9-methoxy-9-borabicyclo[3.3.1]nonane

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

Procedure: To a solution of 899 mg (5.91 mmol) of 9-methoxy-9-bora-bicyclo[3.3.1]nonane in 5 mL of anhydrous tetrahydrofuran is added dropwise 3.71 mL (5.91 mmol) of a solution 1N of methyl lithium in diethylether. After few minutes of stirring, a mixture of 6-amino-3-bromo-5-chloro-1H-indazole-7-carboxylic acid methyl ester, prepared as in step a in example 39, and 104 mg (0.15 mmol) of bis(triphenylphosphine) palladiumI(II) dichloride in 10 mL of anhydrous tetrahydrofuran is added. The reaction mixture is stirred in a microwave oven at 150° C. for 15 minutes. After filtration over Celite and concentration in vacuo, the residue is purified by flash chromatography (SiO2, hexanes/ethyl acetate 1:1) to afford 470 mg of product (66%) as a pale yellowish solid; LC/MS:240/242 (M+H)+. is added The reaction mixture is stirred in a microwave oven at 150° C. for 15 minutes After filtration over Celite and concentration in vacuo the residue is purified by flash chromatography (SiO2, hexanes/ethyl acetate 1:1)

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

Procedure: To a solution of 899 mg (5.91 mmol) of 9-methoxy-9-bora-bicyclo[3.3.1]nonane in 5 mL of anhydrous tetrahydrofuran is added dropwise 3.71 mL (5.91 mmol) of a solution 1N of methyl lithium in diethylether. After few minutes of stirring, a mixture of 6-amino-3-bromo-5-chloro-1H-indazole-7-carboxylic acid methyl ester, prepared as in step a in example 39, and 104 mg (0.15 mmol) of bis(triphenylphosphine) palladiumI(II) dichloride in 10 mL of anhydrous tetrahydrofuran is added. The reaction mixture is stirred in a microwave oven at 150° C. for 15 minutes. After filtration over Celite and concentration in vacuo, the residue is purified by flash chromatography (SiO2, hexanes/ethyl acetate 1:1) to afford 470 mg of product (66%) as a pale yellowish solid; LC/MS:240/242 (M+H)+. is added The reaction mixture is stirred in a microwave oven at 150° C. for 15 minutes After filtration over Celite and concentration in vacuo the residue is purified by flash chromatography (SiO2, hexanes/ethyl acetate 1:1)

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

Procedure: To a cold (−78° C.) solution of 9-methoxy-9-borabicyclo[3.3.1]nonane (1 mL, 1.0 M in hexane, 1.0 mmol) in tetrahydrofuran (5 mL) was added isopropenylmagnesium bromide (2.0 mL, 0.5 M in tetrahydrofuran, 1.0 mmol) dropwise. The resultant solution was stirred at −78° C. for 5 minutes, then allowed to warm to room temperature. After 1 hour, potassium phosphate (0.33 mL, 3 M aqueous, 1.0 mmol) was added followed by N,N-dimethylformamide (5 mL), 2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (100 mg, 0.20 mmol), and bis(diphenylphosphinoferrocene)palladium(II) chloride dichloromethane complex (17 mg, 0.02 mmol). The resultant solution was stirred for 72 hours at room temperature. Ether was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (6:1 to 4:1 to 2:1 hexanes:ethyl acetate) provided impure product. This material was taken up in tetrahydrofuran, cooled to 0° C. and 1 mL each of 10% aqueous sodium hydroxide and 30% hydrogen peroxide were added. After 30 minutes, the mixture was quenched with saturated aqueous sodium thiosulfate. Aqueous workup as reported above followed by similar chromatography provided N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-isopropenylphenyl)pyrazolo[1,5-a]pyridin-7-amine (25 mg, 27%) as an oil. 1H NMR (CDCl3): δ 8.00 (d, 1 H), 7.76 (d, 1 H), 7.62 (d, 2 H), 7.54 (d, 2 H), 7.30 (m, 1 H), 6.35 (d, 1 H), 6.07 (m, 1 H), 5.99 (d, 1 H), 5.46 (s, 2 H), 5.22 (broad, 1 H), 5.14 (s,1 H), 3.47 (m, 2 H), 3.36 (m, 2 H), 2.20 (s, 3 H), 1.77–1.42 (m, 8 H), 1.00–0.95 (m 6 H); MS m/z 455 (M+1). This material was treated with anhydrous hydrochloric acid in ether to provide the corresponding hydrochloride salt. The organic layer was washed with brine The aqueous layer was extracted with ether the combined organics dried over magnesium sulfate Filtration and concentration provided impure product cooled to 0° C. After 30 minutes the mixture was quenched with saturated aqueous sodium thiosulfate

