2,4,6-trifluorobenzoyl chloride

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 100 mL 3-neck round-bottomed flask fitted with condenser and magnetic stirrer were placed dry THF (20 mL) and p-methoxy acetophenone (0.386 g, 2.57 mmol) under nitrogen. To this solution, LHMDS (2.69 mL as a 1M solution in THF, 2.57 mmol) was added drop wise at 25° C. After completion of addition, the mixture was stirred for 30 min at rt, then 2,4,6-trifluoro-benzoyl chloride (0.5 g, 2.57 mmol) in THF (5 mL) was added slowly at rt via syringe. The reaction mixture was stirred overnight at rt. The reaction was quenched with saturated NH4Cl solution (10 mL). The organic layer was separated and aqueous layer was extracted with EtOAc. The combined organic layer was dries over Na2SO4, concentrated to give crude product, which was purified by column chromatography using 20% EtOAc in hexane, to give 215 mg of 1-(2,4,6-trifluoro-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (27%). 1-(2,4,6-trifluoro-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (100 mg) in DMSO (2 mL) was heated at 100-110° C. for 1 h. Then the reaction mixture was cooled to rt and diluted with water. The product was filtered and dried to give 62 mg of 5,7-difluoro-2-(4-methoxy-phenyl)-chromen-4-one (68%). MS (ES) m/z: 289.07 (M+1); 19F-NMR (DMSO-d6): δ −101.9, −109.2. In a 100 mL 3-neck round-bottomed flask fitted with condenser and magnetic stirrer After completion of addition The reaction mixture was stirred overnight at rt The reaction was quenched with saturated NH4Cl solution (10 mL) The organic layer was separated aqueous layer was extracted with EtOAc concentrated to give crude product, which was purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combine 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine (0.20 g, 0.92 mmol), 2,4,6-Trifluorobenzoyl chloride (0.357 g, 1.84 mmol), and 1,4-Dioxane (10 mL), and stir while heating at reflux. After 3 hr., cool the reaction mixture to ambient temperature and concentrate. Load the concentrated mixture onto an SCX column (10 g), wash with methanol, and elute with 2M ammonia in methanol. Concentrate the eluent to obtain the free base of the title compound as an oil (0.365 g (>100%)). Dissolve the oil in methanol (5 mL) and treat with ammonium chloride (0.05 g, 0.92 mmol). Concentrate the mixture and dry under vacuum to obtain the title compound. HRMS Obs. m/z 378.1435, Calc. m/z 378.1429; m.p. 255° C. (dec). while heating at reflux concentrate Load the concentrated mixture onto an SCX column (10 g), wash with methanol elute with 2M ammonia in methanol Concentrate the eluent

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N′-(3,4-Difluoro-thiobenzoyl)-hydrazinecarboxylic acid tert-butyl ester (0.1 mmol) prepared as described in example 3 for N′-(4-fluoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester, is treated with TFA (1 mmol) in dry CH2Cl2 (1 mL) at room temperature for 30 minutes. Solvent is removed and the residue is dissolved in dry CH2Cl2 (1 mL). DIEA (0.57 mmol) is added to the solution and the mixture is treated with 3-(4-formyl-benzooxazol-2-yl)-benzoic acid methyl ester (0.064 mmol) in the presence of 4 Å molecular sieves. 