2-bromo-4-chloro-1-fluorobenzene

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

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

Procedure: In a 250 ml round bottom flask equipped with a stir bar and reflux condenser added 4-chloro-2-bromo-1-fluoro-benzene (5 g, 23.9 mmol), triphenylphosphine (250 mg, 0.10 mmol), (trimethylsilyl)acetylene (5.2 ml, 36.5 mmol)and triethylamine (60 ml). The reaction mixture was purged with argon, followed by addition of palladium (II) acetate (108 mg, 0.05 mmol). The resulting mixture was left stirring at reflux under argon, overnight. The reaction mixture was filtered through a pad of celite using ethyl acetate and the filterate was concentrated in-vacuo. The isolated residue was absorbed on silica gel and filtered using hexanes. The filterate was concentrated in-vacuo to isolate the title compound as brown oil (5.42 g). Step 2: 4-Chloro-2-ethynyl-1-fluoro-benzene: In a 250 ml round bottom flask equipped with stir bar added (5-chloro-2-fluoro-phenylethynyl)-trimethyl-silane (5.42 g, 23.9 mmol), potassium carbonate (16.5 g, 120 mmol) and methanol (60 ml). The reaction mixture was left stirring at room temperature for 1 h. Diluted the reaction mixture with hexanes (200 ml) and washed with water (250 ml). The aqueous phase was extracted with hexanes (2×100 ml). Combined organic phase was washed with brine (200 ml), dried (sodium sulfate), filtered and concentrated in-vacuo to isolate the desired compound as brown oil (3.56 g). 1H-NMR (CDCl3), d (ppm): 7.47 (dd, 1H), 7.30 (m, 1H), 7.05 (t, 1H), 3.36 (s, 1H). Step 3: Chloro-hydroxyimino-acetic acid ethyl ester: In 1 L round bottom flask equipped with stir bar added amino-acetic acid ethyl ester hydrochloride (20 g, 143 mmol) and water (30 ml). The solution was cooled down to 0° C. followed by sequential addition of concentrated hydrochloric acid (11.8 ml, 143 mmol) and dropwise addition of sodium nitrite (9.89 g, 143 mmol) solution in water (15 ml). After 10 min added another equivalent each of concentrated hydrochloric acid and sodium nitrite solution in water. The reaction mixture was left stirring at 0° C. for 1 h. Reaction mixture was extracted with ether (4×100 ml). Combined organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo to isolate a lemon yellow solid. The solid was recrystallized from hexanes to isolate a white solid (11 g, 51%). 1H-NMR (CDCl3), d (ppm): 9.98 (bs, 1H), 4.40 (q, 2H), 1.38 (t, 3H). Step 4: 5-(5-Chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester: In a 250 ml round bottom flask equipped with stir bar added 4-chloro-2-ethynyl-1-fluoro-benzene (2 g, 12.9 mmol), chloro-hydroxyimino-acetic acid ethyl ester (3.92 g, 25.9 mmol), sodium bicarbonate (7.07 g, 84.1 mmol) and toluene (50 ml). Reaction mixture was left stirring at room temperature for 48 h, after which it was concentrated in-vacuo. Residue was taken up in ethyl acetate (200 ml), sequentially washed with water (150 ml), brine (150 ml), dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 3% acetone in hexanes to isolate the title compound as an off-white solid (1.56 g). 1H-NMR (CDCl3), d (ppm): 8.00 (dd, 1H), 7.43 (m, 1H), 7.18 (m, 2H), 4.51 (q, 2H), 1.47 (t, 3H). Step 5: [5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-methanol: In a 50 ml round bottom flask equipped with stir bar and drying tube added 5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (0.78 g, 2.89 mmol) and tetrahydrofuran (10 ml). To this stirred solution added solution of lithium aluminum hydride (0.12 g, 2.89 mmol) in tetrahydrofuran (2 ml). The resulting mixture was left stirring at room temperature for 1 h. Reaction was quenched using sodium sulfate decahydrate. The resulting mixture was stirred at 63° C. for 15 min after which it was filtered through a celite pad. The filterate was concentrated in-vacuo to isolate the title compound as yellow solid (0.65 g, 99%). 1H-NMR (CDCl3), d (ppm): 7.73 (dd, 1H), 7.27 (m, 1H), 7.24 (t, 1H), 6.73 (d, 1H), 4.77 (s, 2H), 4.45 (bs, 1H). In a 250 ml round bottom flask equipped with a stir bar reflux condenser The reaction mixture was purged with argon The resulting mixture was left at reflux under argon, overnight The reaction mixture was filtered through a pad of celite the filterate was concentrated in-vacuo The isolated residue was absorbed on silica gel filtered The filterate was concentrated in-vacuo

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

Procedure: In a 250 ml round bottom flask equipped with a stir bar and reflux condenser added 4-chloro-2-bromo-1-fluoro-benzene (5 g, 23.9 mmol), triphenylphosphine (250 mg, 0.10 mmol), (trimethylsilyl)acetylene (5.2 ml, 36.5 mmol)and triethylamine (60 ml). The reaction mixture was purged with argon, followed by addition of palladium (II) acetate (108 mg, 0.05 mmol). The resulting mixture was left stirring at reflux under argon, overnight. The reaction mixture was filtered through a pad of celite using ethyl acetate and the filterate was concentrated in-vacuo. The isolated residue was absorbed on silica gel and filtered using hexanes. The filterate was concentrated in-vacuo to isolate the title compound as brown oil (5.42 g). Step 2: 4-Chloro-2-ethynyl-1-fluoro-benzene: In a 250 ml round bottom flask equipped with stir bar added (5-chloro-2-fluoro-phenylethynyl)-trimethyl-silane (5.42 g, 23.9 mmol), potassium carbonate (16.5 g, 120 mmol) and methanol (60 ml). The reaction mixture was left stirring at room temperature for 1 h. Diluted the reaction mixture with hexanes (200 ml) and washed with water (250 ml). The aqueous phase was extracted with hexanes (2×100 ml). Combined organic phase was washed with brine (200 ml), dried (sodium sulfate), filtered and concentrated in-vacuo to isolate the desired compound as brown oil (3.56 g). 1H-NMR (CDCl3), d (ppm): 7.47 (dd, 1H), 7.30 (m, 1H), 7.05 (t, 1H), 3.36 (s, 1H). Step 3: Chloro-hydroxyimino-acetic acid ethyl ester: In 1 L round bottom flask equipped with stir bar added amino-acetic acid ethyl ester hydrochloride (20 g, 143 mmol) and water (30 ml). The solution was cooled down to 0° C. followed by sequential addition of concentrated hydrochloric acid (11.8 ml, 143 mmol) and dropwise addition of sodium nitrite (9.89 g, 143 mmol) solution in water (15 ml). After 10 min added another equivalent each of concentrated hydrochloric acid and sodium nitrite solution in water. The reaction mixture was left stirring at 0° C. for 1 h. Reaction mixture was extracted with ether (4×100 ml). Combined organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo to isolate a lemon yellow solid. The solid was recrystallized from hexanes to isolate a white solid (11 g, 51%). 1H-NMR (CDCl3), d (ppm): 9.98 (bs, 1H), 4.40 (q, 2H), 1.38 (t, 3H). Step 4: 5-(5-Chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester: In a 250 ml round bottom flask equipped with stir bar added 4-chloro-2-ethynyl-1-fluoro-benzene (2 g, 12.9 mmol), chloro-hydroxyimino-acetic acid ethyl ester (3.92 g, 25.9 mmol), sodium bicarbonate (7.07 g, 84.1 mmol) and toluene (50 ml). Reaction mixture was left stirring at room temperature for 48 h, after which it was concentrated in-vacuo. Residue was taken up in ethyl acetate (200 ml), sequentially washed with water (150 ml), brine (150 ml), dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 3% acetone in hexanes to isolate the title compound as an off-white solid (1.56 g). 1H-NMR (CDCl3), d (ppm): 8.00 (dd, 1H), 7.43 (m, 1H), 7.18 (m, 2H), 4.51 (q, 2H), 1.47 (t, 3H). Step 5: [5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-methanol: In a 50 ml round bottom flask equipped with stir bar and drying tube added 5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (0.78 g, 2.89 mmol) and tetrahydrofuran (10 ml). To this stirred solution added solution of lithium aluminum hydride (0.12 g, 2.89 mmol) in tetrahydrofuran (2 ml). The resulting mixture was left stirring at room temperature for 1 h. Reaction was quenched using sodium sulfate decahydrate. The resulting mixture was stirred at 63° C. for 15 min after which it was filtered through a celite pad. The filterate was concentrated in-vacuo to isolate the title compound as yellow solid (0.65 g, 99%). 1H-NMR (CDCl3), d (ppm): 7.73 (dd, 1H), 7.27 (m, 1H), 7.24 (t, 1H), 6.73 (d, 1H), 4.77 (s, 2H), 4.45 (bs, 1H). In a 250 ml round bottom flask equipped with a stir bar reflux condenser The reaction mixture was purged with argon The resulting mixture was left at reflux under argon, overnight The reaction mixture was filtered through a pad of celite the filterate was concentrated in-vacuo The isolated residue was absorbed on silica gel filtered The filterate was concentrated in-vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled solution of diisopropylamine (2.4 mL, 17.2 mmol) in dry THF (15 mL) under Argon at 0° C. was added n-butyllithium (7.5 mL, 2.0 M in pentane, 15.0 mmol). After 30 minutes the solution was cooled to −78° C. and a solution of 2-bromo-4-chloro-1-fluorobenzene (3 g, 14.3 mmol) in dry THF (15 mL) was added over 15 minutes. After 1 hour, this solution was transferred via cannula over 10 minutes to a mixture of solid carbon dioxide and THF (30 mL) at −78° C. After 45 minutes the cold bath was removed and excess carbon dioxide was allowed to vent while the solution warmed to room temperature. The reaction mixture was then quenched with aqueous 0.5 M HCl solution (60 mL). After concentrating, the remaining aqueous phase was basified with aqueous 0.5 M NaOH solution and was washed with ethyl acetate (100 mL). The aqueous phase was then acidified with aqueous 1.0 M HCl solution and extracted with chloroform (2×75 mL). The combined organic portions were washed with brine, dried (Na2SO4) and concentrated to give 3.34 g of a semi-crystalline solid as a mixture of regioisomers with the desired isomer as the major: LCMS (m/z) not observed (MH+), tR=0.66 minute; 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J=5.5, 2.7 Hz, 1H), 7.95 (dd, J=5.5, 2.7 Hz, 1H). After 45 minutes the cold bath was removed warmed to room temperature The reaction mixture was then quenched with aqueous 0.5 M HCl solution (60 mL) After concentrating was washed with ethyl acetate (100 mL) extracted with chloroform (2×75 mL) The combined organic portions were washed with brine dried (Na2SO4) concentrated to give 3.34 g of a semi-crystalline solid as a mixture of regioisomers with the desired isomer as the major: LCMS (m/z) not

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled solution of diisopropylamine (2.4 mL, 17.2 mmol) in dry THF (15 mL) under Argon at 0° C. was added n-butyllithium (7.5 mL, 2.0 M in pentane, 15.0 mmol). After 30 minutes the solution was cooled to −78° C. and a solution of 2-bromo-4-chloro-1-fluorobenzene (3 g, 14.3 mmol) in dry THF (15 mL) was added over 15 minutes. After 1 hour, this solution was transferred via cannula over 10 minutes to a mixture of solid carbon dioxide and THF (30 mL) at −78° C. After 45 minutes the cold bath was removed and excess carbon dioxide was allowed to vent while the solution warmed to room temperature. The reaction mixture was then quenched with aqueous 0.5 M HCl solution (60 mL). After concentrating, the remaining aqueous phase was basified with aqueous 0.5 M NaOH solution and was washed with ethyl acetate (100 mL). The aqueous phase was then acidified with aqueous 1.0 M HCl solution and extracted with chloroform (2×75 mL). The combined organic portions were washed with brine, dried (Na2SO4) and concentrated to give 3.34 g of a semi-crystalline solid as a mixture of regioisomers with the desired isomer as the major: LCMS (m/z) not observed (MH+), tR=0.66 minute; 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J=5.5, 2.7 Hz, 1H), 7.95 (dd, J=5.5, 2.7 Hz, 1H). After 45 minutes the cold bath was removed warmed to room temperature The reaction mixture was then quenched with aqueous 0.5 M HCl solution (60 mL) After concentrating was washed with ethyl acetate (100 mL) extracted with chloroform (2×75 mL) The combined organic portions were washed with brine dried (Na2SO4) concentrated to give 3.34 g of a semi-crystalline solid as a mixture of regioisomers with the desired isomer as the major: LCMS (m/z) not

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

Procedure: Starting from 2-bromo-4-chloro-1-fluorobenzene, the procedure for 1-(6-bromo-2-chloro-3-fluorophenyl)ethanol was followed, except column chromatography required a less polar solvent system for product elution (CH2Cl2:Heptane 3:1→1:0→neat EtOAc). Additionally, preparative TLC purification was also required to obtain pure product. 1H NMR (400 MHz, CDCl3) δ=1.65 (d, J=6.8 Hz, 3H), 2.98 (br s, 1H), 5.59 (q, J=6.8 Hz, 1H), 7.01 (dd, J=8.7, 7.5 Hz, 1H), 7.32 (dd, J=8.7, 4.9 Hz, 1H). MS (ES+): m/z 275.99/277.96 [MNa+]. HPLC: tR=3.23 min (ZQ3, polar—5 min). for product elution (CH2Cl2:Heptane 3:1→1:0→neat EtOAc) Additionally, preparative TLC purification to obtain pure product 5 min

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled solution of diisopropylamine (2.4 mL, 17.2 mmol) in dry THF (15 mL) under Argon at 0° C. was added n-butyllithium (7.5 mL, 2.0 M in pentane, 15.0 mmol). After 30 minutes the solution was cooled to −78° C. and a solution of 2-bromo-4-chloro-1-fluorobenzene (3 g, 14.3 mmol) in dry THF (15 mL) was added over 15 minutes. After 1 hour, this solution was transferred via cannula over 10 minutes to a mixture of solid carbon dioxide and THF (30 mL) at −78° C. After 45 minutes the cold bath was removed and excess carbon dioxide was allowed to vent while the solution warmed to room temperature. The reaction mixture was then quenched with aqueous 0.5 M HCl solution (60 mL). After concentrating, the remaining aqueous phase was basified with aqueous 0.5 M NaOH solution and was washed with ethyl acetate (100 mL). The aqueous phase was then acidified with aqueous 1.0 M HCl solution and extracted with chloroform (2×75 mL). The combined organic portions were washed with brine, dried (Na2SO4) and concentrated to give 3.34 g of a semi-crystalline solid as a mixture of regioisomers with the desired isomer as the major: LCMS(m/z) not observed (MH+), tR=0.66 minute; 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J=5.5, 2.7 Hz, 1H), 7.95 (dd, J=5.5, 2.7 Hz, 1H). After 45 minutes the cold bath was removed warmed to room temperature The reaction mixture was then quenched with aqueous 0.5 M HCl solution (60 mL) After concentrating was washed with ethyl acetate (100 mL) extracted with chloroform (2×75 mL) The combined organic portions were washed with brine dried (Na2SO4) concentrated to give 3.34 g of a semi-crystalline solid as a mixture of regioisomers with the desired isomer as the major: LCMS(m/z) not

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

Procedure: In a 250 ml round bottom flask equipped with a stir bar and reflux condenser added 4-chloro-2-bromo-1-fluoro-benzene (5 g, 23.9 mmol), triphenylphosphine (250 mg, 0.10 mmol), (trimethylsilyl)acetylene (5.2 ml, 36.5 mmol)and triethylamine (60 ml). The reaction mixture was purged with argon, followed by addition of palladium (II) acetate (108 mg, 0.05 mmol). The resulting mixture was left stirring at reflux under argon, overnight. The reaction mixture was filtered through a pad of celite using ethyl acetate and the filterate was concentrated in-vacuo. The isolated residue was absorbed on silica gel and filtered using hexanes. The filterate was concentrated in-vacuo to isolate the title compound as brown oil (5.42 g). Step 2: 4-Chloro-2-ethynyl-1-fluoro-benzene: In a 250 ml round bottom flask equipped with stir bar added (5-chloro-2-fluoro-phenylethynyl)-trimethyl-silane (5.42 g, 23.9 mmol), potassium carbonate (16.5 g, 120 mmol) and methanol (60 ml). The reaction mixture was left stirring at room temperature for 1 h. Diluted the reaction mixture with hexanes (200 ml) and washed with water (250 ml). The aqueous phase was extracted with hexanes (2×100 ml). Combined organic phase was washed with brine (200 ml), dried (sodium sulfate), filtered and concentrated in-vacuo to isolate the desired compound as brown oil (3.56 g). 1H-NMR (CDCl3), d (ppm): 7.47 (dd, 1H), 7.30 (m, 1H), 7.05 (t, 1H), 3.36 (s, 1H). Step 3: Chloro-hydroxyimino-acetic acid ethyl ester: In 1 L round bottom flask equipped with stir bar added amino-acetic acid ethyl ester hydrochloride (20 g, 143 mmol) and water (30 ml). The solution was cooled down to 0° C. followed by sequential addition of concentrated hydrochloric acid (11.8 ml, 143 mmol) and dropwise addition of sodium nitrite (9.89 g, 143 mmol) solution in water (15 ml). After 10 min added another equivalent each of concentrated hydrochloric acid and sodium nitrite solution in water. The reaction mixture was left stirring at 0° C . for 1 h. Reaction mixture was extracted with ether (4×100 ml). Combined organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo to isolate a lemon yellow solid. The solid was recrystallized from hexanes to isolate a white solid (11 g, 51%). 1H-NMR (CDCl3), d (ppm): 9.98 (bs, 1H), 4.40 (q, 2H), 1.38 (t, 3H). Step 4: 5-(5-Chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester: In a 250 ml round bottom flask equipped with stir bar added 4-chloro-2-ethynyl-1-fluoro-benzene (2 g, 12.9 mmol), chloro-hydroxyimino-acetic acid ethyl ester (3.92 g, 25.9 mmol), sodium bicarbonate (7.07 g, 84.1 mmol) and toluene (50 ml). Reaction mixture was left stirring at room temperature for 48 h, after which it was concentrated in-vacuo. Residue was taken up in ethyl acetate (200 ml), sequentially washed with water (150 ml), brine (150 ml), dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 3% acetone in hexanes to isolate the title compound as an off-white solid (1.56 g). 1H-NMR (CDCl3), d (ppm): 8.00 (dd, 1H), 7.43 (m, 1H), 7.18 (m, 2H), 4.51 (q, 2H), 1.47 (t, 3H). Step 5: [5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-methanol: In a 50 ml round bottom flask equipped with stir bar and drying tube added 5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (0.78 g, 2.89 mmol) and tetrahydrofuran (10 ml). To this stirred solution added solution of lithium aluminum hydride (0.12 g, 2.89 mmol) in tetrahydrfuran (2 ml). The resulting mixture was left stirring at room temperature for 1 h. Reaction was quenched using sodium sulfate decahydrate. The resulting mixture was stirred at 63° C. for 15 min after which it was filtered through a celite pad. The filterate was concentrated in-vacuo to isolate the title compound as yellow solid (0.65 g, 99%). 1H-NMR (CDCl3), d (ppm): 7.73 (dd, 1H), 7.27 (m, 1H), 7.24 (t, 1H), 6.73 (d, 1H), 4.77 (s, 2H), 4.45 (bs, 1H). In a 250 ml round bottom flask equipped with a stir bar reflux condenser The reaction mixture was purged with argon The resulting mixture was left at reflux under argon, overnight The reaction mixture was filtered through a pad of celite the filterate was concentrated in-vacuo The isolated residue was absorbed on silica gel filtered The filterate was concentrated in-vacuo

