(2-chloro-4-fluorophenyl)boronic acid

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: 2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N,2-dimethylpropanamide (200 mg, 0.363 mmol), 2-chloro-4-fluorobenzene boronic acid (82 mg, 0.472 mmol), sodium carbonate (0.4 mL, 2M solution), tetrakistriphenylphosphinepalladium (4 mg, 0.00363 mmol) in dioxan (2 mL) were heated together in the microwave at 110° C. for 30 minutes. The mixture was partitioned between EtOAc and Brine. The Aqueous layer was extracted with EtOAc×3. The combined extracts were dried and evaporated. The residue was purified on a 25+M column eluting with 0-50% EtOAc/Pet Et2O. Impurities still seen. Sent to MDAP for purification to afford the title compound in a 96% yield. The mixture was partitioned between EtOAc and Brine The Aqueous layer was extracted with EtOAc×3 The combined extracts were dried evaporated The residue was purified on a 25+M column eluting with 0-50% EtOAc/Pet Et2O Sent to MDAP for purification

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,5-dibromo-1-methyl-1H-pyrazole (i.e. the product of Step B) (2.00 g, 8.33 mmol) in toluene (40 mL) was sparged with a stream of argon for 45 minutes, and then 2-chloro-4-fluorophenylboronic acid (1.59 g, 9.11 mmol), potassium phosphate tribasic (5.30 g, 25.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.41 mmol) were added. The reaction mixture was heated at 90° C. for 3 h, and then cooled to room temperature and diluted with ethyl acetate (250 mL). The mixture was washed with water (25 mL) and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (5 to 40% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a white solid (620 mg). was sparged with a stream of argon for 45 minutes cooled to room temperature The mixture was washed with water (25 mL) and saturated aqueous sodium chloride solution dried over sodium sulfate filtered concentrated under reduced pressure The resulting material was purified by silica gel chromatography (5 to 40% gradient of ethyl acetate in hexanes as eluant)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole (2.50 g, 14.3 mmol), 2-chloro-4-fluorophenylboronic acid (2.98 g, 17.2 mmol), cesium carbonate (5.58 g, 17.2 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloro-methane complex (1:1) (1.16 g, 1.43 mmol) in dioxane (50 mL) was heated at 100° C. for approximately 2.5 days. After cooling to room temperature, the reaction mixture was filtered through a pad of Celite® (diatomaceous earth) on a sintered glass frit funnel and the filtrate was concentrated under reduced pressure. The resulting material was dissolved in ethyl acetate and filtered through a plug of silica on a sintered glass frit funnel and the filtrate was concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (5 to 40% gradient of ethyl acetate in hexanes as eluant) to provide the title compound (0.32 g). After cooling to room temperature the reaction mixture was filtered through a pad of Celite® (diatomaceous earth) on a sintered glass frit funnel the filtrate was concentrated under reduced pressure The resulting material was dissolved in ethyl acetate filtered through a plug of silica on a sintered glass frit funnel the filtrate was concentrated under reduced pressure The resulting material was purified by silica gel column chromatography (5 to 40% gradient of ethyl acetate in hexanes as eluant)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-chloro-3-methyl-5-nitropyridine (prepared according to the procedure of Hawkins and Roe, J. Am. Chem. Soc., page 330, 1948) (5.3 g, 30.7 mmol, 1 eq.) in 1,2-dimethoxyethane (50 mL) and ethanol (25 mL) was added 2-chloro-4-fluorobenzeneboronic acid (5.9 g, 33.8 mmol, 1.1 eq.). The resulting mixture was degassed with argon. To the mixture was added a solution of Na2CO3 (11.4 g, 107.45 mmol, 3.5 eq) in water (50 mL). The mixture was degassed with argon, and tetrakis(triphenylphosphine)palladium(0) (1.1 g, 0.95 mmol, 0.03 eq) was added. The mixture was degassed with argon and heated to 90° C. under argon. After 4.5 h, the mixture was cooled. The solvent was removed under reduced pressure. The residue was diluted with water and extracted 3× with ethyl acetate. The aqueous layer was extracted several times with ethyl acetate. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by flash column chromatography on silica gel eluting with 5% Et2O in hexanes giving 2-(2-chloro-4-fluorophenyl)-3-methyl-5-nitropyridine. Mass spectrum (EST) 267 (M+1). The resulting mixture was degassed with argon was added The mixture was degassed with argon the mixture was cooled The solvent was removed under reduced pressure The residue was diluted with water extracted 3× with ethyl acetate The aqueous layer was extracted several times with ethyl acetate dried over anhydrous Na2SO4 filtered concentrated The product was purified by flash column chromatography on silica gel eluting with 5% Et2O in hexanes

