2-fluoro-4-methylbenzonitrile

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: N-Bromosuccinimide and AIBN were added to a carbon tetrachloride solution of 2-fluoro-4-methylbenzonitrile, followed by heating under reflux to obtain 4-(bromomethyl)-2-fluorobenzonitrile. By allowing this to react with morpholine in DMF in the presence of potassium carbonate, 2-fluoro-4-(morpholin-4-ylmethyl)benzonitrile was obtained. In DMF and in the presence of potassium carbonate, this was allowed to react with cyclohexanamine at 160° C. for 30 minutes while carrying out microwave irradiation. By post-treating the reaction liquid, 2-(cyclohexylamino)-4-(morpholin-4-ylmethyl)benzonitrile was obtained. by heating under reflux

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

Procedure: To a solution of the product from Step C (22.2 g, 165 mmol) in 220 mL of carbontetrachloride was added N-bromosuccinimide (29.2 g, 164 mmol) and benzoylperoxide (1.1 g). The reaction was heated to reflux for 30 minutes, then cooled to room temperature. The solution was concentrated in vacuo to one-third the original volume, poured into EtOAc, washed with water, sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Analysis by 1H NMR indicated only partial conversion, so the crude material was resubjected to the same reaction conditions for 2.5 hours, using 18 g (102 mmol) of N-bromosuccinimide. After workup, the crude material was purified by silica gel chromatography (0-10% EtOAc/hexane) to provide the desired product. The reaction was heated to reflux for 30 minutes The solution was concentrated in vacuo to one-third the original volume poured into EtOAc washed with water, sat. aq. NaHCO3, and brine dried (Na2SO4) filtered concentrated in vacuo to provide the crude product After workup, the crude material was purified by silica gel chromatography (0-10% EtOAc/hexane)

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

Procedure: To a degassed solution of 4-bromo-3-fluorotoluene (50.0 g, 264 mmol) in 500 mL of DMF was added Zn(CN)2 (18.6 g, 159 mmol) and Pd(PPh3)4 (6.1 g, 5.3 mmol). The reaction was stirred at 80° C. for 6 hours, then cooled to room temperature. The solution was poured into EtOAc, washed with water, sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography (0-5% EtOAc/hexane) provided the titled product. cooled to room temperature washed with water, sat. aq. NaHCO3, and brine dried (Na2SO4) filtered concentrated in vacuo to provide the crude product Purification by silica gel chromatography (0-5% EtOAc/hexane)

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

Procedure: 2-fluoro-4-methylbenzonitrile (4.6 g, 34.4 mmol) and N-methyl-methanesulphonamide (7.5 g, 68.7 mmol) are dissolved in 15 mL NMP and stirred for 16 h at 120° C. After the reaction has ended the reaction mixture is mixed with 70 mL water and the solid B-1a (HPLC-MS: tRet.=1.22 min; MS (M+NH4)+=242) is suction filtered and used without any further purification. the solid B-1a (HPLC-MS: tRet.=1.22 min; MS (M+NH4)+=242) is suction filtered used without any further purification

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

Procedure: To a solution of 2-fluoro-4-methylbenzonitrile (356mg, 3.96 mmol) and 3-chlorophenol (439 μL, 4.16 mmol) in 10 mL of DMSO was added Cs2CO3 (2.58 g, 7.92 mmol). The solution was heated at 80° C. for 4 h. The solution was diluted with EtOAc and was washed with Sat. NaHCO3 solution, water, and brine. The organics were dried (MgSO4), filtered, and concentrated in vacuo to give the title compound without further purification. was washed with Sat. NaHCO3 solution, water, and brine The organics were dried (MgSO4) filtered concentrated in vacuo

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

Procedure: To a deoxygenated solution of 4-bromo-3-fluorotoluene (25.0 g, 132 mmol) in DMF (500 mL) was added Zn(CN)2 (10.1 g, 86 mmol) and Pd(PPh3)4 (15 g, 13 mmol). The reaction was stirred at 100° C. for 18 hrs, then cooled to room temperature. The solution was poured into toluene (1 L), washed with 30% aq. NH4OH (2×1 L), then brine (800 mL), then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography, eluting with a gradient of hexane—0% to 7% EtOAc, yielded the titled product. cooled to room temperature washed with 30% aq. NH4OH (2×1 L) brine (800 mL), then dried (Na2SO4) filtered concentrated in vacuo to provide the crude product Purification by silica gel chromatography eluting with a gradient of hexane—0% to 7% EtOAc

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

Procedure: To a solution of the product from Step C (22.2 g, 165 mmol) in 220 mL of carbontetrachloride was added N-bromosuccinimide (29.2 g, 164 mmol) and benzoylperoxide (1.1 g). The reaction was heated to reflux for 30 minutes, then cooled to room temperature. The solution was concentrated in vacuo to one-third the original volume, poured into EtOAc, washed with water, sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Analysis by 1H NMR indicated only partial conversion, so the crude material was resubjected to the same reaction conditions for 2.5 hours, using 18 g (102 mmol) of N-bromosuccinimide. After workup, the crude material was purified by silica gel chromatography (0-10% EtOAc/hexane) to provide the desired product. The reaction was heated to reflux for 30 minutes The solution was concentrated in vacuo to one-third the original volume poured into EtOAc washed with water, sat. aq. NaHCO3, and brine dried (Na2SO4) filtered concentrated in vacuo to provide the crude product After workup, the crude material was purified by silica gel chromatography (0-10% EtOAc/hexane)

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

Procedure: To a solution of the product from Step C (22.2 g, 165 mmol) in 220 mL of carbontetrachloride was added N-bromosuccinimide (29.2 g, 164 mmol) and benzoylperoxide (1.1 g). The reaction was heated to reflux for 30 minutes, then cooled to room temperature. The solution was concentrated in vacuo to one-third the original volume, poured into EtOAc, washed with water, sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Analysis by 1H NMR indicated only partial conversion, so the crude material was resubjected to the same reaction conditions for 2.5 hours, using 18 g (102 mmol) of N-bromosuccinimide. After workup, the crude material was purified by silica gel chromatography (0-10% EtOAc/hexane) to provide the desired product. The reaction was heated to reflux for 30 minutes The solution was concentrated in vacuo to one-third the original volume poured into EtOAc washed with water, sat. aq. NaHCO3, and brine dried (Na2SO4) filtered concentrated in vacuo to provide the crude product After workup, the crude material was purified by silica gel chromatography (0-10% EtOAc/hexane)

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

Procedure: To a degassed solution of 4-bromo-3-fluorotoluene (50.0 g, 264 mmol) in 500 mL of DMF was added Zn(CN)2 (18.6 g, 159 mmol) and Pd(PPh3)4 (6.1 g, 5.3 mmol). The reaction was stirred at 80° C. for 6 hours, then cooled to room temperature. The solution was poured into EtOAc, washed with water, sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography (0-5% EtOAc/hexane) provided the titled product. cooled to room temperature washed with water, sat. aq. NaHCO3, and brine dried (Na2SO4) filtered concentrated in vacuo to provide the crude product Purification by silica gel chromatography (0-5% EtOAc/hexane)