N-methyl-N-propan-2-ylpropan-2-amine

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

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

Procedure: A solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (200 mg, 0.83 mmol, 1.00 equiv, 98%), 5-chloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine (180 mg, 1.07 mmol, 1.29 equiv) and methylbis(propan-2-yl)amine (0.3 mL, 98%) in n-butanol (8 mL) was stirred at 130° C. for 96 h. The resulting mixture was concentrated under vacuum and the residue was purified on a C18 column eluted with water/acetonitrile to give 110 mg (31%) of 159 as a light yellow solid. LC-MS: (ES, m/z) 370 [M+H]+, 221, 115. H-NMR: (CD3OD, 300 Hz, ppm) δ 8.86 (s, 1H), 7.70 (s, 1H), 7.65-7.54 (m, 6H), 7.61 (d, 2H), 7.09 (s, 1H), 5.30 (m, 1H), 4.04 (s, 3H), 1.64 (d, 3H) The resulting mixture was concentrated under vacuum the residue was purified on a C18 column eluted with water/acetonitrile

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1.0 g of N-(3-bromophenyl)-4,6-quinazolindiamine and 0.62 g of diisopropyl methylamine in 21 mL of tetrahydrofuran at 0° C. was added 0.62 g of 4-methoxycrotonyl chloride. The mixture was stirred at 0° C. for 1.5 hr and 10 min at room temperature. The mixture was poured into saturated sodium bicarbonate-brine and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate. The solution was filtered through silica gel and the solvent was removed. The residue was recrystallized from 1-butanol to give 1.25 g of 4-Methoxy-but-2-enoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide as a yellow solid: mass spectrum (m/e): M+H 415.0. extracted with ethyl acetate The organic solution was dried over magnesium sulfate The solution was filtered through silica gel the solvent was removed The residue was recrystallized from 1-butanol

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1.0 g of N-(3-bromophenyl)-4,6-quinazolindiamine and 0.62 g of diisopropyl methylamine in 21 mL of tetrahydrofuran at 0° C. was added 0.62 g of 4-methoxycrotonyl chloride. The mixture was stirred at 0° C. for 1.5 hr and 10 min at room temperature. The mixture was poured into saturated sodium bicarbonate-brine and extracted with ethyl acetate. The organic solution was dried over magnesium sulfate. The solution was filtered through silica gel and the solvent was removed. The residue was recrystallized from 1-butanol to give 1.25 g of 4-Methoxy-but-2-enoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide as a yellow solid: mass spectrum (m/e): M+H 415.0. extracted with ethyl acetate The organic solution was dried over magnesium sulfate The solution was filtered through silica gel the solvent was removed The residue was recrystallized from 1-butanol

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

Procedure: A solution of 2.2 g of N-(3-bromophenyl)-4,6-quinazolindiamine and 1.13 g of diisopropyl methylamine in 25 mL of tetrahydrofuran was cooled in an ice bath as 1.0 g of 3-cis-chloroacryoyl chloride was added over 5 min. After stirring and cooling for 30 min and stirring at room temperature for another 30 min, the mixture was poured into a mixture of brine and saturated sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was removed at reduced pressure. The residue was chromatographed on silica gel eluting with chloroform and ethyl acetate mixtures to give N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-3(E)-chloro-2-propenamide as a yellowish solid. mass spectrum (m/e): M+H 404.7. was added over 5 min cooling for 30 min stirring at room temperature for another 30 min The mixture was extracted with ethyl acetate The organic layer was dried over magnesium sulfate the solvent was removed at reduced pressure The residue was chromatographed on silica gel eluting with chloroform and ethyl acetate mixtures

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

Procedure: A solution of 2.2 g of N-(3-bromophenyl)-4,6-quinazolindiamine and 1.13 g of diisopropyl methylamine in 25 mL of tetrahydrofuran was cooled in an ice bath as 1.0 g of 3-cis-chloroacryoyl chloride was added over 5 min. After stirring and cooling for 30 min and stirring at room temperature for another 30 min, the mixture was poured into a mixture of brine and saturated sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was removed at reduced pressure. The residue was chromatographed on silica gel eluting with chloroform and ethyl acetate mixtures to give N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-3(E)-chloro-2-propenamide as a yellowish solid. mass spectrum (m/e): M+H 404.7. was added over 5 min cooling for 30 min stirring at room temperature for another 30 min The mixture was extracted with ethyl acetate The organic layer was dried over magnesium sulfate the solvent was removed at reduced pressure The residue was chromatographed on silica gel eluting with chloroform and ethyl acetate mixtures