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

Procedure: To a solution of 5-bromo-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (200 mg, 0.31 mmol) and 2-chloro-4-fluoro-benzene boronic acid (98 mg, 0.62 mmol) in toluene (3 mL) and ethanol (0.3 mL) was added sodium carbonate (2M solution, 0.39 mL) and tetrakis(triphenylphosphine)palladium (0) (18 mg, 0.0155 mmol). The flask was evacuated and purged with nitrogen a few times. The reaction mixture was heated to reflux for 2 h and diluted with methylene chloride. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by preparative thin layer chromatography using 5% of 2N ammonium in methanol/methylene chloride as eluent provided the 5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-[(5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.03 (s, 3H), 1.08 (s, 3H), 1.64 (m, 2H), 2.40 (m, 1H), 2.57 (brs, 1H), 2.83 (t, 1H, J=7.3 Hz), 2.90 (brs, 1H), 3.14 (s, 1H), 3.53 (m, 2H), 3.63 (t, 1H, J=13.2 Hz), 3.81 (s, 3H), 4.11 (abq, 2H, J=14.9 Hz), 4.55 (abq, 2H, J=14.9 Hz), 6.22 (s, 1H), 6.78 (s, 1H), 6.84 (d, 2H, J=8.4 Hz), 6.99 (t, 1H, J=8.0 Hz), 7.12 (dd, 1H, J1=8.4 Hz, J2=6.0 Hz), 7.21 (d, 3H, J=8.7 Hz), 7.38 (t, 1H, J=8.0 Hz), 7.54 (m, 2H). MS (API-ES+): 695 (M+H). The flask was evacuated purged with nitrogen a few times The reaction mixture was heated to reflux for 2 h diluted with methylene chloride The organic layer was washed with water and brine dried over anhydrous sodium sulfate Removal of the solvent and subsequent purification by preparative thin layer chromatography

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

Procedure: Following the general Suzuki coupling procedure, reaction of bromide 6A (65 mg, 0.2 mmol), 2-chloro-4-fluorophenylboronic acid (52 mg, 0.3 mmol), K2CO3 (82 mg, 0.6 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) provided the coupling product as an off-white powder (15 mg, 20% yield). EIMS 374.1 [M+H]+.

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

Procedure: Following the general Suzuki coupling procedure, reaction of bromide 6A (65 mg, 0.2 mmol), 2-chloro-4-fluorophenylboronic acid (52 mg, 0.3 mmol), K2CO3 (82 mg, 0.6 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) provided the coupling product as an off-white powder (15 mg, 20% yield). EIMS 374.1 [M+H]+.

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

Procedure: The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-chloro-4-fluorophenyl-boronic acid (CAS RN 313545-72-1) and using preparative HPLC for the chromatographic purification. Brown sticky solid (33%). MS (ESI): m/z=476.8 [M+H]+. for the chromatographic purification

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

Procedure: The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-chloro-4-fluorophenyl-boronic acid (CAS RN 313545-72-1) and using preparative HPLC for the chromatographic purification. Brown sticky solid (33%). MS (ESI): m/z=476.8 [M+H]+. for the chromatographic purification