1-(4-chlorophenyl)pentan-1-one

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

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

Procedure: A solution of 0.015 g (0.054 mmole) of methyl azetidin-3-yl(3,5-difluorophenyl)acetate, 0.020 g (0.101 mmol) of 1-(4-chlorophenyl)pentan-1-one and 0.015 mL (0.12 mmol) of triethylamine in 5 mL of dichloroethane was stirred at room temperature. After 5 min, 0.050 g (0.237 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 6 h. The reaction was quenched by addition of saturated K2CO3 solution and the mixture was partitioned between 10 mL ether and 2 mL saturated K2CO3 solution. The layers were separated and the organic layer was dried over Na2SO4, and concentrated. The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) using a gradient of CH3CN—H2O-Et3N (20:80:0.1 to 60:40:0.1). Homogenous fractions were pooled and concentrated to afford the title compound as a mixture of isomers; Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl). Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl). The reaction was quenched by addition of saturated K2CO3 solution the mixture was partitioned between 10 mL ether and 2 mL saturated K2CO3 solution The layers were separated the organic layer was dried over Na2SO4 concentrated The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) concentrated

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

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 3-neck flask was charged with NaOtBu (2.85 g, 28.6 mmol) and dry THF (50 mL) under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (0.26 g, 0.28 mmol) and (S)-Tol-Binap (0.47 g, 0.69 mmol) were then added under nitrogen. After stirring for 15 min, 1-(4-chlorophenyl)pentan-1-one (4.21 g, 21.0 mmol) was added, followed by tert-butyl 4-bromobenzoate (5.0 g, 19.1 mmol) under nitrogen. The mixture was heated at 60° C. for 8 hours. The mixture was diluted with heptane (100 mL) and poured into a solution of saturated NaHCO3 (aq) (60 mL) and ice (40 g). The resulting layers were separated, and the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL). The combined organics were washed with saturated NaHCO3 (aq) then 10% NaCl (aq). The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane), and washed with 1:1 methyl tert-butyl ether/heptane (600 mL). The combined filtrate was concentrated to afford an orange oil that was used directly for the next step: 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=8.1 Hz, 2H); 7.86 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.32 (d, J=8.2 Hz, 2H); 4.53 (1, J=7.2 Hz, 1H); 2.19-2.09 (m, 1H); 1.85-1.76 (m, 1H); 1.56 (s, 9H); 1.35-1.18 (m, 2H); 0.91 (t, J=7.3 Hz, 3H); LC3: 1.35 min. (M-tBu+H)+ 317. The resulting layers were separated the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL) The combined organics were washed with saturated NaHCO3 (aq) The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane) washed with 1:1 methyl tert-butyl ether/heptane (600 mL) The combined filtrate was concentrated to afford an orange oil that 1.35 min.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 3-neck flask was charged with NaOtBu (2.85 g, 28.6 mmol) and dry THF (50 mL) under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (0.26 g, 0.28 mmol) and (S)-Tol-Binap (0.47 g, 0.69 mmol) were then added under nitrogen. After stirring for 15 min, 1-(4-chlorophenyl)pentan-1-one (4.21 g, 21.0 mmol) was added, followed by tert-butyl 4-bromobenzoate (5.0 g, 19.1 mmol) under nitrogen. The mixture was heated at 60° C. for 8 hours. The mixture was diluted with heptane (100 mL) and poured into a solution of saturated NaHCO3 (aq) (60 mL) and ice (40 g). The resulting layers were separated, and the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL). The combined organics were washed with saturated NaHCO3 (aq) then 10% NaCl (aq). The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane), and washed with 1:1 methyl tert-butyl ether/heptane (600 mL). The combined filtrate was concentrated to afford an orange oil that was used directly for the next step: 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=8.1 Hz, 2H); 7.86 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.32 (d, J=8.2 Hz, 2H); 4.53 (1, J=7.2 Hz, 1H); 2.19-2.09 (m, 1H); 1.85-1.76 (m, 1H); 1.56 (s, 9H); 1.35-1.18 (m, 2H); 0.91 (t, J=7.3 Hz, 3H); LC3: 1.35 min. (M-tBu+H)+ 317. The resulting layers were separated the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL) The combined organics were washed with saturated NaHCO3 (aq) The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane) washed with 1:1 methyl tert-butyl ether/heptane (600 mL) The combined filtrate was concentrated to afford an orange oil that 1.35 min.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 3-neck flask was charged with NaOtBu (2.85 g, 28.6 mmol) and dry THF (50 mL) under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (0.26 g, 0.28 mmol) and (S)-Tol-Binap (0.47 g, 0.69 mmol) were then added under nitrogen. After stirring for 15 min, 1-(4-chlorophenyl)pentan-1-one (4.21 g, 21.0 mmol) was added, followed by tert-butyl 4-bromobenzoate (5.0 g, 19.1 mmol) under nitrogen. The mixture was heated at 60° C. for 8 hours. The mixture was diluted with heptane (100 mL) and poured into a solution of saturated NaHCO3 (aq) (60 mL) and ice (40 g). The resulting layers were separated, and the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL). The combined organics were washed with saturated NaHCO3 (aq) then 10% NaCl (aq). The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane), and washed with 1:1 methyl tert-butyl ether/heptane (600 mL). The combined filtrate was concentrated to afford an orange oil that was used directly for the next step: 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=8.1 Hz, 2H); 7.86 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.32 (d, J=8.2 Hz, 2H); 4.53 (1, J=7.2 Hz, 1H); 2.19-2.09 (m, 1H); 1.85-1.76 (m, 1H); 1.56 (s, 9H); 1.35-1.18 (m, 2H); 0.91 (t, J=7.3 Hz, 3H); LC3: 1.35 min. (M-tBu+H)+ 317. The resulting layers were separated the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL) The combined organics were washed with saturated NaHCO3 (aq) The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane) washed with 1:1 methyl tert-butyl ether/heptane (600 mL) The combined filtrate was concentrated to afford an orange oil that 1.35 min.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 3-neck flask was charged with NaOtBu (2.85 g, 28.6 mmol) and dry THF (50 mL) under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (0.26 g, 0.28 mmol) and (S)-Tol-Binap (0.47 g, 0.69 mmol) were then added under nitrogen. After stirring for 15 min, 1-(4-chlorophenyl)pentan-1-one (4.21 g, 21.0 mmol) was added, followed by tert-butyl 4-bromobenzoate (5.0 g, 19.1 mmol) under nitrogen. The mixture was heated at 60° C. for 8 hours. The mixture was diluted with heptane (100 mL) and poured into a solution of saturated NaHCO3 (aq) (60 mL) and ice (40 g). The resulting layers were separated, and the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL). The combined organics were washed with saturated NaHCO3 (aq) then 10% NaCl(aq). The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane), and washed with 1:1 methyl tert-butyl ether/heptane (600 mL). The combined filtrate was concentrated to afford an orange oil that was used directly for the next step: 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=8.1 Hz, 2H); 7.86 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.32 (d, J=8.2 Hz, 2H); 4.53 (t, J=7.2 Hz, 1H); 2.19-2.09 (m, 1H); 1.85-1.76 (m, 1H); 1.56 (s, 9H); 1.35-1.18 (m, 2H); 0.91 (t, J=7.3 Hz, 3H); LC1: 1.35 min. (M-tBu+H)+ 317. The resulting layers were separated the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL) The combined organics were washed with saturated NaHCO3 (aq) The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane) washed with 1:1 methyl tert-butyl ether/heptane (600 mL) The combined filtrate was concentrated to afford an orange oil that 1.35 min.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 3-neck flask was charged with NaOtBu (2.85 g, 28.6 mmol) and dry THF (50 mL) under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (0.26 g, 0.28 mmol) and (S)-Tol-Binap (0.47 g, 0.69 mmol) were then added under nitrogen. After stirring for 15 min, 1-(4-chlorophenyl)pentan-1-one (4.21 g, 21.0 mmol) was added, followed by tert-butyl 4-bromobenzoate (5.0 g, 19.1 mmol) under nitrogen. The mixture was heated at 60° C. for 8 hours. The mixture was diluted with heptane (100 mL) and poured into a solution of saturated NaHCO3 (aq) (60 mL) and ice (40 g). The resulting layers were separated, and the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL). The combined organics were washed with saturated NaHCO3 (aq) then 10% NaCl (aq). The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane), and washed with 1:1 methyl tert-butyl ether/heptane (600 mL). The combined filtrate was concentrated to afford an orange oil that was used directly for the next step: 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=8.1 Hz, 2H); 7.86 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.32 (d, J=8.2 Hz, 2H); 4.53 (t, J=7.2 Hz, 1H); 2.19-2.09 (m, 1H); 1.85-1.76 (m, 1H); 1.56 (s, 9H); 1.35-1.18 (m, 2H); 0.91 (t, J=7.3 Hz, 3H); LC1 1.35 min. [M-tBu+H]+ 317. The resulting layers were separated the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL) The combined organics were washed with saturated NaHCO3 (aq) The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane) washed with 1:1 methyl tert-butyl ether/heptane (600 mL) The combined filtrate was concentrated to afford an orange oil that LC1 1.35 min.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 3-neck flask was charged with NaOtBu (2.85 g, 28.6 mmol) and dry THF (50 mL) under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (0.26 g, 0.28 mmol) and (S)-Tol-Binap (0.47 g, 0.69 mmol) were then added under nitrogen. After stirring for 15 min, 1-(4-chlorophenyl)pentan-1-one (4.21 g, 21.0 mmol) was added, followed by tert-butyl 4-bromobenzoate (5.0 g, 19.1 mmol) under nitrogen. The mixture was heated at 60° C. for 8 hours. The mixture was diluted with heptane (100 mL) and poured into a solution of saturated NaHCO3 (aq) (60 mL) and ice (40 g). The resulting layers were separated, and the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL). The combined organics were washed with saturated NaHCO3 (aq) then 10% NaCl (aq). The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane), and washed with 1:1 methyl tert-butyl ether/heptane (600 mL). The combined filtrate was concentrated to afford an orange oil that was used directly for the next step: 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J=8.1 Hz, 2 H); 7.86 (d, J=8.4 Hz, 2H); 7.35 (d, =8.4 Hz, 2H); 7.32 (d, J=8.2 Hz, 2H); 4.53 (t, J=7.2 Hz, 1H); 2.19-2.09 (m, 1H); 1.85-1.76 (m, 1H); 1.56 (s, 9H); 1.35-1.18 (m, 2H); 0.91 (t, J=7.3 Hz, 3H); LC1: 1.35 min. (M−tBu+H)=317. The resulting layers were separated the aqueous phase was back-extracted with methyl tert-butyl ether (50 mL) The combined organics were washed with saturated NaHCO3 (aq) The organic solution was filtered through a bed of silica 60 (84 g, wetted with 1:1 methyl tert-butyl ether/heptane) washed with 1:1 methyl tert-butyl ether/heptane (600 mL) The combined filtrate was concentrated to afford an orange oil that

