methyl 3-bromo-5-fluorobenzoate

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

Procedure: The same operation as in Example (42a) was performed using benzyl benzyl[cis(±)-3-methoxypiperidin-4-yl]carbamate obtained in Example (259c) (507 mg, 1.4 mmol), methyl 3-bromo-5-fluorobenzoate known in the literature (Org. Lett., 9(23), 2007, 4893-4896) (400 mg, 1.7 mmol), tris(dibenzylideneacetone)dipalladium (65 mg, 0.07 mmol), (±)-BINAP (178 mg, 0.29 mmol), cesium carbonate (1.02 g, 3.2 mmol), 1,4-dioxane (10 mL) and DMF (2.5 mL), to obtain 31 mg of the title compound as a yellow oily substance (4%).

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of Methyl-3-bromo-5-fluorobenzoate (1.97 g, 8.44 mmol) in toluene (40 ml) added Pyridine-3-boronic acid-1,3-propanediol ester (1.79 g, 7.63 mmol), potassium carbonate (11.66 g, 84.4 mmol) and tetrakis(triphenylphoshine)palladium (0) (0.49, 0.42 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 120° C. under argon overnight. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated in-vacuo. The residue was purified on silica gel using 1% methanol in dichloromethane to isolate the title compound (0.92 g, 47%) as a yellow solid. The reaction mixture was cooled to room temperature filtered through a pad of celite and concentrated in-vacuo The residue was purified on silica gel using 1% methanol in dichloromethane

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

Procedure: The same operation as in Example (42a) was performed using benzyl benzyl[cis(±)-3-methoxypiperidin-4-yl]carbamate obtained in Example (259c) (507 mg, 1.4 mmol), methyl 3-bromo-5-fluorobenzoate known in the literature (Org. Lett., 9(23), 2007, 4893-4896) (400 mg, 1.7 mmol), tris(dibenzylideneacetone)dipalladium (65 mg, 0.07 mmol), (±)-BINAP (178 mg, 0.29 mmol), cesium carbonate (1.02 g, 3.2 mmol), 1,4-dioxane (10 mL) and DMF (2.5 mL), to obtain 31 mg of the title compound as a yellow oily substance (4%).

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

Procedure: The same operation as in Example (42a) was performed using benzyl benzyl[cis(±)-3-methoxypiperidin-4-yl]carbamate obtained in Example (259c) (507 mg, 1.4 mmol), methyl 3-bromo-5-fluorobenzoate known in the literature (Org. Lett., 9(23), 2007, 4893-4896) (400 mg, 1.7 mmol), tris(dibenzylideneacetone)dipalladium (65 mg, 0.07 mmol), (±)-BINAP (178 mg, 0.29 mmol), cesium carbonate (1.02 g, 3.2 mmol), 1,4-dioxane (10 mL) and DMF (2.5 mL), to obtain 31 mg of the title compound as a yellow oily substance (4%).

Conditions: temp:80.01; pressure:0.00; stir:

Procedure: To methyl 3-bromo-5-fluorobenzoate (1.5 g, 6.44 mmol) dissolved in dry THF (20 mL) was added tert-butyl piperazine-1-carboxylate (1.199 g, 6.44 mmol), Sodium-t-butoxide (1.856 g, 19.31 mmol) and purged with N2 gas for 10 min followed by the addition of2-(Dicyclohexylphosphino)-2',4',6'-tri-i- propyl-1,1'-biphenyl (0.307 g, 0.64 mmol), Palladium II acetate (0.145 g, 0.64 mmol) . The contents were further purged with N2 gas for further 10 min and heated at 85 °C for overnight. The reaction mass was concentrated and the reside diluted with water and extracted with ethyl acetate . The combined organic extracts were washed with brine solution and dried over anhydrous sodium sulphate. The organic layer was evaporated under reduced pressure to obtain the crude product which was purified by 60-120 mesh silica gel column chromatography using 25% Ethyl acetate ; hexanes mixture to obtain 3-(4-(tert- butoxycarbonyl)piperazin-1-yl)-5-fluorobenzoic acid (1.500 g, 71.8 %) an oil. m/z (ES-), M- = 323

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of Methyl-3-bromo-5-fluorobenzoate (1.97 g, 8.44 mmol) in toluene (40 ml) added Pyridine-3-boronic acid-1,3-propanediol ester (1.79 g, 7.63 mmol), potassium carbonate (11.66 g, 84.4 mmol) and tetrakis(triphenylphoshine)palladium (O) (0.49, 0.42 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 120° C. under argon overnight. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated in-vacuo. The residue was purified on silica gel using 1% methanol in dichloromethane to isolate the title compound (0.92 g, 47%) as a yellow solid. The reaction mixture was cooled to room temperature filtered through a pad of celite and concentrated in-vacuo The residue was purified on silica gel using 1% methanol in dichloromethane

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

Procedure: The same operation as in Example (42a) was performed using benzyl benzyl[cis(±)-3-methoxypiperidin-4-yl]carbamate obtained in Example (259c) (507 mg, 1.4 mmol), methyl 3-bromo-5-fluorobenzoate known in the literature (Org. Lett., 9(23), 2007, 4893-4896) (400 mg, 1.7 mmol), tris(dibenzylideneacetone)dipalladium (65 mg, 0.07 mmol), (±)-BINAP (178 mg, 0.29 mmol), cesium carbonate (1.02 g, 3.2 mmol), 1,4-dioxane (10 mL) and DMF (2.5 mL), to obtain 31 mg of the title compound as a yellow oily substance (4%).

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the solution of Methyl-3-bromo-5-fluorobenzoate (1.97 g, 8.44 mmol) in toluene (40 ml) added Pyridine-3-boronic acid-1,3-propanediol ester (1.79 g, 7.63 mmol), potassium carbonate (11.66 g, 84.4 mmol) and tetrakis(triphenylphoshine)palladium (0) (0.49, 0.42 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 120° C. under argon overnight. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated in-vacuo. The residue was purified on silica gel using 1% methanol in dichloromethane to isolate the title compound (0.92 g, 47%) as a yellow solid. The reaction mixture was cooled to room temperature filtered through a pad of celite and concentrated in-vacuo The residue was purified on silica gel using 1% methanol in dichloromethane

Conditions: temp:80.01; pressure:0.00; stir: