6-chloro-2-fluoro-3-methylbenzoyl chloride

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

Procedure: Step 1 To a solution of 6-chloro-2-fluoro-3-methyl-benzoyl chloride (2.07 g, 10.0 mmol) in anhydrous tetrahydrofuran (50 ml), stirred under nitrogen in an acetonitrile/CO2 bath, was added tributyl phosphine (2.75 ml, 11.0 mmol). The mixture was stirred for 15 minutes before phenylmagnesium bromide (3M in diethyl ether, 3.67 ml, 11.0 mmol) was added dropwise. After 45 minutes, the reaction was quenched by addition of hydrochloric acid (2N, 50 ml). The mixture was extracted with ethyl acetate. The organic liquors were washed with sodium bicarbonate solution and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica chromatography eluting with 0-10% diethyl ether/petroleum ether furnishing (6-chloro-2-fluoro-3-methyl-phenyl)-phenyl-methanone as a yellow oil that slowly crystallised (1.12 g, ca. 80% pure). Trituration with petroleum ether produced an analytically pure sample. MS: [M+H]+ 249 was added dropwise the reaction was quenched by addition of hydrochloric acid (2N, 50 ml) The mixture was extracted with ethyl acetate The organic liquors were washed with sodium bicarbonate solution and brine dried (MgSO4) concentrated in vacuo The residue was purified by silica chromatography eluting with 0-10% diethyl ether/petroleum ether

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

Procedure: Step 1 To a solution of 6-chloro-2-fluoro-3-methyl-benzoyl chloride (2.07 g, 10.0 mmol) in anhydrous tetrahydrofuran (50 ml), stirred under nitrogen in an acetonitrile/CO2 bath, was added tributyl phosphine (2.75 ml, 11.0 mmol). The mixture was stirred for 15 minutes before phenylmagnesium bromide (3M in diethyl ether, 3.67 ml, 11.0 mmol) was added dropwise. After 45 minutes, the reaction was quenched by addition of hydrochloric acid (2N, 50 ml). The mixture was extracted with ethyl acetate. The organic liquors were washed with sodium bicarbonate solution and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica chromatography eluting with 0-10% diethyl ether/petroleum ether furnishing (6-chloro-2-fluoro-3-methyl-phenyl)-phenyl-methanone as a yellow oil that slowly crystallised (1.12 g, ca. 80% pure). Trituration with petroleum ether produced an analytically pure sample. MS: [M+H]+ 249 was added dropwise the reaction was quenched by addition of hydrochloric acid (2N, 50 ml) The mixture was extracted with ethyl acetate The organic liquors were washed with sodium bicarbonate solution and brine dried (MgSO4) concentrated in vacuo The residue was purified by silica chromatography eluting with 0-10% diethyl ether/petroleum ether

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

Procedure: Step 1 To a solution of 6-chloro-2-fluoro-3-methyl-benzoyl chloride (2.07 g, 10.0 mmol) in anhydrous tetrahydrofuran (50 ml), stirred under nitrogen in an acetonitrile/CO2 bath, was added tributyl phosphine (2.75 ml, 11.0 mmol). The mixture was stirred for 15 minutes before phenylmagnesium bromide (3M in diethyl ether, 3.67 ml, 11.0 mmol) was added dropwise. After 45 minutes, the reaction was quenched by addition of hydrochloric acid (2N, 50 ml). The mixture was extracted with ethyl acetate. The organic liquors were washed with sodium bicarbonate solution and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica chromatography eluting with 0-10% diethyl ether/petroleum ether furnishing (6-chloro-2-fluoro-3-methyl-phenyl)-phenyl-methanone as a yellow oil that slowly crystallised (1.12 g, ca. 80% pure). Trituration with petroleum ether produced an analytically pure sample. MS: [M+H]+ 249 was added dropwise the reaction was quenched by addition of hydrochloric acid (2N, 50 ml) The mixture was extracted with ethyl acetate The organic liquors were washed with sodium bicarbonate solution and brine dried (MgSO4) concentrated in vacuo The residue was purified by silica chromatography eluting with 0-10% diethyl ether/petroleum ether

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

Procedure: To a 13×100 mm test tube were added one 3×6 mm stir bar, compound 71b, (0.1 M in CH2Cl2, 80 μmol, 1.0 eq), DIPEA solution (2 M in CH2Cl2, 160 μmol, 2.0 equiv), and 6-chloro-2-fluoro-3-methylbenzoyl chloride (0.1 M in CH2Cl2, 160 μmol, 2.0 eq.). The reaction was covered and stirred at RT for 12 h. NaOH (1M, 1000 μmol, 12.5 equiv) was added, and the reaction mixture was agitated for 15 minutes. After centrifugation, the top layer was removed. The organic layer was evaporated. MeOH (500 μL) and TEA (500 μL) were added, and the reaction mixture was allowed to stir at RT overnight. The solvents were evaporated, and the residue was reconstituted in DMSO. 1H NMR (500 MHz, D2O) d ppm 1.52 (s, 3H) 1.59 (s, 3H) 2.13 (s, 6H) 2.21 (s, 3H) 2.34 (dd, J=12.22, 5.63 Hz, 1H) 2.59 (dd, J=12.91, 10.16 Hz, 1H) 4.48 (d, J=11.81 Hz, 1H) 4.52 (d, J=12.09 Hz, 1H) 4.81 (q, J=5.77 Hz, 1H) 6.18 (br. s., 1H) 7.14 (t, J=7.55 Hz, 1H) 7.21-7.27 (m, 3H) 7.28-7.38 (m, 3H). LCMS: M+H+: 513.2 To a 13×100 mm test tube were added one 3×6 mm stirred at RT for 12 h the reaction mixture was agitated for 15 minutes After centrifugation, the top layer was removed The organic layer was evaporated MeOH (500 μL) and TEA (500 μL) were added to stir at RT overnight The solvents were evaporated