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

Procedure: A solution of 0.015 g (0.054 mmole) of methyl azetidin-3-yl(3,5-difluorophenyl)acetate, 0.020 g (0.101 mmol) of 1-(4-chlorophenyl)pentan-1-one and 0.015 mL (0.12 mmol) of triethylamine in 5 mL of dichloroethane was stirred at room temperature. After 5 min, 0.050 g (0.237 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 6 h. The reaction was quenched by addition of saturated K2CO3 solution and the mixture was partitioned between 10 mL ether and 2 mL saturated K2CO3 solution. The layers were separated and the organic layer was dried over Na2SO4, and concentrated. The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) using a gradient of CH3CN—H2O-Et3N (20:80:0.1 to 60:40:0.1). Homogenous fractions were pooled and concentrated to afford the title compound as a mixture of isomers; Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl). Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl). The reaction was quenched by addition of saturated K2CO3 solution the mixture was partitioned between 10 mL ether and 2 mL saturated K2CO3 solution The layers were separated the organic layer was dried over Na2SO4 concentrated The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) concentrated

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

Procedure: A solution of 0.015 g (0.054 mmole) of methyl azetidin-3-yl(3,5-difluorophenyl)acetate, 0.020 g (0.101 mmol) of 1-(4-chlorophenyl)pentan-1-one and 0.015 mL (0.12 mmol) of triethylamine in 5 mL of dichloroethane was stirred at room temperature. After 5 min, 0.050 g (0.237 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 6 h. The reaction was quenched by addition of saturated K2CO3 solution and the mixture was partitioned between 10 mL ether and 2 mL saturated K2CO3 solution. The layers were separated and the organic layer was dried over Na2SO4, and concentrated. The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) using a gradient of CH3CN—H2O-Et3N (20:80:0.1 to 60:40:0.1). Homogenous fractions were pooled and concentrated to afford the title compound as a mixture of isomers; Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl). Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl). The reaction was quenched by addition of saturated K2CO3 solution the mixture was partitioned between 10 mL ether and 2 mL saturated K2CO3 solution The layers were separated the organic layer was dried over Na2SO4 concentrated The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) concentrated

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