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

Procedure: In a 250 ml round bottom flask equipped with a stir bar and reflux condenser added 4-chloro-2-bromo-1-fluoro-benzene (5 g, 23.9 mmol), triphenylphosphine (250 mg, 0.10 mmol), (trimethylsilyl)acetylene (5.2 ml, 36.5 mmol)and triethylamine (60 ml). The reaction mixture was purged with argon, followed by addition of palladium (II) acetate (108 mg, 0.05 mmol). The resulting mixture was left stirring at reflux under argon, overnight. The reaction mixture was filtered through a pad of celite using ethyl acetate and the filterate was concentrated in-vacuo. The isolated residue was absorbed on silica gel and filtered using hexanes. The filterate was concentrated in-vacuo to isolate the title compound as brown oil (5.42 g). Step 2: 4-Chloro-2-ethynyl-1-fluoro-benzene: In a 250 ml round bottom flask equipped with stir bar added (5-chloro-2-fluoro-phenylethynyl)-trimethyl-silane (5.42 g, 23.9 mmol), potassium carbonate (16.5 g, 120 mmol) and methanol (60 ml). The reaction mixture was left stirring at room temperature for 1 h. Diluted the reaction mixture with hexanes (200 ml) and washed with water (250 ml). The aqueous phase was extracted with hexanes (2×100 ml). Combined organic phase was washed with brine (200 ml), dried (sodium sulfate), filtered and concentrated in-vacuo to isolate the desired compound as brown oil (3.56 g). 1H-NMR (CDCl3), d (ppm): 7.47 (dd, 1H), 7.30 (m, 1H), 7.05 (t, 1H), 3.36 (s, 1H). Step 3: Chloro-hydroxyimino-acetic acid ethyl ester: In 1 L round bottom flask equipped with stir bar added amino-acetic acid ethyl ester hydrochloride (20 g, 143 mmol) and water (30 ml). The solution was cooled down to 0° C. followed by sequential addition of concentrated hydrochloric acid (11.8 ml, 143 mmol) and dropwise addition of sodium nitrite (9.89 g, 143 mmol) solution in water (15 ml). After 10 min added another equivalent each of concentrated hydrochloric acid and sodium nitrite solution in water. The reaction mixture was left stirring at 0° C . for 1 h. Reaction mixture was extracted with ether (4×100 ml). Combined organic phase was dried (sodium sulfate), filtered and concentrated in-vacuo to isolate a lemon yellow solid. The solid was recrystallized from hexanes to isolate a white solid (11 g, 51%). 1H-NMR (CDCl3), d (ppm): 9.98 (bs, 1H), 4.40 (q, 2H), 1.38 (t, 3H). Step 4: 5-(5-Chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester: In a 250 ml round bottom flask equipped with stir bar added 4-chloro-2-ethynyl-1-fluoro-benzene (2 g, 12.9 mmol), chloro-hydroxyimino-acetic acid ethyl ester (3.92 g, 25.9 mmol), sodium bicarbonate (7.07 g, 84.1 mmol) and toluene (50 ml). Reaction mixture was left stirring at room temperature for 48 h, after which it was concentrated in-vacuo. Residue was taken up in ethyl acetate (200 ml), sequentially washed with water (150 ml), brine (150 ml), dried (sodium sulfate), filtered and concentrated in-vacuo. The crude residue was purified on silica gel using 3% acetone in hexanes to isolate the title compound as an off-white solid (1.56 g). 1H-NMR (CDCl3), d (ppm): 8.00 (dd, 1H), 7.43 (m, 1H), 7.18 (m, 2H), 4.51 (q, 2H), 1.47 (t, 3H). Step 5: [5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-methanol: In a 50 ml round bottom flask equipped with stir bar and drying tube added 5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (0.78 g, 2.89 mmol) and tetrahydrofuran (10 ml). To this stirred solution added solution of lithium aluminum hydride (0.12 g, 2.89 mmol) in tetrahydrfuran (2 ml). The resulting mixture was left stirring at room temperature for 1 h. Reaction was quenched using sodium sulfate decahydrate. The resulting mixture was stirred at 63° C. for 15 min after which it was filtered through a celite pad. The filterate was concentrated in-vacuo to isolate the title compound as yellow solid (0.65 g, 99%). 1H-NMR (CDCl3), d (ppm): 7.73 (dd, 1H), 7.27 (m, 1H), 7.24 (t, 1H), 6.73 (d, 1H), 4.77 (s, 2H), 4.45 (bs, 1H). In a 250 ml round bottom flask equipped with a stir bar reflux condenser The reaction mixture was purged with argon The resulting mixture was left at reflux under argon, overnight The reaction mixture was filtered through a pad of celite the filterate was concentrated in-vacuo The isolated residue was absorbed on silica gel filtered The filterate was concentrated in-vacuo

