tert-butyl N-[(4-fluorobenzoyl)amino]carbamate

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)

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

Procedure: To a solution of 4-fluorobenzoic acid (35.7 mmol) in 72 mL of a mixture of DMF and THF (1:1), is added tert-butyl carbazate (37.5 mmol), EDC (39.3 mmol) and N,N-dimethylaminopyridine (0.54 mmol). After 10 minutes the mixture becomes homogeneous and stirring is continued for 3 hours until the reaction is complete by TLC and LC/MS. The reaction mixture is poured into ice. Upon addition of diethylether the organic layer is separated. The organic layer is washed with sodium bisulfite, saturated sodium bicarbonate and saturated sodium chloride solution, dried over magnesium sulfate and concentrated to yield N′-(4-fluoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester: MS: (ES+) 255 (M+1)+. is continued for 3 hours until the reaction The reaction mixture is poured into ice is separated The organic layer is washed with sodium bisulfite, saturated sodium bicarbonate and saturated sodium chloride solution dried over magnesium sulfate concentrated

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′-(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, J1=8.3 Hz, 2H), 6.67 (dd, J=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)

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

Procedure: To a solution of 4-fluorobenzoic acid (35.7 mmol) in 72 mL of a mixture of DMF and THF (1:1), is added tert-butyl carbazate (37.5 mmol), EDC (39.3 mmol) and N,N-dimethylaminopyridine (0.54 mmol). After 10 minutes the mixture becomes homogeneous and stirring is continued for 3 hours until the reaction is complete by TLC and LC/MS. The reaction mixture is poured into ice. Upon addition of diethylether the organic layer is separated. The organic layer is washed with sodium bisulfite, saturated sodium bicarbonate and saturated sodium chloride solution, dried over magnesium sulfate and concentrated to yield N′-(4-fluoro-benzoyl)-hydrazinecarboxylic acid tert-butyl ester: MS: (ES+) 255 (M+1)+. is continued for 3 hours until the reaction The reaction mixture is poured into ice is separated The organic layer is washed with sodium bisulfite, saturated sodium bicarbonate and saturated sodium chloride solution dried over magnesium sulfate concentrated

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)