4-(bromomethyl)-1-chloro-2-fluorobenzene

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: KCN (1.25 g, 19.2 mmol) was added to a solution of 4-(bromomethyl)-1-chloro-2-fluorobenzene (3.90 g, 17.5 mmol) in DMSO (60 mL). Several milliliters of H2O were added to help dissolve the KCN. After 1 hour, the reaction mixture was diluted with H2O and extracted with EtOAc. The extracts were dried (Na2SO4), filtered, and concentrated. The crude product was flashed on silica (Biotage 40M, 9:1 to 4:1 hex:EtOAc) to give 2-(4-chloro-3-fluorophenyl)acetonitrile (1.81 g, 61.2% yield) as a yellow crystalline solid. extracted with EtOAc The extracts were dried (Na2SO4) filtered concentrated

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

Procedure: KCN (1.25 g, 19.2 mmol) was added to a solution of 4-(bromomethyl)-1-chloro-2-fluorobenzene (3.90 g, 17.5 mmol) in DMSO (60 mL). Several milliliters of H2O were added to help dissolve the KCN. After 1 hour, the reaction mixture was diluted with H2O and extracted with EtOAc. The extracts were dried (Na2SO4), filtered, and concentrated. The crude product was flashed on silica (Biotage 40M, 9:1 to 4:1 hex:EtOAc) to give 2-(4-chloro-3-fluorophenyl)acetonitrile (1.81 g, 61.2% yield) as a yellow crystalline solid. extracted with EtOAc The extracts were dried (Na2SO4) filtered concentrated

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

Procedure: KCN (1.25 g, 19.2 mmol) was added to a solution of 4-(bromomethyl)-1-chloro-2-fluorobenzene (3.90 g, 17.5 mmol) in DMSO (60 mL). Several milliliters of H2O were added to help dissolve the KCN. After 1 hour, the reaction mixture was diluted with H2O and extracted with EtOAc. The extracts were dried (Na2SO4), filtered, and concentrated. The crude product was flashed on silica (Biotage 40M, 9:1 to 4:1 hex:EtOAc) to give 2-(4-chloro-3-fluorophenyl)acetonitrile (1.81 g, 61.2% yield) as a yellow crystalline solid. extracted with EtOAc The extracts were dried (Na2SO4) filtered concentrated

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

Procedure: According to Scheme 8 Step 3: The title compound was prepared from 2-methoxy-5-(2-(3-methoxyphenyl)ethyl)pyridine (1 eq, 0.25 mmol, 0.06 g) and 4-chloro-3-fluorobenzylbromide (2 eq, 0.49 mmol, 0.11 g) according to the procedure described for Example 6 Step 2. Reaction conditions: 12 hours at 100° C. The resulting dark brown oil was purified by flash chromatography (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/MeOH 98/2) to afford 5-(3-methoxyphenethyl)-1-(4-chloro-3-fluorobenzyl)pyridin-2(1H)-one (0.14 mmol, 55.0 mg, 60%) as a yellow oil. Reaction conditions 12 hours at 100° C The resulting dark brown oil was purified by flash chromatography (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/MeOH 98/2)

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

Procedure: KCN (1.25 g, 19.2 mmol) was added to a solution of 4-(bromomethyl)-1-chloro-2-fluorobenzene (3.90 g, 17.5 mmol) in DMSO (60 mL). Several milliliters of H2O were added to help dissolve the KCN. After 1 hour, the reaction mixture was diluted with H2O and extracted with EtOAc. The extracts were dried (Na2SO4), filtered, and concentrated. The crude product was flashed on silica (Biotage 40M, 9:1 to 4:1 hex:EtOAc) to give 2-(4-chloro-3-fluorophenyl)acetonitrile (1.81 g, 61.2% yield) as a yellow crystalline solid. extracted with EtOAc The extracts were dried (Na2SO4) filtered concentrated

