]+.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[CH2:6][N:5]([C@@H:15]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:16]([O:18]CC2C=CC(OC)=CC=2)=[O:17])[CH2:4]1)=O.[CH2:33]([C:40]1[S:41][C:42]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[C:43]([CH2:45][CH3:46])[N:44]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([C:40]1[S:41][C:42]([CH:47]2[CH2:52][CH2:51][N:50]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=4)[CH2:6][N:5]([C@@H:15]([CH:28]([CH2:29][CH3:30])[CH2:31][CH3:32])[C:16]([OH:18])=[O:17])[CH2:4]3)[CH2:49][CH2:48]2)=[C:43]([CH2:45][CH3:46])[N:44]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCC(CC)[C@@H](C(=O)OCc1ccc(OC)cc1)N1C[C@H](c2cccc(F)c2)[C@@H](C=O)C1
Reactant: CCc1nc(Cc2ccccc2)sc1C1CCNCC1
Product: CCc1nc(Cc2ccccc2)sc1C1CCN(C[C@H]2CN([C@H](C(=O)O)C(CC)CC)C[C@@H]2c2cccc(F)c2)CC1
Yield: 26.3 %

Procedure:
Reductive amination of 20 mg (0.045 mmol) of 2(S)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-ethylvaleric acid, 4-methoxybenzyl ester with 15 mg (0.42 mmol) of 4-(2-benzyl-4-ethyl-thiazol-5-yl)piperidine as described in example 527 step D, and removal of 4-methoxybenzyl ester according to example 527 step E furnished 7 mg of the title compound. Mass spec. 592.4 (M+1), HPLC A 2.36 min.