3,4-dimethoxyphenol

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: The title compound was synthesized in a yield of 68% using (2R)-1-acetoxy-2-acetylamino-2-methyl-4-[5-(3-bromoprop-1-ynyl)furan-2-yl]butane obtained in Example (22b) and 3,4-dimethoxyphenol as the starting materials by conducting successively the reactions similar to those mentioned in Examples (22c) and (22d).

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

Procedure: A cooled (0° C.) mixture of 4-(1-hydroxy-3-butenyl)benzonitrile (14.6 g, 84.3 mmol) and 3,4-dimethoxyphenol (19.5 g, 125.4 mmol) in toluene (500 mL) was treated with tributylphosphine (32.14 mL of 97% purity, 25.6 g, 126.4 mmol), followed by 1,1′-(azodicarbonyl)dipiperidine (31.8 g, 126.4 mmol). After addition was complete, the reaction mixture thickened and the temperature rose to 15° C. Additional toluene was added (500 mL), and the mixture stirred at rt overnight. The precipitate of tributylphosphine oxide was then removed by filtration and the filtrate concentrated in vacuo to give 65.8 g of crude product. This was purified by chromatography on silica gel, eluting with toluene:methanol (98:2), to yield 17.9 g of the sub-title compound. A cooled After addition rose to 15° C The precipitate of tributylphosphine oxide was then removed by filtration the filtrate concentrated in vacuo to give 65.8 g of crude product This was purified by chromatography on silica gel eluting with toluene:methanol (98:2)

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

Procedure: A cooled (0° C.) mixture of 4-(1-hydroxy-3-butenyl)benzonitrile (14.6 g, 84.3 mmol) and 3,4-dimethoxyphenol (19.5 g, 125.4 mmol) in toluene (500 mL) was treated with tributylphosphine (32.14 mL of 97% purity, 25.6 g, 126.4 mmol), followed by 1,1′-(azodicarbonyl)dipiperidine (31.8 g, 126.4 mmol). After addition was complete, the reaction mixture thickened and the temperature rose to 15° C. Additional toluene was added (500 mL), and the mixture stirred at rt overnight. The precipitate of tributylphosphine oxide was then removed by filtration and the filtrate concentrated in vacuo to give 65.8 g of crude product. This was purified by chromatography on silica gel, eluting with toluene:methanol (98:2), to yield 17.9 g of the sub-title compound. A cooled After addition rose to 15° C The precipitate of tributylphosphine oxide was then removed by filtration the filtrate concentrated in vacuo to give 65.8 g of crude product This was purified by chromatography on silica gel eluting with toluene:methanol (98:2)

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

Procedure: Part C: To a solution of the propargyl amine of part B (8 g, 22.63 mmol) and powdered K2CO3 (8.8 g, 56.6 mmol) in N,N-dimethylformamide (150 mL) was added 3,4-dimethoxyphenol (6.98 g, 45 mmol) at ambient temperature. The composition was heated to 90 degrees Celsius for 36 hours. The solution was concentrated under high vacuum and the residue was dissolved in ethyl acetate. The organic layer was washed with 1N NaOH, H2O and dried over MgSO4. Chromatography (on silica, ethyl acetate/hexane) provided phenoxy propargyl amine as light yellow gel (10 g, 90.9%). The composition was heated to 90 degrees Celsius for 36 hours The solution was concentrated under high vacuum the residue was dissolved in ethyl acetate The organic layer was washed with 1N NaOH, H2O dried over MgSO4

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

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

Conditions: temp:155.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.040 g, 0.141 mmoles) was dissolved in 2 mL DMF. 3,4-Dimethoxyphenol 8c (0.035 g, 0.281 mmol) was added followed by the addition of potassium carbonate (0.2 g, 1.41 mmol) and the resultant reaction mixture was heated in a microwave at 155° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered. The organic portions were washed with saturated sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate, solvent removed and purified to obtain 108 as a white solid (10 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.81 (s, 1H), 7.76-7.40 (m, 4H), 7.14-6.87 (m, 2H), 6.87-6.65 (m, 2H), 4.25 (d, J=16.2, 3H), 3.91 (d, J=31.0, 6H) MS (ESI) m/z 402.2 (M+1)+ the resultant reaction mixture filtered The organic portions were washed with saturated sodium bicarbonate solution dried over anhydrous sodium sulfate, solvent removed purified

Conditions: temp:155.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (0.040 g, 0.141 mmoles) was dissolved in 2 mL DMF. 3,4-Dimethoxyphenol 8c (0.035 g, 0.281 mmol) was added followed by the addition of potassium carbonate (0.2 g, 1.41 mmol) and the resultant reaction mixture was heated in a microwave at 155° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and filtered. The organic portions were washed with saturated sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate, solvent removed and purified to obtain 108 as a white solid (10 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 8.81 (s, 1H), 7.76-7.40 (m, 4H), 7.14-6.87 (m, 2H), 6.87-6.65 (m, 2H), 4.25 (d, J=16.2, 3H), 3.91 (d, J=31.0, 6H) MS (ESI) m/z 402.2 (M+1)+ the resultant reaction mixture filtered The organic portions were washed with saturated sodium bicarbonate solution dried over anhydrous sodium sulfate, solvent removed purified

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

Procedure: The title compound was prepared from 3,4-dimethoxy-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.