1-bromo-3-methylsulfonylbenzene

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:

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

Procedure: 3-Bromothioanisole was dissolved in methanol (20 ml) and cooled to 0° C. (ice/water bath). A solution of Oxone® (9.22 g) in water (30 ml) was added to this and the resultant cloudy slurry was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and product extracted with dichloromethane. The combined fractions of dichloromethane were washed with brine and dried over anhydrous magnesium sulfate. After filtration, solvent was removed by evaporation under reduced pressure to give the sub-title compound as a solid (1.02 g). extracted with dichloromethane The combined fractions of dichloromethane were washed with brine dried over anhydrous magnesium sulfate After filtration, solvent was removed by evaporation under reduced pressure

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: A mixture of 1-bromo-3-methanesulfonyl-benzene (0.8 g), piperazine (1 g), sodium tert-butoxide (0.5 g) BINAP (42 mg) and [Pd2(dba)3 (38 mg) in toluene (7 ml) was heated under argon at 80° C. for 24 h. After cooling to room temperature, the solvent was evaporated to dryness. The crude material was purified by flash chromatography on silica gel using EtOAc. Yield 0.48 g: MS m/z (rel. intensity, 70 eV) 240 (M+, 17), 199 (12), 198 (bp), 119 (9), 56 (7). the solvent was evaporated to dryness The crude material was purified by flash chromatography on silica gel

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

Procedure: Following the procedure of Step A and Step B of Example 19, 4-(3,4-dichlorophenyl)-6-fluoro-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (500 mg, 1.1 mmol), 1-bromo-3-(methylsulfonyl)benzene (517 mg, 2.2 mmol), cesium carbonate (1.08 g, 3.3 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (44 mg, 0.06 mmol) in N,N-dimethylformamide (10 mL) and water (3 mL) followed by N-de-methylation with N1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (240 mg, 1.12 mmol) and 1-chlorethyl chloroformate (0.31 mL, 2.8 mmol) gave after purification by preparative HPLC followed by preparative thin layer chromatography (90:10:1 diethyl ether/methanol/concentrated ammonium hydroxide) 4-(3,4-dichlorophenyl)-6-fluoro-7-(3-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (38 mg, 15%) as a colorless oil: 1H NMR (CDCl3, 500 MHz) δ 8.10 (s, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.65 (dd, J=8.0, 8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.01 (dd, J=8.0, 2.0 Hz, 1H), 6.71 (d, J=11.0 Hz, 1H), 4.20-4.09 (m, 3H), 3.43 (dd, J=13.0, 5.5 Hz, 1H), 3.10 (s, 3H), 3.07 (dd, J=13.0, 6.5 Hz, 1H), 2.04 (br s, 1H); ESI MS m/z 450 [M+H]+ gave after purification by preparative HPLC

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

Procedure: 1-Bromo-3-methanesulfonyl-benzene (11.0 mmol) (see Intermediate 11) and 4-hydroxy-benzoic acid methyl ester (1.2 mmol) are dissolved in toluene (0.1M). Palladium acetate (0.02 mmol), biphenyl-2-yl-di-tert-butyl-phosphane (0.03 mmol) and tri-basic potassium phosphate (2.0 mmol) are added and the reaction heated reaction at 90° C. for 18 h. The reaction is allowed to cool to room temperature, washed with water while and then the aqueous extracted with dichloromethane. The organic portions are combined and concentrated in vacuo and purified by radial silica chromatography, eluting with ethyl acetate and hexane. the reaction heated reaction at 90° C. for 18 h washed with water while and then the aqueous extracted with dichloromethane concentrated in vacuo purified by radial silica chromatography eluting with ethyl acetate and hexane

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

Procedure: (3-Methanesulfonyl-phenyl)-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 1-bromo-3-methanesulfonyl-benzene (75.0 mg, 0.319 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow solid (0.089 g, 77%). MP=230-234° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.55 (d, J=6.9 Hz, 1H), 8.47 (s, 1H), 8.26 (d, J=7.9 Hz, 2H), 8.12 (d, J=7.5 Hz, 2H), 7.74-7.69 (m, 2H), 7.58-7.50 (m, 2H), 7.17 (s, 1H), 7.12-7.07 (m, 1H), 3.11 (s, 6H). MS=443 (MH)+.