1-bromo-2-fluoro-4-methylsulfanylbenzene

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

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

Procedure: A stirred solution of 1-bromo-2-fluoro-4-(methylthio)benzene (180 g, 814 mmol) at −78° C. in THF (500 mL) was treated with n-BuLi (358 mL, 2.5M in hexanes, 895 mmol) over 1.5 h. After 15 min at −78° C., B(OMe)3 (254 g, 244 mol) was added over 1.5 h, and the reaction mixture was slowly warmed to ambient temperature. 10% Aqueous HCl (100 mL) was added and the mixture was stirred for 5 min. Et2O (500 mL) was added and the organic layer was separated and washed with 2M NaOH (300 mL). The aqueous phase was rinsed one more time with Et2O. The aqueous phase was then acidified with 10% aqueous HCl to pH ˜4 and the resulting solid was collected to give [2-fluoro-4-(methylthio)phenyl]boronic acid (24.7 g). 1H NMR (400 MHz, CDCl3): δ 7.70 (t, 1H, J=7.6 Hz), 7.03 (dd, 1H, Ja=8.1 Hz, Jb=1.6 Hz), 6.88 (dd, 1H, Ja=11.7 Hz, Jb=1.6 Hz), 2.49 (s, 3H). the organic layer was separated washed with 2M NaOH (300 mL) The aqueous phase was rinsed one more time with Et2O the resulting solid was collected

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

Procedure: A stirred suspension of 1-bromo-2-fluoro-4-iodobenzene (100 g, 332 mmol), NiBr2 (7.26 g, 33.2 mmol), 2,2-dipyridyl (5.19 g, 33.2 mmol) and zinc dust (27.2 g, 415 mmol) in DMF (600 mL) was treated with MeS—SMe (15.65 g, 166 mmol), and the mixture was heated in a sand bath set for 80° C. After 10 min (color changes to black and reaction was complete according to HPLC analysis), the mixture was poured onto water. 1N HCl (100 mL) was added along with Et2O (300 mL), and the suspension was filtered through a glass fritted funnel. The zinc plug was further washed with Et2O and the Et2O layer was separated and the aqueous layer was extracted with Et2O (3×). The organic extracts were then dried over Na2SO4 and the solvent evaporated (note that the product is very volatile) to afford 1-bromo-2-fluoro-4-(methylthio)benzene (180 g), which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 7.43-7.38 (m, 1H), 6.97 (dd, 1H, Ja=9.1 Hz, Jb=2.0 Hz), 6.90-6.86 (m, 1H), 2.46 (s, 3H). the mixture was heated in a sand bath set for 80° C After 10 min (color changes to black and reaction was complete according to HPLC analysis) the mixture was poured onto water the suspension was filtered through a glass fritted funnel The zinc plug was further washed with Et2O the Et2O layer was separated the aqueous layer was extracted with Et2O (3×) The organic extracts were then dried over Na2SO4 the solvent evaporated (note that the product

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

Procedure: A stirred solution of 1-bromo-2-fluoro-4-(methylthio)benzene (180 g, 814 mmol) at −78° C. in THF (500 mL) was treated with n-BuLi (358 mL, 2.5M in hexanes, 895 mmol) over 1.5 h. After 15 min at −78° C., B(OMe)3 (254 g, 244 mol) was added over 1.5 h, and the reaction mixture was slowly warmed to ambient temperature. 10% Aqueous HCl (100 mL) was added and the mixture was stirred for 5 min. Et2O (500 mL) was added and the organic layer was separated and washed with 2M NaOH (300 mL). The aqueous phase was rinsed one more time with Et2O. The aqueous phase was then acidified with 10% aqueous HCl to pH ˜4 and the resulting solid was collected to give [2-fluoro-4-(methylthio)phenyl]boronic acid (24.7 g). 1H NMR (400 MHz, CDCl3): δ 7.70 (t, 1H, J=7.6 Hz), 7.03 (dd, 1H, Ja=8.1 Hz, Jb=1.6 Hz), 6.88 (dd, 1H, Ja=11.7 Hz, Jb=1.6 Hz), 2.49 (s, 3H). the organic layer was separated washed with 2M NaOH (300 mL) The aqueous phase was rinsed one more time with Et2O the resulting solid was collected