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

Procedure: A solution of 2-bromo-4-chloro-1-fluorobenzene (175 μL, 1.377 mmol) in THF (4.59 mL) at 78° C. was treated with n-BuLi (2.6 M, 741 μL, 1.928 mmol) and the reaction mixture was stirred for 30 min. To this was added tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (250 mg, 0.918 mmol) in one portion. The cooling bath was removed and the resulting reaction mixture was allowed to warm to rt and stirred for 1.5 h. Purification by automated flash silica gel chromatography using 10% EtOAc in hexanes afforded tert-butyl 4-(5-chloro-2-fluorobenzoyl)piperidine-1-carboxylate (287.9 mg, 92%) as a yellow oil. ESI-MS m/z [M+Na]+ 364.20. The cooling bath was removed the resulting reaction mixture stirred for 1.5 h Purification by automated flash silica gel chromatography

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-bromo-4-chloro-1-fluorobenzene (4.31 g, 20 mmol) was added dropwise to a −78° C. solution of LDA in THF (prepared from diisopropylamine (3.38 ml, 24 mmol) and n-BuLi (1.6 M, 13.1 ml, 21 mmol)). The mixture was stirred at −78° C. for 1 h, and then was transferred slowly (˜30-60 min) via cannula to a stirred −78° C. mixture of dry ice and THF (40 ml). The mixture was stirred at −78° C. for 1 h, and then was allowed to warm to rt (gas evolution). The mixture was concentrated, and was then treated with 50 ml of 1 N sodium hydroxide solution. The mixture was extracted with ethyl acetate (discarded). The aqueous layer was acidified with 1N hydrochloric acid, and then was extracted with chloroform (3×400 ml). The chloroform extract was dried over sodium sulfate, filtered, and concentrated to provide the crude title compound. The product was contaminated with a small amount of the isomeric product 2-bromo-6-chloro-3-fluorobenzoic acid. 1H NMR for title compound 3-Bromo-5-chloro-2-fluorobenzoic acid: (400 MHz, CDCl3) δ 7.93 (dd, 1H, J=2.8, 5.6 Hz), 7.79 (dd, 1H, J=2.8, 5.6 Hz) ppm. (˜30-60 min) to a stirred −78° C. The mixture was stirred at −78° C. for 1 h to warm to rt (gas evolution) The mixture was concentrated was then treated with 50 ml of 1 N sodium hydroxide solution The mixture was extracted with ethyl acetate (discarded) was extracted with chloroform (3×400 ml) The chloroform extract was dried over sodium sulfate filtered concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled solution of diisopropylamine (2.4 mL, 17.2 mmol) in dry THF (15 mL) under Argon at 0° C. was added n-butyllithium (7.5 mL, 2.0 M in pentane, 15.0 mmol). After 30 minutes the solution was cooled to −78° C. and a solution of 2-bromo-4-chloro-1-fluorobenzene (3 g, 14.3 mmol) in dry THF (15 mL) was added over 15 minutes. After 1 hour, this solution was transferred via cannula over 10 minutes to a mixture of solid carbon dioxide and THF (30 mL) at −78° C. After 45 minutes the cold bath was removed and excess carbon dioxide was allowed to vent while the solution warmed to room temperature. The reaction mixture was then quenched with aqueous 0.5 M HCl solution (60 mL). After concentrating, the remaining aqueous phase was basified with aqueous 0.5 M NaOH solution and was washed with ethyl acetate (100 mL). The aqueous phase was then acidified with aqueous 1.0 M HCl solution and extracted with chloroform (2×75 mL). The combined organic portions were washed with brine, dried (Na2SO4) and concentrated to give 3.34 g of a semi-crystalline solid as a mixture of regioisomers with the desired isomer as the major: LCMS (m/z) not observed (MH+), tR=0.66 minute; 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J=5.5, 2.7 Hz, 1H), 7.95 (dd, J=5.5, 2.7 Hz, 1H). After 45 minutes the cold bath was removed warmed to room temperature The reaction mixture was then quenched with aqueous 0.5 M HCl solution (60 mL) After concentrating was washed with ethyl acetate (100 mL) extracted with chloroform (2×75 mL) The combined organic portions were washed with brine dried (Na2SO4) concentrated to give 3.34 g of a semi-crystalline solid as a mixture of regioisomers with the desired isomer as the major: LCMS (m/z) not