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

Procedure: In a 50 ml flame-dried round bottom flask, a suspension of zinc (0.183 g, 0.00280 mol), chlorotrimethylsilane (8.9 uL, 0.000070 mol) and 1,2-dibromoethane (6.0 uL, 0.000070 mol) in N,N-dimethylformamide (2.4 mL, 0.031 mol) was stirred for 15 minutes. To this was added a solution of 3-fluoro-4-chlorobenzylbromide (0.626 g, 0.00280 mol) in N,N-dimethylformamide (4.8 mL, 0.062 mol), and the resulting suspension was stirred overnight at room temperature. To a flame-dried 50 ml round bottom flask containing ethyl 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxy late (0.300 g, 0.000934 mol) and bis(tri-t-butylphosphine)palladium(0) (36 mg, 0.000070 mol) was added the organozinc solution from above, and the reaction was heated with stirring at 60° C. for 60 min. Reaction was quenched with saturated ammonium chloride, and then transferred to a separatory funnel containing water (10 mL) and EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM, adsorbed onto silica gel and purified via column chromotography (24 gram Isco column, gradient elution, 0-50% EtOAc/hexanes) to afford ethyl 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (245 mg, yield 68.2%). In a 50 ml flame-dried round bottom flask the resulting suspension was stirred overnight at room temperature was heated with stirring at 60° C. for 60 min Reaction was quenched with saturated ammonium chloride transferred to a separatory funnel containing water (10 mL) and EtOAc (40 mL) The layers were separated the aqueous layer was extracted 2×30 mL with EtOAc The combined organic layers were washed 1× brine dried over Na2SO4 filtered concentrated in vacuo The resulting residue was dissolved in DCM purified via column chromotography (24 gram Isco column, gradient elution, 0-50% EtOAc/hexanes)

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

Procedure: In a 50 ml flame-dried round bottom flask, a suspension of zinc (0.183 g, 0.00280 mol), chlorotrimethylsilane (8.9 uL, 0.000070 mol) and 1,2-dibromoethane (6.0 uL, 0.000070 mol) in N,N-dimethylformamide (2.4 mL, 0.031 mol) was stirred for 15 minutes. To this was added a solution of 3-fluoro-4-chlorobenzylbromide (0.626 g, 0.00280 mol) in N,N-dimethylformamide (4.8 mL, 0.062 mol), and the resulting suspension was stirred overnight at room temperature. To a flame-dried 50 ml round bottom flask containing ethyl 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxy late (0.300 g, 0.000934 mol) and bis(tri-t-butylphosphine)palladium(0) (36 mg, 0.000070 mol) was added the organozinc solution from above, and the reaction was heated with stirring at 60° C. for 60 min. Reaction was quenched with saturated ammonium chloride, and then transferred to a separatory funnel containing water (10 mL) and EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM, adsorbed onto silica gel and purified via column chromotography (24 gram Isco column, gradient elution, 0-50% EtOAc/hexanes) to afford ethyl 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (245 mg, yield 68.2%). In a 50 ml flame-dried round bottom flask the resulting suspension was stirred overnight at room temperature was heated with stirring at 60° C. for 60 min Reaction was quenched with saturated ammonium chloride transferred to a separatory funnel containing water (10 mL) and EtOAc (40 mL) The layers were separated the aqueous layer was extracted 2×30 mL with EtOAc The combined organic layers were washed 1× brine dried over Na2SO4 filtered concentrated in vacuo The resulting residue was dissolved in DCM purified via column chromotography (24 gram Isco column, gradient elution, 0-50% EtOAc/hexanes)

