4-bromo-3-fluorobenzonitrile

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

Procedure: Placed 4-bromo-3-fluorobenzonitrile (15 mg, 0.075 mmol) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (6 mg, 0.012 mmol) into a reaction vessel in a dry-glove box. Then 6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano-[3,2-d][1,3]dioxin-7-yl)oxy)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (45 mg, 0.062 mmol) was added as a solution in anhydrous dioxane (0.50 mL) which had been degassed. To this mixture was added a solution of degassed, aqueous 1N K3PO4 (0.19 mL, 0.19 mmol). The reaction vessel was sealed and heated to 80° C. with stirring. After 16 hours, the mixture was allowed to cool to room temperature, then diluted with DCM (2.0 mL) and water (1.0 mL), and vigorously stirred for 30 minutes. The organic layer was separated and concentrated under reduced pressure. The resultant oil was dissolved in DCM (1.0 mL), and SiliaMetS® Dimercaptotriazine (100 mg) was added. The resulting suspension was stirred for 2 hours at 35° C. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The resultant residue was dissolved in DCM (0.50 mL) and TFA (0.50 mL) and stirred at room temperature. After 3 hours the mixture was concentrated under reduced pressure. The resultant oil was dissolved in methanol (0.50 mL), then a 5N aqueous solution of NaOH (0.10 mL) was added and the mixture was allowed to stir at room temperature. After 15 minutes the solution was acidified with a few drops of formic acid and diluted with DMSO. The resulting mixture was filtered to remove solids and purified via reverse phase preparatory HPLC using MeCN/water/formic acid as the mobile phase. The fractions containing product were combined and concentrated under reduced pressure to provide the title compound as a white solid. LC-MS: calculated for C25H20ClFN4O4 494.12, observed m/e: 495.12 (M+H)+ (Rt 0.48/2 min). had been degassed To this mixture was added a solution of degassed The reaction vessel was sealed to cool to room temperature vigorously stirred for 30 minutes The organic layer was separated concentrated under reduced pressure The resultant oil was dissolved in DCM (1.0 mL) SiliaMetS® Dimercaptotriazine (100 mg) was added The resulting suspension was stirred for 2 hours at 35° C After cooling to room temperature the mixture was filtered concentrated under reduced pressure The resultant residue was dissolved in DCM (0.50 mL) TFA (0.50 mL) and stirred at room temperature After 3 hours the mixture was concentrated under reduced pressure The resultant oil was dissolved in methanol (0.50 mL) a 5N aqueous solution of NaOH (0.10 mL) was added to stir at room temperature After 15 minutes the solution was acidified with a few drops of formic acid diluted with DMSO The resulting mixture was filtered to remove solids purified via reverse phase preparatory HPLC The fractions containing product concentrated under reduced pressure

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

Procedure: Placed 4-bromo-3-fluorobenzonitrile (15 mg, 0.075 mmol) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (6 mg, 0.012 mmol) into a reaction vessel in a dry-glove box. Then 6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano-[3,2-d][1,3]dioxin-7-yl)oxy)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (45 mg, 0.062 mmol) was added as a solution in anhydrous dioxane (0.50 mL) which had been degassed. To this mixture was added a solution of degassed, aqueous 1N K3PO4 (0.19 mL, 0.19 mmol). The reaction vessel was sealed and heated to 80° C. with stirring. After 16 hours, the mixture was allowed to cool to room temperature, then diluted with DCM (2.0 mL) and water (1.0 mL), and vigorously stirred for 30 minutes. The organic layer was separated and concentrated under reduced pressure. The resultant oil was dissolved in DCM (1.0 mL), and SiliaMetS® Dimercaptotriazine (100 mg) was added. The resulting suspension was stirred for 2 hours at 35° C. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The resultant residue was dissolved in DCM (0.50 mL) and TFA (0.50 mL) and stirred at room temperature. After 3 hours the mixture was concentrated under reduced pressure. The resultant oil was dissolved in methanol (0.50 mL), then a 5N aqueous solution of NaOH (0.10 mL) was added and the mixture was allowed to stir at room temperature. After 15 minutes the solution was acidified with a few drops of formic acid and diluted with DMSO. The resulting mixture was filtered to remove solids and purified via reverse phase preparatory HPLC using MeCN/water/formic acid as the mobile phase. The fractions containing product were combined and concentrated under reduced pressure to provide the title compound as a white solid. LC-MS: calculated for C25H20ClFN4O4 494.12, observed m/e: 495.12 (M+H)+ (Rt 0.48/2 min). had been degassed To this mixture was added a solution of degassed The reaction vessel was sealed to cool to room temperature vigorously stirred for 30 minutes The organic layer was separated concentrated under reduced pressure The resultant oil was dissolved in DCM (1.0 mL) SiliaMetS® Dimercaptotriazine (100 mg) was added The resulting suspension was stirred for 2 hours at 35° C After cooling to room temperature the mixture was filtered concentrated under reduced pressure The resultant residue was dissolved in DCM (0.50 mL) TFA (0.50 mL) and stirred at room temperature After 3 hours the mixture was concentrated under reduced pressure The resultant oil was dissolved in methanol (0.50 mL) a 5N aqueous solution of NaOH (0.10 mL) was added to stir at room temperature After 15 minutes the solution was acidified with a few drops of formic acid diluted with DMSO The resulting mixture was filtered to remove solids purified via reverse phase preparatory HPLC The fractions containing product concentrated under reduced pressure

