(5-fluoro-2-methoxyphenyl)boronic acid

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: Example 54 was synthesized in 4 steps from 3-,5-dibromophenol. 2-Methoxy-5-fluorophenyl boronic acid was reacted as described above, step 1. In this manner was isolated 5-bromo-5′-fluoro-2′-methoxy-biphenyl-3-ol, which was then reacted with 3-fluorophenyl boronic reacted as described above, Step 2. In this manner, 3,5″-difluoro-2″-methoxy-[1,1′;3′,1″]terphenyl-5′-ol was obtained.

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

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone (50 mg, 0.079 mmol), 5-fluoro-2-methoxyphenylboronic acid (20 mg, 0.118 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (7.9 mg, 0.10 mmol) and sodium carbonate (2M aqueous solution, 0.119 mL, 0.237 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 90° C. for 30 min. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography purification of the crude product afford (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-(5-fluoro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone as a light yellow oil. MS: m/z 633.3 (M+H+). extracted with ethyl acetate dried over sodium sulfate filtered concentrated to dryness Silica gel chromatography purification of the crude product

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone (50 mg, 0.079 mmol), 5-fluoro-2-methoxyphenylboronic acid (20 mg, 0.118 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (7.9 mg, 0.10 mmol) and sodium carbonate (2M aqueous solution, 0.119 mL, 0.237 mmol) in acetonitrile (1 mL) was heated in a Personal microwave at 90° C. for 30 min. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography purification of the crude product afford (4-(2-(dimethylamino)ethyl)piperazin-1-yl)(3-(3-(5-fluoro-2-methoxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)phenyl)methanone as a light yellow oil. MS: m/z 633.3 (M+H+). extracted with ethyl acetate dried over sodium sulfate filtered concentrated to dryness Silica gel chromatography purification of the crude product

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

Procedure: (S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with (5-fluoro-2-methoxyphenyl)boronic acid (55 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and bis(triphenylphosphine)palladium(II) dichloride (10 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 30%, hexane-ethyl acetate) to give 55 mg (64% yield) of the title compound. Purity 92%. described in Preparation 62 The residue was purified SP1® Purification System (0% to 30%, hexane-ethyl acetate)

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

Procedure: Prepared in 89% yield from 2-chloronicotinonitrile and 5-fluoro-2-methoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 228.9 (M+H)+; 1H NMR (CDCl3) δ 3.86 (s, 3H), 6.98 (dd, J=8.8, 4.0 Hz, 1H), 7.13-7.22 (m, 2H), 7.40 (dd, J=8.0, 4.9 Hz, 1H), 8.04 (dd, J=8.1, 1.7 Hz, 1H), 8.88 (dd, J=5.1, 1.7 Hz, 1H).

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

Procedure: Prepared in 89% yield from 2-chloronicotinonitrile and 5-fluoro-2-methoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 228.9 (M+H)+; 1H NMR (CDCl3) δ 3.86 (s, 3H), 6.98 (dd, J=8.8, 4.0 Hz, 1H), 7.13-7.22 (m, 2H), 7.40 (dd, J=8.0, 4.9 Hz, 1H), 8.04 (dd, J=8.1, 1.7 Hz, 1H), 8.88 (dd, J=5.1, 1.7 Hz, 1H).

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

Procedure: To a stirred mixture of 4-(6-chloro-pyrimidin-4-ylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (VIII) (0.60 g, 1.6 mmol) and 5-fluoro-2-methoxy-phenylboronic acid (0.300 g, 1.76 mmol) in saturated sodium carbonate solution (5 ml) and 1,4-dioxane (5 ml) was added palladium(II) acetate (0.072 g, 0.32 mmol) followed by triphenylphosphine (0.084 g, 0.32 mmol) at room temperature under an atmosphere of nitrogen. The resulting mixture was heated to reflux at 110° C. for one hour and the reaction monitored by TLC. The reaction mixture was filtered through a celite bed and the filtrate was extracted with ethyl acetate (3×100 ml). The organic layers were separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, elution with 50% ethyl acetate/n-hexanes) to afford 4-[6-(5-fluoro-2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXI) (0.39 g, 52%) as a pale yellow oil. The resulting mixture was heated The reaction mixture was filtered through a celite bed the filtrate was extracted with ethyl acetate (3×100 ml) The organic layers were separated dried over sodium sulfate concentrated under reduced pressure The crude product was purified by flash column chromatography (silica gel, elution with 50% ethyl acetate/n-hexanes)