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

Procedure: In a flame-dried scintillation vial, to a suspension of zinc (0.0998 g, 1.53 mmol) in N,N-dimethylformamide (1.36 mL, 17.6 mmol) were added 1,2-dibromoethane (0.003279 mL, 0.03805 mmol) and chlorotrimethylsilane (0.004830 mL, 0.03805 mmol). Stirred at room temperature for 15 min, at which point a solution of 3-fluoro-4-chlorobenzylbromide (0.341 g, 1.53 mmol) in N,N-dimethylformamide (1.36 mL, 17.6 mmol) was added. The resulting suspension was stirred at room temperature for 16 hours. A scintillation vial containing ethyl 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (199 mg, 0.507 mmol and bis(tri-t-butylphosphine)palladium(0) (12.96 mg, 0.02537 mmol) was purged via vacuum/backfilling with argon. To this was added the organozinc solution from above, and the resulting solution was stirred at 45° C. for 6 hours, at which point LC/MS showed complete conversion to a single new peak with mass representing desired product. The reaction mixture was transferred to a separatory funnel containing saturated NaHCO3 (aq., 10 mL) and water (10 mL), and then diluted with EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford crude ethyl 3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate as a brown oil that was used without further purification. LCMS: (FA) ES+ 409, 411 was added was purged via vacuum/backfilling with argon To this was added the organozinc solution from above, and the resulting solution was stirred at 45° C. for 6 hours, at which point LC/MS The reaction mixture was transferred to a separatory funnel containing saturated NaHCO3 (aq., 10 mL) and water (10 mL) diluted with EtOAc (40 mL) The layers were separated the aqueous layer was extracted 2×30 mL with EtOAc The combined organic layers were washed 1× brine dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: In a 50 ml flame-dried round bottom flask, a suspension of zinc (0.183 g, 0.00280 mol), chlorotrimethylsilane (8.9 uL, 0.000070 mol) and 1,2-dibromoethane (6.0 uL, 0.000070 mol) in N,N-dimethylformamide (2.4 mL, 0.031 mol) was stirred for 15 minutes. To this was added a solution of 3-fluoro-4-chlorobenzylbromide (0.626 g, 0.00280 mol) in N,N-dimethylformamide (4.8 mL, 0.062 mol), and the resulting suspension was stirred overnight at room temperature. To a flame-dried 50 ml round bottom flask containing ethyl 4-bromo-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (0.300 g, 0.000934 mol) and bis(tri-t-butylphosphine)palladium(0) (36 mg, 0.000070 mol) was added the organozinc solution from above, and the reaction was heated with stirring at 60° C. for 60 min. Reaction was quenched with saturated ammonium chloride, and then transferred to a separatory funnel containing water (10 mL) and EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM, adsorbed onto silica gel and purified via column chromotography (24 gram Isco column, gradient elution, 0-50% EtOAc/hexanes) to afford ethyl 4-(4-chloro-3-fluorobenzyl)-2-morpholin-4-yl-1,3-thiazole-5-carboxylate (245 mg, yield 68.2%). In a 50 ml flame-dried round bottom flask the resulting suspension was stirred overnight at room temperature was heated with stirring at 60° C. for 60 min Reaction was quenched with saturated ammonium chloride transferred to a separatory funnel containing water (10 mL) and EtOAc (40 mL) The layers were separated the aqueous layer was extracted 2×30 mL with EtOAc The combined organic layers were washed 1× brine dried over Na2SO4 filtered concentrated in vacuo The resulting residue was dissolved in DCM purified via column chromotography (24 gram Isco column, gradient elution, 0-50% EtOAc/hexanes)

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

Procedure: In a flame-dried scintillation vial, to a suspension of zinc (0.0998 g, 1.53 mmol) in N,N-dimethylformamide (1.36 mL, 17.6 mmol) were added 1,2-dibromoethane (0.003279 mL, 0.03805 mmol) and chlorotrimethylsilane (0.004830 mL, 0.03805 mmol). Stirred at room temperature for 15 min, at which point a solution of 3-fluoro-4-chlorobenzylbromide (0.341 g, 1.53 mmol) in N,N-dimethylformamide (1.36 mL, 17.6 mmol) was added. The resulting suspension was stirred at room temperature for 16 hours. A scintillation vial containing ethyl 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (199 mg, 0.507 mmol and bis(tri-t-butylphosphine)palladium(0) (12.96 mg, 0.02537 mmol) was purged via vacuum/backfilling with argon. To this was added the organozinc solution from above, and the resulting solution was stirred at 45° C. for 6 hours, at which point LC/MS showed complete conversion to a single new peak with mass representing desired product. The reaction mixture was transferred to a separatory funnel containing saturated NaHCO3 (aq., 10 mL) and water (10 mL), and then diluted with EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford crude ethyl 3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate as a brown oil that was used without further purification. LCMS: (FA) ES+ 409, 411 was added was purged via vacuum/backfilling with argon To this was added the organozinc solution from above, and the resulting solution was stirred at 45° C. for 6 hours, at which point LC/MS The reaction mixture was transferred to a separatory funnel containing saturated NaHCO3 (aq., 10 mL) and water (10 mL) diluted with EtOAc (40 mL) The layers were separated the aqueous layer was extracted 2×30 mL with EtOAc The combined organic layers were washed 1× brine dried over Na2SO4 filtered concentrated in vacuo