(4-fluorophenyl)methanesulfonyl chloride

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

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

Procedure: 3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (822 mg, 3.29 mmol), was treated with (4-fluorophenyl)methanesulfonyl chloride (1.03 ml, 4.93 mmol) according to the method described in Preparation 15b to give 1.26 g (94% yield) of the title compound. Purity 97%.

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

Procedure: To 100 mg (0.256 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) in dichloromethane (4 ml) were added 160 mg (0.77 mmol) (4-fluorophenyl)methanesulfonyl chloride and 0.11 ml (0.77 mmol) triethylamine. The mixture was stirred at reflux for 12 h. Then, further batches of 160 mg (0.77 mmol) (4-fluorophenyl)-methanesulfonyl chloride and 0.11 ml (0.77 mmol) triethylamine were added, and the mixture was again stirred at reflux for 1 h. After concentration under reduced pressure, the residue was dissolved in ethyl acetate and washed with brine. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 28 mg (19% of th.) of the title compound. at reflux for 12 h the mixture was again stirred at reflux for 1 h After concentration under reduced pressure the residue was dissolved in ethyl acetate washed with brine The aqueous layer was re-extracted with ethyl acetate the combined organic layers were washed with brine dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified by preparative RP-HPLC (acetonitrile/water gradient)

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

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

Procedure: According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added (4-fluoro-phenyl)-methanesulfonyl chloride (20 mg, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-1-(4-fluoro-phenyl)-methanesulfonamide (8.2 mg, >95% purity, yield: 23.4%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 2): ESI-MS m/z: 402 [M+H]+, retention time=2.24 min, 1H NMR (400 MHz, DMSO-d6) δ ppm 4.67 (s, 2H) 7.09-7.16 (m, 2H) 7.29-7.37 (m, 2H) 7.66 (t, J=2.27 Hz, 1H) 7.78 (dd, J=8.15, 1.71 Hz, 1H) 8.02 (d, J=1.64 Hz, 1H) 8.09 (d, J=8.08 Hz, 1H) 8.34 (d, J=2.40 Hz, 1H) 8.61 (d, J=2.02 Hz, 1H) 10.24 (br. s., 1H). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min) eluting with mixtures of dichloromethane/methanol

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

Procedure: 3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (822 mg, 3.29 mmol), was treated with (4-fluorophenyl)methanesulfonyl chloride (1.03 ml, 4.93 mmol) according to the method described in Preparation 15b to give 1.26 g (94% yield) of the title compound. Purity 97%.

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

Procedure: To 100 mg (0.256 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) in dichloromethane (4 ml) were added 160 mg (0.77 mmol) (4-fluorophenyl)methanesulfonyl chloride and 0.11 ml (0.77 mmol) triethylamine. The mixture was stirred at reflux for 12 h. Then, further batches of 160 mg (0.77 mmol) (4-fluorophenyl)-methanesulfonyl chloride and 0.11 ml (0.77 mmol) triethylamine were added, and the mixture was again stirred at reflux for 1 h. After concentration under reduced pressure, the residue was dissolved in ethyl acetate and washed with brine. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 28 mg (19% of th.) of the title compound. at reflux for 12 h the mixture was again stirred at reflux for 1 h After concentration under reduced pressure the residue was dissolved in ethyl acetate washed with brine The aqueous layer was re-extracted with ethyl acetate the combined organic layers were washed with brine dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified by preparative RP-HPLC (acetonitrile/water gradient)

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