5-CHLORO-2-(TRIFLUOROMETHYL)PHENYLBORONIC ACID

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (5-chloro-2-(trifluoromethyl)phenyl)boronic acid (0.453 g, 2.02 mmol), tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.669 g, 2.02 mmol), tetrakis(triphenylphosphine)palladium (0.117 g, 0.1 mmol), sodium carbonate (2 M, 5 mL), and 1,2-dimethoxyethane (10 mL) was heated at 80° C. under microwave irradiation for 1.5 h. After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The extract was washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-25% EtOAc in hexanes) to give tert-butyl 4-(5-chloro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as colorless oil (0.614 g, 84%): 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.5 Hz, 1H), 7.37-7.22 (m, 1H), 7.22 (d, J=1.68 Hz, 1H), 5.60 (br, 1H), 4.02 (br, 2H), 3.61 (br, 2H), 2.34 (br, 2H), 1.50 (s, 9H); MS (ESI+) m/z 306 [M+H]+. After cooling to ambient temperature extracted with ethyl acetate (80 mL) The extract was washed with brine (2×50 mL) dried over Na2SO4 filtered concentrated under reduced pressure The resulting residue was chromatographed over silica gel (0-25% EtOAc in hexanes)

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

Procedure: Under argon (in a flask dried by heating), 113 mg (0.25 mmol) of tert-butyl 4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate), 67 mg (0.30 mmol, 1.2 eq.) of 5-chloro-2-trifluoromethylphenylboronic acid, 103 mg (0.74 mmol, 3.0 eq.) of potassium carbonate and 20 mg (0.03 mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxane and stirred overnight in an oil bath already preheated to 110° C. A further 10 mg (0.01 mmol, 0.05 eq.) of [1,1-bis-(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct and 22 mg (0.10 mmol, 0.4 eq.) of 5-chloro-2-trifluoromethylphenylboronic acid were added and the reaction mixture was stirred at 110° C. for a further 20 h and then filtered through Celite. The residue was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The residue was triturated with water, filtered off, washed with water and dried under reduced pressure. Yield: 145 mg (purity 84%, 89% of theory) already preheated to 110° C the reaction mixture was stirred at 110° C. for a further 20 h filtered through Celite The residue was washed with dioxane The combined filtrates were concentrated under reduced pressure The residue was triturated with water filtered off washed with water dried under reduced pressure

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

Procedure: 127 mg (purity 70%, 0.2 mmol) of tert-butyl 4-{[2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate) and 54 mg (0.24 mmol) of 5-chloro-2-trifluoromethylphenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. After aqueous work-up, the crude product was triturated with water and the solid was filtered off, dried and purified further by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 124 mg (quant.) After aqueous work-up, the crude product was triturated with water the solid was filtered off dried purified further by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures)

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

Procedure: 2.04 g (7.8 mmol) of ethyl (4-bromo-2-oxopyridin-1(2H)-yl)acetate and 1.98 g (8.6 mmol) of 5-chloro-2-trifluoromethylphenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 2.89 g (quant.)

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

Procedure: 250 mg (0.8 mmol) of ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoate (racemate) and 214 mg (0.96 mmol) of 5-chloro-2-trifluoromethylphenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 35 mg (purity 87%, 9% of theory) of the title compound and 70 mg (22% of theory) of the product which is already hydrolysed (Example 6.1F)

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

Procedure: 2.0 g (6.4 mmol) of tert-butyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)propanoate (racemate) and 1.7 g (7.7 mmol) of 5-chloro-2-(trifluoromethyl)phenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 2.3 g (purity 91%, 82% of theory)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (5-chloro-2-(trifluoromethyl)phenyl)boronic acid (0.453 g, 2.02 mmol), tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.669 g, 2.02 mmol), tetrakis(triphenylphosphine)palladium (0.117 g, 0.1 mmol), sodium carbonate (2 M, 5 mL), and 1,2-dimethoxyethane (10 mL) was heated at 80° C. under microwave irradiation for 1.5 h. After cooling to ambient temperature, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL). The extract was washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-25% EtOAc in hexanes) to give tert-butyl 4-(5-chloro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate as colorless oil (0.614 g, 84%): 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.5 Hz, 1H), 7.37-7.22 (m, 1H), 7.22 (d, J=1.68 Hz, 1H), 5.60 (br, 1H), 4.02 (br, 2H), 3.61 (br, 2H), 2.34 (br, 2H), 1.50 (s, 9H); MS (ESI+) m/z 306 [M+H]+. After cooling to ambient temperature extracted with ethyl acetate (80 mL) The extract was washed with brine (2×50 mL) dried over Na2SO4 filtered concentrated under reduced pressure The resulting residue was chromatographed over silica gel (0-25% EtOAc in hexanes)

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

Procedure: Under argon (in a flask dried by heating), 113 mg (0.25 mmol) of tert-butyl 4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate), 67 mg (0.30 mmol, 1.2 eq.) of 5-chloro-2-trifluoromethylphenylboronic acid, 103 mg (0.74 mmol, 3.0 eq.) of potassium carbonate and 20 mg (0.03 mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxane and stirred overnight in an oil bath already preheated to 110° C. A further 10 mg (0.01 mmol, 0.05 eq.) of [1,1-bis-(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct and 22 mg (0.10 mmol, 0.4 eq.) of 5-chloro-2-trifluoromethylphenylboronic acid were added and the reaction mixture was stirred at 110° C. for a further 20 h and then filtered through Celite. The residue was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The residue was triturated with water, filtered off, washed with water and dried under reduced pressure. Yield: 145 mg (purity 84%, 89% of theory) already preheated to 110° C the reaction mixture was stirred at 110° C. for a further 20 h filtered through Celite The residue was washed with dioxane The combined filtrates were concentrated under reduced pressure The residue was triturated with water filtered off washed with water dried under reduced pressure

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

Procedure: 127 mg (purity 70%, 0.2 mmol) of tert-butyl 4-{[2-(4-bromo-5-cyano-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate) and 54 mg (0.24 mmol) of 5-chloro-2-trifluoromethylphenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. After aqueous work-up, the crude product was triturated with water and the solid was filtered off, dried and purified further by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures). Yield: 124 mg (quant.) After aqueous work-up, the crude product was triturated with water the solid was filtered off dried purified further by flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures)

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

Procedure: 2.04 g (7.8 mmol) of ethyl (4-bromo-2-oxopyridin-1(2H)-yl)acetate and 1.98 g (8.6 mmol) of 5-chloro-2-trifluoromethylphenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 2.89 g (quant.)

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

Procedure: 250 mg (0.8 mmol) of ethyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoate (racemate) and 214 mg (0.96 mmol) of 5-chloro-2-trifluoromethylphenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 35 mg (purity 87%, 9% of theory) of the title compound and 70 mg (22% of theory) of the product which is already hydrolysed (Example 6.1F)

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

Procedure: 2.0 g (6.4 mmol) of tert-butyl 2-(4-bromo-2-oxopyridin-1(2H)-yl)propanoate (racemate) and 1.7 g (7.7 mmol) of 5-chloro-2-(trifluoromethyl)phenylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0) were reacted according to General Method 2A. Yield: 2.3 g (purity 91%, 82% of theory)