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

Procedure: A stirred suspension of 1-bromo-2-fluoro-4-iodobenzene (100 g, 332 mmol), NiBr2 (7.26 g, 33.2 mmol), 2,2-dipyridyl (5.19 g, 33.2 mmol) and zinc dust (27.2 g, 415 mmol) in DMF (600 mL) was treated with MeS—SMe (15.65 g, 166 mmol), and the mixture was heated in a sand bath set for 80° C. After 10 min (color changes to black and reaction was complete according to HPLC analysis), the mixture was poured onto water. 1N HCl (100 mL) was added along with Et2O (300 mL), and the suspension was filtered through a glass fritted funnel. The zinc plug was further washed with Et2O and the Et2O layer was separated and the aqueous layer was extracted with Et2O (3×). The organic extracts were then dried over Na2SO4 and the solvent evaporated (note that the product is very volatile) to afford 1-bromo-2-fluoro-4-(methylthio)benzene (180 g), which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 7.43-7.38 (m, 1H), 6.97 (dd, 1H, Ja=9.1 Hz, Jb=2.0 Hz), 6.90-6.86 (m, 1H), 2.46 (s, 3H). the mixture was heated in a sand bath set for 80° C After 10 min (color changes to black and reaction was complete according to HPLC analysis) the mixture was poured onto water the suspension was filtered through a glass fritted funnel The zinc plug was further washed with Et2O the Et2O layer was separated the aqueous layer was extracted with Et2O (3×) The organic extracts were then dried over Na2SO4 the solvent evaporated (note that the product

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

Procedure: A stirred solution of 1-bromo-2-fluoro-4-(methylthio)benzene (180 g, 814 mmol) at −78° C. in THF (500 mL) was treated with n-BuLi (358 mL, 2.5M in hexanes, 895 mmol) over 1.5 h. After 15 min at −78° C., B(OMe)3 (254 g, 244 mol) was added over 1.5 h, and the reaction mixture was slowly warmed to ambient temperature. 10% Aqueous HCl (100 mL) was added and the mixture was stirred for 5 min. Et2O (500 mL) was added and the organic layer was separated and washed with 2M NaOH (300 mL). The aqueous phase was rinsed one more time with Et2O. The aqueous phase was then acidified with 10% aqueous HCl to pH ˜4 and the resulting solid was collected to give [2-fluoro-4-(methylthio)phenyl]boronic acid (24.7 g). 1H NMR (400 MHz, CDCl3): δ 7.70 (t, 1H, J=7.6 Hz), 7.03 (dd, 1H, Ja=8.1 Hz, Jb=1.6 Hz), 6.88 (dd, 1H, Ja=11.7 Hz, Jb=1.6 Hz), 2.49 (s, 3H). the organic layer was separated washed with 2M NaOH (300 mL) The aqueous phase was rinsed one more time with Et2O the resulting solid was collected

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

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

Procedure: A degassed solution of 3-amino-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (0.610 g, 3 mmol), 1-bromo-2-fluoro-4-methylsulfanyl-benzene (1.13 g, 5.1 mmol), Pd2dba3 (0.14 g, 0.15 mmol), Xantphos (0.17 g, 0.3 mmol) and cesium carbonate (1.94 g, 6.0 mmol) in toluene (20 ml) was subjected to microwave irradiation at 150° C. for 2 hours. The reaction mixture was cooled to ambient temperature then diluted with ethyl acetate and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give a residue that was purified by flash chromatography (Si-PPC, ethyl acetate: DCM, gradient 0:100 to 40:100) to afford the title compound as a yellow solid (0.25 g, 24%). LCMS (method B): RT=2.45 min, M+H+=346. irradiation at 150° C. for 2 hours filtered through a pad of Celite® The filtrate was concentrated under reduced pressure to give a residue that was purified by flash chromatography (Si-PPC, ethyl acetate: DCM, gradient 0:100 to 40:100)

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

Procedure: A solution of 4-bromo-3-fluoro-benzenethiol (225 mg, 1.09 mmol) in tetrahydrofuran (3 ml) was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 52 mg, 1.31 mmol) was added and the mixture was stirred for 5 minutes. Iodomethane (78 μl, 1.25 mmol) was then added and the mixture was allowed to return to room temperature with stirring over 20 minutes. Dichloromethane (10 ml) was added and the reaction was quenched with 1 M aqueous hydrochloric acid. The layers were separated and the organic layer was washed with water, dried (MgSO4), then concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, pentane:diethyl ether, gradient 100:0 to 90:10) to afford the title compound as a bright yellow oil (208 mg, 86%). 1H NMR (CDCl3, 400 MHz) 7.43 (1H, dd, J=8.4, 7.2), 7.00 (1H, dd, J=9.4, 2.3), 6.91 (1H, ddd, J=8.4, 2.1, 0.7), 2.48 (3H, s). to return to room temperature with stirring over 20 minutes the reaction was quenched with 1 M aqueous hydrochloric acid The layers were separated the organic layer was washed with water dried (MgSO4) concentrated in vacuo The residue was purified by flash chromatography (Si-PPC, pentane:diethyl ether, gradient 100:0 to 90:10)