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

Procedure: To a cold (−78° C.) solution of 9-methoxy-9-borabicyclo[3.3.1]nonane (1 mL, 1.0 M in hexane, 1.0 mmol) in tetrahydrofuran (5 mL) was added isopropenylmagnesium bromide (2.0 mL, 0.5 M in tetrahydrofuran, 1.0 mmol) dropwise. The resultant solution was stirred at −78° C. for 5 minutes, then allowed to warm to room temperature. After 1 hour, potassium phosphate (0.33 mL, 3 M aqueous, 1.0 mmol) was added followed by N,N-dimethylformamide (5 mL), 2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (100 mg, 0.20 mmol), and bis(diphenylphosphinoferrocene)palladium(II) chloride dichloromethane complex (17 mg, 0.02 mmol). The resultant solution was stirred for 72 hours at room temperature. Ether was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (6:1 to 4:1 to 2:1 hexanes:ethyl acetate) provided impure product. This material was taken up in tetrahydrofuran, cooled to 0° C. and 1 mL each of 10% aqueous sodium hydroxide and 30% hydrogen peroxide were added. After 30 minutes, the mixture was quenched with saturated aqueous sodium thiosulfate. Aqueous workup as reported above followed by similar chromatography provided N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-isopropenylphenyl)pyrazolo[1,5-a]pyridin-7-amine (25 mg, 27%) as an oil. 1H NMR (CDCl3): δ 8.00 (d, 1 H), 7.76 (d, 1 H), 7.62 (d, 2 H), 7.54 (d, 2 H), 7.30 (m, 1 H), 6.35 (d, 1 H), 6.07 (m, 1 H), 5.99 (d, 1 H), 5.46 (s, 2 H), 5.22 (broad, 1 H), 5.14 (s,1 H), 3.47 (m, 2 H), 3.36 (m, 2 H), 2.20 (s, 3 H), 1.77–1.42 (m, 8 H), 1.00–0.95 (m 6 H); MS m/z 455 (M+1). This material was treated with anhydrous hydrochloric acid in ether to provide the corresponding hydrochloride salt. The organic layer was washed with brine The aqueous layer was extracted with ether the combined organics dried over magnesium sulfate Filtration and concentration provided impure product cooled to 0° C. After 30 minutes the mixture was quenched with saturated aqueous sodium thiosulfate

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

Procedure: For example, the appropriate lithium trisubstituted-silylacetylene (2) is contacted with an equimolar amount of B-methoxy-9-borabicyclo[3.3.1]nonane (3) in a suitable anhydrous inert organic solvent such as tetrahydrofuran, hexane, t-butyl methyl ether, diethyl ether, pentane and the like with tetrahydrofuran being preferred. The reactants are typically stirred together under an inert atmosphere for a period of time ranging from 5 minutes to 48 hours at a temperature range of from -78° C. to room temperature. A temperature range of -78° C. to -40° C. and a reaction time of 1.5 hours to 5 hours are preferred. The intermediate "ate" complex thus formed is contacted with a molar excess of a suitable lewis acid such as boron trifluoride etherate, boron trichloride and the like with boron trifluoride etherate being preferred. The reactants are typically stirred together under an inert atmosphere for a period of time ranging from 5 minutes to 24 hours and at a temperature range of from -78° C. to room temperature. A temperature range of -78° C. to -40° C. and a reaction time of 15 minutes to 1 hour are preferred. The B-(2-(trisubstitutedsilyl)ethynyl)-9-boracyclo[3.3.1]nonane of formula (I) is isolated as a tetrahydrofuran complex by evaporation of the volatiles. It may be purified by crystallization from a suitable inert organic solvent such as pentane, hexane and the like. Starting materials for use in Scheme A are readily available to one of ordinary skill in the art. ranging from 5 minutes to 48 hours at a temperature range of from -78° C. to room temperature A temperature range of -78° C. to -40° C. a reaction time of 1.5 hours to 5 hours thus formed The reactants are typically stirred together under an inert atmosphere for a period of time ranging from 5 minutes to 24 hours and at a temperature range of from -78° C. to room temperature A temperature range of -78° C. to -40° C. a reaction time of 15 minutes to 1 hour

