1-(bromomethyl)-3-fluoro-2-methylbenzene

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-fluoro-2-methylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-fluoro-2-methylbenzene (0.295 g, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (62.7 mg, 0.164 mmol, 22.51% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 3H) 2.87 (s, 3H) 3.07-3.20 (m, 4H) 3.81-3.92 (m, 4H) 5.55 (s, 2H) 6.29-6.38 (m, 1H) 6.85-6.90 (m, 1H) 7.03-7.17 (m, 2H) 7.55 (m, 1H). MS (ES+) m/e 383.8 [M+H]+. The resulting reaction mixture The solution was cooled to room temperature was extracted with EtOAc The combined organic phase was washed with Brine concentrated The residue was purified on Biotage Isolera purification system eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes The expected compound was collected evaporated to yield a tan solid The reaction was stirred at 50° C. for 2 h The reaction was cooled to room temperature the organic solvent was removed in vacuo The solution was diluted with water (20 mL) The mixture was then filtered the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes The appropriate fractions were collected evaporated

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-fluoro-2-methylbenzene (0.295 g, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (62.7 mg, 0.164 mmol, 22.51% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 3H) 2.87 (s, 3H) 3.07-3.20 (m, 4H) 3.81-3.92 (m, 4H) 5.55 (s, 2H) 6.29-6.38 (m, 1H) 6.85-6.90 (m, 1H) 7.03-7.17 (m, 2H) 7.55 (m, 1H). MS (ES+) m/e 383.8 [M+H]+. The resulting reaction mixture The solution was cooled to room temperature was extracted with EtOAc The combined organic phase was washed with Brine concentrated The residue was purified on Biotage Isolera purification system eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes The expected compound was collected evaporated to yield a tan solid The reaction was stirred at 50° C. for 2 h The reaction was cooled to room temperature the organic solvent was removed in vacuo The solution was diluted with water (20 mL) The mixture was then filtered the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes The appropriate fractions were collected evaporated

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-fluoro-2-methylbenzene (0.295 g, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (62.7 mg, 0.164 mmol, 22.51% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 3H) 2.87 (s, 3H) 3.07-3.20 (m, 4H) 3.81-3.92 (m, 4H) 5.55 (s, 2H) 6.29-6.38 (m, 1H) 6.85-6.90 (m, 1H) 7.03-7.17 (m, 2H) 7.55 (m, 1H). MS (ES+) m/e 383.8 [M+H]+. The resulting reaction mixture The solution was cooled to room temperature was extracted with EtOAc The combined organic phase was washed with Brine concentrated The residue was purified on Biotage Isolera purification system eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes The expected compound was collected evaporated to yield a tan solid The reaction was stirred at 50° C. for 2 h The reaction was cooled to room temperature the organic solvent was removed in vacuo The solution was diluted with water (20 mL) The mixture was then filtered the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes The appropriate fractions were collected evaporated

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-fluoro-2-methylbenzene (0.295 g, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (62.7 mg, 0.164 mmol, 22.51% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 3 H) 2.87 (s, 3 H) 3.07-3.20 (m, 4 H) 3.81-3.92 (m, 4 H) 5.55 (s, 2 H) 6.29-6.38 (m, 1 H) 6.85-6.90 (m, 1 H) 7.03-7.17 (m, 2 H) 7.55 (m, 1 H). MS(ES+) m/e 383.8 [M+H]+. The resulting reaction mixture The solution was cooled to room temperature was extracted with EtOAc The combined organic phase was washed with Brine concentrated The residue was purified on Biotage Isolera purification system eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes The expected compound was collected evaporated to yield a tan solid The reaction was stirred at 50° C. for 2 h The reaction was cooled to room temperature the organic solvent was removed in vacuo The solution was diluted with water (20 mL) The mixture was then filtered the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes The appropriate fractions were collected evaporated