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

Procedure: A solution of 4-bromo-3-fluoro-benzenethiol (225 mg, 1.09 mmol) in tetrahydrofuran (3 ml) was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 52 mg, 1.31 mmol) was added and the mixture was stirred for 5 minutes. Iodomethane (78 μl, 1.25 mmol) was then added and the mixture was allowed to return to room temperature with stirring over 20 minutes. Dichloromethane (10 ml) was added and the reaction was quenched with 1 M aqueous hydrochloric acid. The layers were separated and the organic layer was washed with water, dried (MgSO4), then concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, pentane:diethyl ether, gradient 100:0 to 90:10) to afford the title compound as a bright yellow oil (208 mg, 86%). 1H NMR (CDCl3, 400 MHz) 7.43 (1H, dd, J=8.4, 7.2), 7.00 (1H, dd, J=9.4, 2.3), 6.91 (1H, ddd, J=8.4, 2.1, 0.7), 2.48 (3H, s). to return to room temperature with stirring over 20 minutes the reaction was quenched with 1 M aqueous hydrochloric acid The layers were separated the organic layer was washed with water dried (MgSO4) concentrated in vacuo The residue was purified by flash chromatography (Si-PPC, pentane:diethyl ether, gradient 100:0 to 90:10)

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

Procedure: A stirred solution of 1-bromo-2-fluoro-4-(methylthio)benzene (180 g, 814 mmol) at −78° C. in THF (500 mL) was treated with n-BuLi (358 mL, 2.5M in hexanes, 895 mmol) over 1.5 h. After 15 min at −78° C., B(OMe)3 (254 g, 244 mol) was added over 1.5 h, and the reaction mixture was slowly warmed to ambient temperature. 10% Aqueous HCl (100 mL) was added and the mixture was stirred for 5 min. Et2O (500 mL) was added and the organic layer was separated and washed with 2M NaOH (300 mL). The aqueous phase was rinsed one more time with Et2O. The aqueous phase was then acidified with 10% aqueous HCl to pH ˜4 and the resulting solid was collected to give [2-fluoro-4-(methylthio)phenyl]boronic acid (24.7 g). 1H NMR (400 MHz, CDCl3): δ 7.70 (t, 1H, J=7.6 Hz), 7.03 (dd, 1H, Ja=8.1 Hz, Jb=1.6 Hz), 6.88 (dd, 1H, Ja=11.7 Hz, Jb=1.6 Hz), 2.49 (s, 3H). the organic layer was separated washed with 2M NaOH (300 mL) The aqueous phase was rinsed one more time with Et2O the resulting solid was collected

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

Procedure: A stirred suspension of 1-bromo-2-fluoro-4-iodobenzene (100 g, 332 mmol), NiBr2 (7.26 g, 33.2 mmol), 2,2-dipyridyl (5.19 g, 33.2 mmol) and zinc dust (27.2 g, 415 mmol) in DMF (600 mL) was treated with MeS—SMe (15.65 g, 166 mmol), and the mixture was heated in a sand bath set for 80° C. After 10 min (color changes to black and reaction was complete according to HPLC analysis), the mixture was poured onto water. 1N HCl (100 mL) was added along with Et2O (300 mL), and the suspension was filtered through a glass fritted funnel. The zinc plug was further washed with Et2O and the Et2O layer was separated and the aqueous layer was extracted with Et2O (3×). The organic extracts were then dried over Na2SO4 and the solvent evaporated (note that the product is very volatile) to afford 1-bromo-2-fluoro-4-(methylthio)benzene (180 g), which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 7.43-7.38 (m, 1H), 6.97 (dd, 1H, Ja=9.1 Hz, Jb=2.0 Hz), 6.90-6.86 (m, 1H), 2.46 (s, 3H). the mixture was heated in a sand bath set for 80° C After 10 min (color changes to black and reaction was complete according to HPLC analysis) the mixture was poured onto water the suspension was filtered through a glass fritted funnel The zinc plug was further washed with Et2O the Et2O layer was separated the aqueous layer was extracted with Et2O (3×) The organic extracts were then dried over Na2SO4 the solvent evaporated (note that the product