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

Procedure: For example, the appropriate lithium trisubstituted-silylacetylene (2) is contacted with an equimolar amount of B-methoxy-9-borabicyclo[3.3.1]nonane (3) in a suitable anhydrous inert organic solvent such as tetrahydrofuran, hexane, t-butyl methyl ether, diethyl ether, pentane and the like with tetrahydrofuran being preferred. The reactants are typically stirred together under an inert atmosphere for a period of time ranging from 5 minutes to 48 hours at a temperature range of from -78° C. to room temperature. A temperature range of -78° C. to -40° C. and a reaction time of 1.5 hours to 5 hours are preferred. The intermediate "ate" complex thus formed is contacted with a molar excess of a suitable lewis acid such as boron trifluoride etherate, boron trichloride and the like with boron trifluoride etherate being preferred. The reactants are typically stirred together under an inert atmosphere for a period of time ranging from 5 minutes to 24 hours and at a temperature range of from -78° C. to room temperature. A temperature range of -78° C. to -40° C. and a reaction time of 15 minutes to 1 hour are preferred. The B-(2-(trisubstitutedsilyl)ethynyl)-9-boracyclo[3.3.1]nonane of formula (I) is isolated as a tetrahydrofuran complex by evaporation of the volatiles. It may be purified by crystallization from a suitable inert organic solvent such as pentane, hexane and the like. Starting materials for use in Scheme A are readily available to one of ordinary skill in the art. ranging from 5 minutes to 48 hours at a temperature range of from -78° C. to room temperature A temperature range of -78° C. to -40° C. a reaction time of 1.5 hours to 5 hours thus formed The reactants are typically stirred together under an inert atmosphere for a period of time ranging from 5 minutes to 24 hours and at a temperature range of from -78° C. to room temperature A temperature range of -78° C. to -40° C. a reaction time of 15 minutes to 1 hour

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

Procedure: To a solution of 899 mg (5.91 mmol) of 9-methoxy-9-bora-bicyclo[3.3.1]nonane in 5 mL of anhydrous tetrahydrofuran is added dropwise 3.71 mL (5.91 mmol) of a solution 1N of methyl lithium in diethylether. After few minutes of stirring, a mixture of 6-amino-3-bromo-5-chloro-1H-indazole-7-carboxylic acid methyl ester, prepared as in step a in example 39, and 104 mg (0.15 mmol) of bis(triphenylphosphine) palladiumI(II) dichloride in 10 mL of anhydrous tetrahydrofuran is added. The reaction mixture is stirred in a microwave oven at 150° C. for 15 minutes. After filtration over Celite and concentration in vacuo, the residue is purified by flash chromatography (SiO2, hexanes/ethyl acetate 1:1) to afford 470 mg of product (66%) as a pale yellowish solid; LC/MS:240/242 (M+H)+. is added The reaction mixture is stirred in a microwave oven at 150° C. for 15 minutes After filtration over Celite and concentration in vacuo the residue is purified by flash chromatography (SiO2, hexanes/ethyl acetate 1:1)