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combined 4-bromo-3-fluorobenzonitrile (2.0 g, 10.00 mmol), Pd(dba)2 (0.287 g, 0.500 mmol), and 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (0.394 g, 1.000 mmol) in THF (60 mL) with nitrogen purge. Then (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride (0.5M, 30 mL, 15.0 mmol) was added via syringe. The reaction mixture was heated in an oil bath at 50° C. for 18 hours and then was adsorbed onto silica gel (11 g) and purified by flash chromatography using an eluent of 1:1 heptane/EtOAc on an 80 g silica gel column (Single Step™) to give a residue. The residue was dissolved in toluene (0.5 mL) and purified by flash chromatography using a gradient eluent of heptane/EtOAc (0-25% EtOAc) on an 80 g silica gel column (Single Step™) to give the title compound (1.752 g, 74.5% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 1.45 (s, 9 H) 3.64 (d, J=1.26 Hz, 2 H) 7.36 (dd, J=8.97, 1.39 Hz, 1 H) 7.40 (d, J=7.07 Hz, 1 H) 7.42-7.45 (m, 1 H). MS m/z [M+H]+ 236.1. purified by flash chromatography to give a residue purified by flash chromatography

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Combined 4-bromo-3-fluorobenzonitrile (2.0 g, 10.00 mmol), Pd(dba)2 (0.287 g, 0.500 mmol), and 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (0.394 g, 1.000 mmol) in THF (60 mL) with nitrogen purge. Then (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride (0.5M, 30 mL, 15.0 mmol) was added via syringe. The reaction mixture was heated in an oil bath at 50° C. for 18 hours and then was adsorbed onto silica gel (11 g) and purified by flash chromatography using an eluent of 1:1 heptane/EtOAc on an 80 g silica gel column (Single Step™) to give a residue. The residue was dissolved in toluene (0.5 mL) and purified by flash chromatography using a gradient eluent of heptane/EtOAc (0-25% EtOAc) on an 80 g silica gel column (Single Step™) to give the title compound (1.752 g, 74.5% yield) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 1.45 (s, 9H) 3.64 (d, J=1.26 Hz, 2H) 7.36 (dd, J=8.97, 1.39 Hz, 1H) 7.40 (d, J=7.07 Hz, 1H) 7.42-7.45 (m, 1H). MS m/z [M+H]+ 236.1. purified by flash chromatography to give a residue purified by flash chromatography

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

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

Procedure: A mixture of 59 g (0.31 mol) of anhydrous SnCl2 and 320 cm3 of diethyl ether was placed on an ice water bath and saturated with hydrogen chloride gas generated by the drop-wise addition of concentrated sulfuric acid to concentrated hydrochloric acid until the SnCl2 assumed a liquid state and the mixture was dried with concentrated sulfuric acid. 31 g (0.16 mol) of 4-bromo-3-fluorobenzonitrile was added to the mixture and the resulting mixture was stirred at room temperature for 1 hour and allowed to stand overnight. 300 cm3 of water was added to the reaction product and the mixture was stirred over a hot water bath at 50° C. The diethyl ether was distilled off. The oily layer was separated out and the aqueous layer was extracted with ether. The two layers were combined, washed with water, and dried overnight with anhydrous Na2SO4. Diethyl ether was distilled off the resulting dried mixture. Diethyl ether was distilled off the distillation residue. The distillation residue was distilled under a vacuum (b.p. 122° C./25 mmHg) to yield 26 g (0.13 mol) of 4-bromo-3-fluorobenzaldehyde. the mixture was dried with concentrated sulfuric acid to stand overnight the mixture was stirred over a hot water bath at 50° C The diethyl ether was distilled off The oily layer was separated out the aqueous layer was extracted with ether washed with water dried overnight with anhydrous Na2SO4 Diethyl ether was distilled off the resulting dried mixture Diethyl ether was distilled off the distillation residue The distillation residue was distilled under a vacuum (b.p. 122° C./25 mmHg)

