(5-chloro-2-methylphenyl)boronic acid

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

Procedure: Methyl 5-bromopicolinate (5.0 g, 23.1 mmol), (5-chloro-2-methylphenyl)boronic acid (4.5 g, 26.6 mmol), Pd(dppf)Cl2 (1.9 g, 2.3 mmol), and K2CO3 (6.4 g, 46.3 mmol) were dissolved in 1,4-dioxane (100 mL) and water (25 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound. washed with water and brine dried (Na2SO4) dry

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

Procedure: A mixture of ethyl 3-acetyl-1H-pyrazole-5-carboxylate (364 mg, 2.0 mmol), (5-chloro-2-methylphenyl)boronic acid (680 mg, 4.0 mmol), copper(II) acetate (571 mg, 3.0 mmol) and pyridine (0.32 mL, 4 mmol) in DCM (10 mL) was stirred at r.t. under an air atmosphere for 48 h. After removal of the insolubles by filtration, the filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (hexane/AcOEt, 90/10) to obtain ethyl 3-acetyl-1-(5-chloro-2-methylphenyl)-1H-pyrazole-5-carboxylate as a white solid (269 mg, 43%), After removal of the insolubles by filtration the filtrate was washed with water and saturated brine dried over anhydrous sodium sulfate concentrated in vacuo purified by flash chromatography (hexane/AcOEt, 90/10)

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

Procedure: A mixture of ethyl 3-acetyl-1H-pyrazole-5-carboxylate (364 mg, 2.0 mmol), (5-chloro-2-methylphenyl)boronic acid (680 mg, 4.0 mmol), copper(II) acetate (571 mg, 3.0 mmol) and pyridine (0.32 mL, 4 mmol) in DCM (10 mL) was stirred at r.t. under an air atmosphere for 48 h. After removal of the insolubles by filtration, the filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by flash chromatography (hexane/AcOEt, 90/10) to obtain ethyl 3-acetyl-1-(5-chloro-2-methylphenyl)-1H-pyrazole-5-carboxylate as a white solid (269 mg, 43%), After removal of the insolubles by filtration the filtrate was washed with water and saturated brine dried over anhydrous sodium sulfate concentrated in vacuo purified by flash chromatography (hexane/AcOEt, 90/10)

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

Procedure: The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-2,2-dimethyl-propionamide (CAS RN 113975-32-9) and 5-chloro-2-methylphenylboronic acid (CAS RN 148839-33-2) and using a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (99%). MS (ESI): m/z=303.126 [M+H]+.

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.1 g of 3-(S)-benzyl-1-(4-bromo-benzyl)-piperazine were combined with 1.5 equiv. of 5-chloro-2-methylphenyl boronic acid, 0.05 equiv. of tetrakis(triphenylphosphine)palladium(0), 6 equiv. of 2M aqueous sodium carbonate solution, toluene and ethanol. The reaction mixture was heated at 85° C. under nitrogen overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to afford 0.077 g of the title compound. Yield 68% ES MS (+) m/z 391. The reaction mixture was concentrated in vacuo The residue was diluted with water extracted with ethyl acetate The combined organic phases were washed with brine dried over sodium sulfate filtered concentrated in vacuo The crude material was purified by flash chromatography