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

Procedure: To a cold (−78° C.) solution of 9-methoxy-9-borabicyclo[3.3.1]nonane (1 mL, 1.0 M in hexane, 1.0 mmol) in tetrahydrofuran (5 mL) was added isopropenylmagnesium bromide (2.0 mL, 0.5 M in tetrahydrofuran, 1.0 mmol) dropwise. The resultant solution was stirred at −78° C. for 5 minutes, then allowed to warm to room temperature. After 1 hour, potassium phosphate (0.33 mL, 3 M aqueous, 1.0 mmol) was added followed by N,N-dimethylformamide (5 mL), 2-(4-Bromophenyl)-N-butyl-3-[2-(butylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (100 mg, 0.20 mmol), and bis(diphenylphosphinoferrocene)palladium(II) chloride dichloromethane complex (17 mg, 0.02 mmol). The resultant solution was stirred for 72 hours at room temperature. Ether was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (6:1 to 4:1 to 2:1 hexanes:ethyl acetate) provided impure product. This material was taken up in tetrahydrofuran, cooled to 0° C. and 1 mL each of 10% aqueous sodium hydroxide and 30% hydrogen peroxide were added. After 30 minutes, the mixture was quenched with saturated aqueous sodium thiosulfate. Aqueous workup as reported above followed by similar chromatography provided N-butyl-3-[2-(butylamino)-4-pyrimidinyl]-2-(4-isopropenylphenyl)pyrazolo[1,5-a]pyridin-7-amine (25 mg, 27%) as an oil. 1H NMR (CDCl3): δ 8.00 (d, 1 H), 7.76 (d, 1 H), 7.62 (d, 2 H), 7.54 (d, 2 H), 7.30 (m, 1 H), 6.35 (d, 1 H), 6.07 (m, 1 H), 5.99 (d, 1 H), 5.46 (s, 2 H), 5.22 (broad, 1 H), 5.14 (s,1 H), 3.47 (m, 2 H), 3.36 (m, 2 H), 2.20 (s, 3 H), 1.77–1.42 (m, 8 H), 1.00–0.95 (m 6 H); MS m/z 455 (M+1). This material was treated with anhydrous hydrochloric acid in ether to provide the corresponding hydrochloride salt. The organic layer was washed with brine The aqueous layer was extracted with ether the combined organics dried over magnesium sulfate Filtration and concentration provided impure product cooled to 0° C. After 30 minutes the mixture was quenched with saturated aqueous sodium thiosulfate

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

Procedure: For example, the appropriate lithium trisubstituted-silylacetylene (2) is contacted with an equimolar amount of B-methoxy-9-borabicyclo[3.3.1]nonane (3) in a suitable anhydrous inert organic solvent such as tetrahydrofuran, hexane, t-butyl methyl ether, diethyl ether, pentane and the like with tetrahydrofuran being preferred. The reactants are typically stirred together under an inert atmosphere for a period of time ranging from 5 minutes to 48 hours at a temperature range of from -78° C. to room temperature. A temperature range of -78° C. to -40° C. and a reaction time of 1.5 hours to 5 hours are preferred. The intermediate "ate" complex thus formed is contacted with a molar excess of a suitable lewis acid such as boron trifluoride etherate, boron trichloride and the like with boron trifluoride etherate being preferred. The reactants are typically stirred together under an inert atmosphere for a period of time ranging from 5 minutes to 24 hours and at a temperature range of from -78° C. to room temperature. A temperature range of -78° C. to -40° C. and a reaction time of 15 minutes to 1 hour are preferred. The B-(2-(trisubstitutedsilyl)ethynyl)-9-boracyclo[3.3.1]nonane of formula (I) is isolated as a tetrahydrofuran complex by evaporation of the volatiles. It may be purified by crystallization from a suitable inert organic solvent such as pentane, hexane and the like. Starting materials for use in Scheme A are readily available to one of ordinary skill in the art. ranging from 5 minutes to 48 hours at a temperature range of from -78° C. to room temperature A temperature range of -78° C. to -40° C. a reaction time of 1.5 hours to 5 hours thus formed The reactants are typically stirred together under an inert atmosphere for a period of time ranging from 5 minutes to 24 hours and at a temperature range of from -78° C. to room temperature A temperature range of -78° C. to -40° C. a reaction time of 15 minutes to 1 hour

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

Procedure: To a solution of 899 mg (5.91 mmol) of 9-methoxy-9-bora-bicyclo[3.3.1]nonane in 5 mL of anhydrous tetrahydrofuran is added dropwise 3.71 mL (5.91 mmol) of a solution 1N of methyl lithium in diethylether. After few minutes of stirring, a mixture of 6-amino-3-bromo-5-chloro-1H-indazole-7-carboxylic acid methyl ester, prepared as in step a in example 39, and 104 mg (0.15 mmol) of bis(triphenylphosphine) palladiumI(II) dichloride in 10 mL of anhydrous tetrahydrofuran is added. The reaction mixture is stirred in a microwave oven at 150° C. for 15 minutes. After filtration over Celite and concentration in vacuo, the residue is purified by flash chromatography (SiO2, hexanes/ethyl acetate 1:1) to afford 470 mg of product (66%) as a pale yellowish solid; LC/MS:240/242 (M+H)+. is added The reaction mixture is stirred in a microwave oven at 150° C. for 15 minutes After filtration over Celite and concentration in vacuo the residue is purified by flash chromatography (SiO2, hexanes/ethyl acetate 1:1)