2,4,6-Trifluorobenzoyl chloride (0.15 mmol) is added after 5 minutes. The mixture is kept at room temperature for 16 hours and purified by preparative HPLC (20-100% MeCN/H2O) to yield 3-{4-[5-(3,4-difluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-benzooxazol-2-yl}-benzoic acid methyl ester. LC/MS (ES+): (M+1) 610.0, (M+Na) 632.0. Solvent is removed the residue is dissolved in dry CH2Cl2 (1 mL) purified by preparative HPLC (20-100% MeCN/H2O)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N′-(3,4-Difluoro-thiobenzoyl)-hydrazinecarboxylic acid tert-butyl ester (0.1 mmol) prepared as described in example 3 for N′-(4-fluoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester, is treated with TFA (1 mmol) in dry CH2Cl2 (1 mL) at room temperature for 30 minutes. Solvent is removed and the residue is dissolved in dry CH2Cl2 (1 mL). DIEA (0.57 mmol) is added to the solution and the mixture is treated with 3-(4-formyl-benzooxazol-2-yl)-benzoic acid methyl ester (0.064 mmol) in the presence of 4 Å molecular sieves. 2,4,6-Trifluorobenzoyl chloride (0.15 mmol) is added after 5 minutes. The mixture is kept at room temperature for 16 hours and purified by preparative HPLC (20-100% MeCN/H2O) to yield 3-{4-[5-(3,4-difluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-benzooxazol-2-yl}-benzoic acid methyl ester. LC/MS (ES+): (M+1) 610.0, (M+Na) 632.0. Solvent is removed the residue is dissolved in dry CH2Cl2 (1 mL) purified by preparative HPLC (20-100% MeCN/H2O)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N′-(6-fluoro-pyridine-3-carbothioyl)-hydrazinecarboxylic acid tert-butyl ester (0.044 mmol) prepared as described in example 3 for N′-(4-fluoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester, is treated with TFA (0.44 mmol) and thioanisole (0.44 mmol) in dry CH2Cl2 (1 mL) at room temperature for 30 minutes. The solvent is removed and the residue is dissolved in dry CH2Cl2 (1 mL). DIEA (0.22 mmol) is added to the solution and the mixture is treated with 2-difluoromethoxy-benzaldehyde (0.067 mmol) in the presence of 4 Å molecular sieves. 2,4,6-Trifluorobenzoyl chloride (0.089 mmol) is added after 5 minutes. The mixture is kept at room temperature for 16 hours and purified by preparative silica gel TLC (30% EtOAc/hexane) to yield [2-(2-difluoromethoxy-phenyl)-5-(6-fluoro-pyridin-3-yl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone: 1H NMR (400 MHz, CDCl3) 8.39 (s, 1H), 7.93-7.97 (m, 1H), 7.54 (s, 1H), 7.37-7.41 (m, 2H), 7.24-7.27 (m, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.97 (dd, J1=8.6 Hz, J2=2.7 Hz, 1H), 6.78 (t, J=8.3 Hz, 2H), 6.67 (dd, J1=75.0 Hz, J2=71.7 Hz, 1H); LC/MS (ES+): (M+1) 484.1. The solvent is removed the residue is dissolved in dry CH2Cl2 (1 mL) purified by preparative silica gel TLC (30% EtOAc/hexane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N′-(6-Methyl-pyridine-3-carbothioyl)-hydrazinecarboxylic acid tert-butyl ester (0.1 mmol) prepared as described in example 3 for N′-(4-fluoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester, is treated with TFA (1 mmol) in dry CH2Cl2 (1 mL) at room temperature for 30 minutes. Solvent is removed and the residue is dissolved in dry CH2Cl2 (1 mL). DIEA (0.287 mmol) is added to the solution and the mixture is treated with 2-difluoromethoxy-benzaldehyde (0.12 mmol) in the presence of 4 Å molecular sieves. 2,4,6-Trifluorobenzoyl chloride (0.15 mmol) is added after 5 minutes. The mixture is kept at ambient temperature for 16 hours and purified by preparative HPLC (20-100% MeCN/H2O) to yield [2-(2-difluoromethoxy-phenyl)-5-(6-methyl-pyridin-3-yl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone: 1H NMR (400 MHz, CDCl3) 8.71 (d, J=2.1 Hz, 1H), 7.81 (dd, J1=8.2 Hz, J2=2.2 Hz, 1H), 7.53 (s, 1H), 7.36-7.4 (m, 2H), 7.26 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.3 Hz, 1H), 6.78 (t, J=8.3 Hz, 2H), 6.67 (dd, J1=75.0 Hz, J2=71.7 Hz, 1H), 2.64 (s, 3H); LC/MS (ES+): (M+1) 480.1. Solvent is removed the residue is dissolved in dry CH2Cl2 (1 mL) purified by preparative HPLC (20-100% MeCN/H2O)