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

Procedure: A mixture of 59 g (0.31 mol) of anhydrous SnCl2 and 320 cm3 of diethyl ether was placed on an ice water bath and saturated with hydrogen chloride gas generated by the drop-wise addition of concentrated sulfuric acid to concentrated hydrochloric acid until the SnCl2 assumed a liquid state and the mixture was dried with concentrated sulfuric acid. 31 g (0.16 mol) of 4-bromo-3-fluorobenzonitrile was added to the mixture and the resulting mixture was stirred at room temperature for 1 hour and allowed to stand overnight. 300 cm3 of water was added to the reaction product and the mixture was stirred over a hot water bath at 50° C. The diethyl ether was distilled off. The oily layer was separated out and the aqueous layer was extracted with ether. The two layers were combined, washed with water, and dried overnight with anhydrous Na2SO4. Diethyl ether was distilled off the resulting dried mixture. Diethyl ether was distilled off the distillation residue. The distillation residue was distilled under a vacuum (b.p. 122° C./25 mmHg) to yield 26 g (0.13 mol) of 4-bromo-3-fluorobenzaldehyde. the mixture was dried with concentrated sulfuric acid to stand overnight the mixture was stirred over a hot water bath at 50° C The diethyl ether was distilled off The oily layer was separated out the aqueous layer was extracted with ether washed with water dried overnight with anhydrous Na2SO4 Diethyl ether was distilled off the resulting dried mixture Diethyl ether was distilled off the distillation residue The distillation residue was distilled under a vacuum (b.p. 122° C./25 mmHg)

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

Procedure: A mixture of 59 g (0.31 mol) of anhydrous SnCl2 and 320 cm3 of diethyl ether was placed on an ice water bath and saturated with hydrogen chloride gas generated by the drop-wise addition of concentrated sulfuric acid to concentrated hydrochloric acid until the SnCl2 assumed a liquid state and the mixture was dried with concentrated sulfuric acid. 31 g (0.16 mol) of 4-bromo-3-fluorobenzonitrile was added to the mixture and the resulting mixture was stirred at room temperature for 1 hour and allowed to stand overnight. 300 cm3 of water was added to the reaction product and the mixture was stirred over a hot water bath at 50° C. The diethyl ether was distilled off. The oily layer was separated out and the aqueous layer was extracted with ether. The two layers were combined, washed with water, and dried overnight with anhydrous Na2SO4. Diethyl ether was distilled off the resulting dried mixture. Diethyl ether was distilled off the distillation residue. The distillation residue was distilled under a vacuum (b.p. 122° C./25 mmHg) to yield 26 g (0.13 mol) of 4-bromo-3-fluorobenzaldehyde. the mixture was dried with concentrated sulfuric acid to stand overnight the mixture was stirred over a hot water bath at 50° C The diethyl ether was distilled off The oily layer was separated out the aqueous layer was extracted with ether washed with water dried overnight with anhydrous Na2SO4 Diethyl ether was distilled off the resulting dried mixture Diethyl ether was distilled off the distillation residue The distillation residue was distilled under a vacuum (b.p. 122° C./25 mmHg)

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

Procedure: To a solution of 6-chloro-2-fluoro-3-methylphenol (3.25 g, 20.24 mmol) and 18-crown-6 (0.535 g, 2.024 mmol) in DMSO (40 ml) was added potassium tert-butoxide (20 wt % in THF) (12.49 g, 22.26 mmol) and the reaction mixture was stirred at rt for 30 minutes. Next, 4-bromo-3-fluorobenzonitrile (4.05 g, 20.24 mmol) was added and the reaction mixture stirred at 135° C. for 3 days. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-3-fluorobenzonitrile (4.56 g, 16.30 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05 (dd, 1H), 7.59 (d, 1H), 7.35-7.43 (m, 1H), 7.30 (t, 1H), 6.89 (t, 1H), 2.24 (d, 3H). the reaction mixture stirred at 135° C. for 3 days washed with water The solvent was removed the crude material was purified via silica gel chromatography