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-chloro-2-phenylpyrimidine-5-carbaldehyde (50 mg, 0.23 mmol) and 4-chloro-o-toluene boronic acid (48 mg, 0.29 mmol) in dioxane (1 mL) and H2O (0.5 mL) was added Pd(PPh3)4 (26.5 mg, 0.02 mmol), K2CO3 (126.5 mg, 0.92 mmol). The reaction was heated to 85° C. for 6 hrs. After concentration under reduced pressure, the residue was diluted with EtOAc (10 mL) and the organic layer was washed with saturated NH4Cl solution (10 mL), and brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the crude product (70 mg). The crude product was purified by flash chromatography (silica gel, 20% EtOAc/hexane) to give 4-(4-chloro-2-methylphenyl)-2-phenylpyrimidine-5-carbaldehyde (63 mg, 75%) as a white solid. After concentration under reduced pressure the residue was diluted with EtOAc (10 mL) the organic layer was washed with saturated NH4Cl solution (10 mL), and brine (10 mL) dried (MgSO4) filtered concentrated under reduced pressure to give the crude product (70 mg) The crude product was purified by flash chromatography (silica gel, 20% EtOAc/hexane)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-chloro-2-phenylpyrimidine-5-carbaldehyde (50 mg, 0.23 mmol) and 4-chloro-o-toluene boronic acid (48 mg, 0.29 mmol) in dioxane (1 mL) and H2O (0.5 mL) was added Pd(PPh3)4 (26.5 mg, 0.02 mmol), K2CO3 (126.5 mg, 0.92 mmol). The reaction was heated to 85° C. for 6 hrs. After concentration under reduced pressure, the residue was diluted with EtOAc (10 mL) and the organic layer was washed with saturated NH4Cl solution (10 mL), and brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the crude product (70 mg). The crude product was purified by flash chromatography (silica gel, 20% EtOAc/hexane) to give 4-(4-chloro-2-methylphenyl)-2-phenylpyrimidine-5-carbaldehyde (63 mg, 75%) as a white solid. After concentration under reduced pressure the residue was diluted with EtOAc (10 mL) the organic layer was washed with saturated NH4Cl solution (10 mL), and brine (10 mL) dried (MgSO4) filtered concentrated under reduced pressure to give the crude product (70 mg) The crude product was purified by flash chromatography (silica gel, 20% EtOAc/hexane)

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

Procedure: In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 5-chloro-2-methylphenylboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(5′-chloro-2′-methyl-biphenyl-3-yl)-3-isopropyl-imidazolidin-2-one as a light yellow oil. MS: 469.1 ([M+H]+)

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

Procedure: Methyl 5-bromopicolinate (5.0 g, 23.1 mmol), (5-chloro-2-methylphenyl)boronic acid (4.5 g, 26.6 mmol), Pd(dppf)Cl2 (1.9 g, 2.3 mmol), and K2CO3 (6.4 g, 46.3 mmol) were dissolved in 1,4-dioxane (100 mL) and water (25 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound. washed with water and brine dried (Na2SO4) dry

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

Procedure: Methyl 5-bromopicolinate (5.0 g, 23.1 mmol), (5-chloro-2-methylphenyl)boronic acid (4.5 g, 26.6 mmol), Pd(dppf)Cl2 (1.9 g, 2.3 mmol), and K2CO3 (6.4 g, 46.3 mmol) were dissolved in 1,4-dioxane (100 mL) and water (25 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound. washed with water and brine dried (Na2SO4) dry

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

Procedure: Under argon (in a flask dried by heating), 92 mg (0.20 mmol) of tert-butyl 4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate), 41 mg (0.24 mmol, 1.2 eq.) of 5-chloro-2-methylphenylboronic acid, 84 mg (0.61 mmol, 3.0 eq.) of potassium carbonate and 16 mg (0.02 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. The reaction mixture was filtered through Celite and 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: 105 mg (purity 91%, 95% of theory) already preheated to 110° C The reaction mixture was 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: To a mixture of 4,6-dichloro-2-amino-pyrimidine (0.481 g, 2.93 mmol), 5-chloro-2-methyl-phenyl boronic acid (0.5 g, 2.93 mmol), palladium (II) acetate (0.1 g, 0.44 mmol), and triphenylphosphine (0.23 g, 0.88 mmol) was added a solution of sodium carbonate (1.5 g, 14.6 mmol) in water (5.0 ml) followed by glyme (20 ml). The mixture was stirred under an argon atmosphere for 16 hours. After addition of acetone (15 ml), the mixture was filtered through a pad of celite under suction and the filtrate was concentrated under vacuum. The residual solid was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:9). After concentration under reduced pressure, the solid was dissolved in methanol and a solution of hydrogen chloride in dioxane (4.0 M, 5 ml) was added. After concentration under vacuum, the solid was treated with ethyl acetate (5 ml) and stirred for one hour. Filtration provided the hydrochloride salt of 4-chloro-6-(5-chloro-2-methyl-phenyl) pyrimidin-2-yl-amine (0.30 g, 35% yield) as a white powder. the mixture was filtered through a pad of celite under suction the filtrate was concentrated under vacuum The residual solid was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:9) After concentration under reduced pressure the solid was dissolved in methanol a solution of hydrogen chloride in dioxane (4.0 M, 5 ml) was added After concentration under vacuum the solid was treated with ethyl acetate (5 ml) stirred for one hour Filtration