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (3 g, 8.08 mmol), (5)-methyl 2-amino-4-methylpentanoate hydrochloride (2.94 g, 16.16 mmol), and N-isopropyl-N-methylpropan-2-amine (3.76 mL, 24.25 mmol) in ACN (50 mL) was stirred at 100° C. for 3 d. The solvent was removed and the resulting residue was used in the next step without further purification. [M+H] calc'd for C23H27ClFN3O5, 480. found, 480. The solvent was removed the resulting residue was used in the next step without further purification

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (200 mg, 0.539 mmol), (R)-2-amino-4-methylpentanamide (140 mg, 1.078 mmol), and N-isopropyl-N-methylpropan-2-amine (310 mg, 2.69 mmol) in acetonitrile (2 mL) was stirred at 85° C. for 3 d. The resulting crude material was reconstituted in MeOH/DCM/DMF (10.0 mL) and purified via preparative HPLC. The fractions were collected and stripped to dryness via rotary evaporation to yield the title compound (83 mg, 33%). [M+H] calc'd for C22H26ClFN4O4, 465. found, 465. purified via preparative HPLC The fractions were collected stripped to dryness via rotary evaporation

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of benzyl (3-(3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)prop-2-yn-1-yl)(methyl)carbamate (100 mg, 0.158 mmol) in DCM (4 ml), 1M BBr3 in DCM (3 ml, 10.50 mmol) was added and the reaction was stirred overnight. Then, the solution was cooled to 0° C. and stirred for 1 h. Then, EtOH (1 ml) was added and solvent was removed under reduced. The resulting material was reacted in DCM (4 ml) with trioxane (0.049 ml, 0.472 mmol), N-isopropyl-N-methylpropan-2-amine (18.14 mg, 0.157 mmol) for 30 min. Then, sodium triacetoxyborohydride (100 mg, 0.472 mmol) and acetic acid (28.4 mg, 0.472 mmol) were added and the reaction stirred for 1 h. Solvent was removed and crude was purified by C18 flash chromatography ((H2O/ACN)) 95:5+0.1% HCOOH}:{(ACN/H2O) 95:5+HCOOH 0.1%} from 100:0 to 0:100 affording the title compound (5 mg, 10.03 mmol, 6.37% yield) as a white solid. stirred for 1 h solvent was removed the reaction stirred for 1 h Solvent was removed crude was purified by C18 flash chromatography ((H2O/ACN)) 95:5+0.1% HCOOH

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of benzyl (3-(3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)prop-2-yn-1-yl)(methyl)carbamate (100 mg, 0.158 mmol) in DCM (4 ml), 1M BBr3 in DCM (3 ml, 10.50 mmol) was added and the reaction was stirred overnight. Then, the solution was cooled to 0° C. and stirred for 1 h. Then, EtOH (1 ml) was added and solvent was removed under reduced. The resulting material was reacted in DCM (4 ml) with trioxane (0.049 ml, 0.472 mmol), N-isopropyl-N-methylpropan-2-amine (18.14 mg, 0.157 mmol) for 30 min. Then, sodium triacetoxyborohydride (100 mg, 0.472 mmol) and acetic acid (28.4 mg, 0.472 mmol) were added and the reaction stirred for 1 h. Solvent was removed and crude was purified by C18 flash chromatography ((H2O/ACN)) 95:5+0.1% HCOOH}:{(ACN/H2O) 95:5+HCOOH 0.1%} from 100:0 to 0:100 affording the title compound (5 mg, 10.03 mmol, 6.37% yield) as a white solid. stirred for 1 h solvent was removed the reaction stirred for 1 h Solvent was removed crude was purified by C18 flash chromatography ((H2O/ACN)) 95:5+0.1% HCOOH

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (3 g, 8.08 mmol), (S)-methyl 2-amino-4-methylpentanoate hydrochloride (2.94 g, 16.16 mmol), and N-isopropyl-N-methylpropan-2-amine (3.76 mL, 24.25 mmol) in ACN (50 mL) was stirred at 100° C. for 3 d. The solvent was removed and the resulting residue was used in the next step without further purification. [M+H] calc'd for C23H27ClFN3O5, 480; found, 480. The solvent was removed the resulting residue was used in the next step without further purification

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (3 g, 8.08 mmol), (S)-methyl 2-amino-4-methylpentanoate hydrochloride (2.94 g, 16.16 mmol), and N-isopropyl-N-methylpropan-2-amine (3.76 mL, 24.25 mmol) in ACN (50 mL) was stirred at 100° C. for 3 d. The solvent was removed and the resulting residue was used in the next step without further purification. [M+H] calc'd for C23H27ClFN3O5, 480; found, 480. The solvent was removed the resulting residue was used in the next step without further purification