2-bromo-1,3-difluorobenzene

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

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

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: To a cooled (0° C.) solution of 2,2,6,6-tetramethylpiperidine (1.64 mL, 9.75 mmol) in THF (20 mL) was added 1.6 M n-butyllithium in hexane (5.54 mL, 8.86 mmol). The solution was stirred for 20 min, then brought to −78° C. 1-bromo-2,6-difluorobenzene (1.00 mL, 8.86 mmol) in THF was added slowly, and the solution was stirred at −78° C. for 30 min. DMF (1 mL) was added slowly, and the solution was stirred at −78° C. for 20 min. Saturated aqueous ammonium chloride was added and the reaction was allowed to warm to rt. The organic solvent was removed in vacuo, and the residual material was extracted with EtOAc and washed with water (2×). The organic layer was purified by column chromatography (1 to 2% EtOAc:hexanes) to afford 350 mg (18%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 6.97 (td, J=9.2, 1.5 Hz, 1 H), 7.78 (ddd, J=9.0, 7.5, 5.7 Hz, 1 H), 10.34 (s, 1 H). brought to −78° C the solution was stirred at −78° C. for 30 min the solution was stirred at −78° C. for 20 min The organic solvent was removed in vacuo the residual material was extracted with EtOAc washed with water (2×) The organic layer was purified by column chromatography (1 to 2% EtOAc:hexanes)

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

Procedure: This compound was synthesized from (3,5-dimethoxy-4-1-propylphenyl)-ethene and 1-bromo-2,6-difluorobenzene quantitatively in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.90 (s, 6H), 6.73 (s, 2H), 6.8-7.2 (m, 4H), 7.41 (d, J=16.6 Hz, 1H).

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

Procedure: This compound was synthesized from (3,5-dimethoxy-4-1-propylphenyl)-ethene and 1-bromo-2,6-difluorobenzene quantitatively in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.90 (s, 6H), 6.73 (s, 2H), 6.8-7.2 (m, 4H), 7.41 (d, J=16.6 Hz, 1H).

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

Procedure: 1-Bromo-2,6-difluorobenzene (Oakwood Products Inc., West Columbia, S.C.) (15.4 mL, 104 mmol) was treated with H2SO4 (77 mL of 95-98% pure, 1445 mmol) and cooled in an ice bath. It was treated with HNO3 (68 mL of 69-70% pure, 1050 mmol) slowly dropwise via a dropping funnel and stiffed for and additional 30 min. The mixture was poured onto ice (500 mL) and stirred vigorously for 3 min. The resulting suspension was extracted with DCM (4×100 mL), washed with brine (500 mL) and dried over Na2SO4, filtered and concentrated affording crude 2-bromo-1,3-difluoro-4-nitrobenzene (32.55 g, 137 mmol) as a bright yellow crystalline solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (1H, ddd, J=9.1, 8.1, 5.5 Hz), 7.13 (1H, ddd, J=9.3, 7.1, 2.0 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −92.06 (1F, s), −104.31 (1F, s). m/z (ESI, +ve ion) 259.1/261.1 (M+Na)+. cooled in an ice bath additional 30 min The mixture was poured onto ice (500 mL) The resulting suspension was extracted with DCM (4×100 mL) washed with brine (500 mL) dried over Na2SO4 filtered concentrated

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

Procedure: 1-Bromo-2,6-difluorobenzene (Oakwood Products Inc., West Columbia, S.C.) (15.4 mL, 104 mmol) was treated with H2SO4 (77 mL of 95-98% pure, 1445 mmol) and cooled in an ice bath. It was treated with HNO3 (68 mL of 69-70% pure, 1050 mmol) slowly dropwise via a dropping funnel and stiffed for and additional 30 min. The mixture was poured onto ice (500 mL) and stirred vigorously for 3 min. The resulting suspension was extracted with DCM (4×100 mL), washed with brine (500 mL) and dried over Na2SO4, filtered and concentrated affording crude 2-bromo-1,3-difluoro-4-nitrobenzene (32.55 g, 137 mmol) as a bright yellow crystalline solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (1H, ddd, J=9.1, 8.1, 5.5 Hz), 7.13 (1H, ddd, J=9.3, 7.1, 2.0 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −92.06 (1F, s), −104.31 (1F, s). m/z (ESI, +ve ion) 259.1/261.1 (M+Na)+. cooled in an ice bath additional 30 min The mixture was poured onto ice (500 mL) The resulting suspension was extracted with DCM (4×100 mL) washed with brine (500 mL) dried over Na2SO4 filtered concentrated

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

Procedure: The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 1-bromo-2,6-difluorobenzene. White solid. MS (ESI): 427.1 (MH+)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (11.34 g, 46.6 mmol), and 1-bromo-2,6-difluorobenzene (9 g, 46.6 mmol) in 1,2-dimethoxyethane (204 mL) were added Palladium catalyst Pd(PPh3)4 (1.62 g, 1.4 mmol) and the freshly prepared sodium carbonate solution (15.19 g in 66 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 110° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 9.77 g (91%) of 4-(2,6-difluoro-phenyl)-1H-indole. The system was degassed charged with nitrogen the completion of the coupling reaction The mixture was cooled to room temperature separated from water layer The ethyl acetate solution was washed with brine dried over Na2SO4 After filtration the solvents were evaporated the crude product was purified by a silica gel column

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

Procedure: Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 2-bromo-1,3-difluorobenzene. Prepared