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-fluoro-2-methylbenzene (0.295 g, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (62.7 mg, 0.164 mmol, 22.51% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 3H) 2.87 (s, 3H) 3.07-3.20 (m, 4H) 3.81-3.92 (m, 4H) 5.55 (s, 2H) 6.29-6.38 (m, 1H) 6.85-6.90 (m, 1H) 7.03-7.17 (m, 2H) 7.55 (m, 1H). MS(ES+) m/e 383.8 [M+H]+. The resulting reaction mixture The solution was cooled to room temperature was extracted with EtOAc The combined organic phase was washed with Brine concentrated The residue was purified on Biotage Isolera purification system eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes The expected compound was collected evaporated to yield a tan solid The reaction was stirred at 50° C. for 2 h The reaction was cooled to room temperature the organic solvent was removed in vacuo The solution was diluted with water (20 mL) The mixture was then filtered the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes The appropriate fractions were collected evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To zinc (167 mg, 2.55 mmol) in dry THF (500 μl) in a dry flask under an argon atmosphere was added 1,2-dibromoethane (5.49 μl, 63.7 μmol). The mixture was heated three times to reflux with a heat gun and allowed to cool to room temperature. Then chlorotrimethylsilane (0.27 μl, 2.12 μmol) was added and the mixture was stirred at room temperature for 20 min. Subsequently the flask was placed in an ice bath and a solution of 3-fluoro-2-methyl-benzylbromide (259 mg, 1.27 mmol) in dry THF (1 ml) was added slowly so that the temperature remained at 0° C. The mixture was stirred at 0° C. for 4.5 h and placed in the refrigerator overnight. Then the cooled mixture was added dropwise to a precooled solution (−78° C.) of B-OM-9-BBN (2.12 ml, 2.12 mmol, 1 M) in hexane. The mixture was stirred at room temperature for 30 min. DMF (5 ml) was added, followed by the compound of step 6 (100 mg, 212 μmol), palladium(II) acetate (4.77 mg, 21.2 μmol) and S—PHOS (17.4 mg, 42.5 μmol). The reaction mixture was stirred at 100° C. for 3 h. After cooling, the mixture was quenched with water and extracted with EA. The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel chromatography (EA (10 to 60%) HEP) to give 90 mg of the title compound. The mixture was heated three times to reflux with a heat gun Subsequently the flask was placed in an ice bath remained at 0° C The mixture was stirred at 0° C. for 4.5 h placed in the refrigerator overnight The mixture was stirred at room temperature for 30 min The reaction mixture was stirred at 100° C. for 3 h After cooling the mixture was quenched with water extracted with EA The organic layer was dried over sodium sulfate filtered evaporated under reduced pressure The residue was purified by silica gel chromatography (EA (10 to 60%) HEP)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-fluoro-2-methylbenzene (0.295 g, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (62.7 mg, 0.164 mmol, 22.51% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 3H) 2.87 (s, 3H) 3.07-3.20 (m, 4H) 3.81-3.92 (m, 4H) 5.55 (s, 2H) 6.29-6.38 (m, 1H) 6.85-6.90 (m, 1H) 7.03-7.17 (m, 2H) 7.55 (m, 1H). MS(ES+) m/e 383.8 [M+H]+. The resulting reaction mixture The solution was cooled to room temperature was extracted with EtOAc The combined organic phase was washed with Brine concentrated The residue was purified on Biotage Isolera purification system eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes The expected compound was collected evaporated to yield a tan solid The reaction was stirred at 50° C. for 2 h The reaction was cooled to room temperature the organic solvent was removed in vacuo The solution was diluted with water (20 mL) The mixture was then filtered the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes The appropriate fractions were collected evaporated

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a suspension of zinc (322 mg, 4.92 mmol) in dry THF (770 μl) in a dry flask under argon was added 1,2-dibromoethane (10.6 μl, 0.123 mmol). The mixture was heated three times to reflux with a heat-gun. After 5 min the flask was placed in an ice bath and a solution of 3-fluoro-2-methyl-benzylbromide (500 mg, 2.46 mmol) in dry THF (1.5 ml) was added slowly, so that the temperature remained at 0° C. The mixture was stirred at 0° C. for 3 h. The cooled suspension was added dropwise to a precooled solution (−78° C.) of B-OM-9-BBN (2.45 ml, 2.45 mmol, 1 M in hexane). The mixture was then stirred at room temperature for 30 min. DMF (7 ml) was added, followed by the compound of step 5 (115 mg, 245 μmol), palladium(II) acetate (5.49 mg, 24.5 μmol) and S—PHOS (20.1 mg, 48.9 μmol). The reaction mixture was stirred at 100° C. for 2 h. The cooled mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative HPLC. The eluate was lyophilized overnight to give 72 mg of the title compound. The mixture was heated three times to reflux with a heat-gun remained at 0° C The mixture was then stirred at room temperature for 30 min The reaction mixture was stirred at 100° C. for 2 h The cooled mixture was quenched with water extracted with EA The organic layer was separated dried over sodium sulfate filtered evaporated under reduced pressure The residue was purified by preparative HPLC The eluate was lyophilized overnight

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-fluoro-2-methylbenzene (0.295 g, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (62.7 mg, 0.164 mmol, 22.51% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 3H) 2.87 (s, 3H) 3.07-3.20 (m, 4H) 3.81-3.92 (m, 4H) 5.55 (s, 2H) 6.29-6.38 (m, 1H) 6.85-6.90 (m, 1H) 7.03-7.17 (m, 2H) 7.55 (m, 1H). MS (ES+) m/e 383.8 [M+H]+. The resulting reaction mixture The solution was cooled to room temperature was extracted with EtOAc The combined organic phase was washed with Brine concentrated The residue was purified on Biotage Isolera purification system eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes The expected compound was collected evaporated to yield a tan solid The reaction was stirred at 50° C. for 2 h The reaction was cooled to room temperature the organic solvent was removed in vacuo The solution was diluted with water (20 mL) The mixture was then filtered the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes The appropriate fractions were collected evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-fluoro-2-methylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-fluoro-2-methylbenzene (0.295 g, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (62.7 mg, 0.164 mmol, 22.51% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 3H) 2.87 (s, 3H) 3.07-3.20 (m, 4H) 3.81-3.92 (m, 4H) 5.55 (s, 2H) 6.29-6.38 (m, 1H) 6.85-6.90 (m, 1H) 7.03-7.17 (m, 2H) 7.55 (m, 1H). MS (ES+) m/e 383.8 [M+H]+. The resulting reaction mixture The solution was cooled to room temperature was extracted with EtOAc The combined organic phase was washed with Brine concentrated The residue was purified on Biotage Isolera purification system eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes The expected compound was collected evaporated to yield a tan solid The reaction was stirred at 50° C. for 2 h The reaction was cooled to room temperature the organic solvent was removed in vacuo The solution was diluted with water (20 mL) The mixture was then filtered the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (10-40%) over 10 minutes The appropriate fractions were collected evaporated