6-(dimethylamino)-2-fluoro-3-formylbenzonitrile

Conditions: temp:22.01; pressure:0.00; stir:

Procedure: The next morning, the Mosquito(R) was used to dilute the 100 mM reactions to 50 mM via addition of 1 uL DMSO to each reaction well, followed by dispense mixing. The reactions were quenched with 1 uL saturated aqueous NaHCO3. The reactions were quenched with 1 uL water. The reactions were diluted to approximately 10 mM. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC.

Conditions: temp:22.01; pressure:0.00; stir:

Procedure: The next morning, the Mosquito(R) was used to dilute the 100 mM reactions to 50 mM via addition of 1 uL DMSO to each reaction well, followed by dispense mixing. The reactions were quenched with 1 uL saturated aqueous NaHCO3. The reactions were quenched with 1 uL water. The reactions were diluted to approximately 10 mM. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC.

Conditions: temp:22.01; pressure:0.00; stir:

Procedure: The next morning, the Mosquito(R) was used to dilute the 100 mM reactions to 50 mM via addition of 1 uL DMSO to each reaction well, followed by dispense mixing. The reactions were quenched with 1 uL saturated aqueous NaHCO3. The reactions were quenched with 1 uL water. The reactions were diluted to approximately 10 mM. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC.

Conditions: temp:22.01; pressure:0.00; stir:

Procedure: The next morning, the Mosquito(R) was used to dilute the 100 mM reactions to 50 mM via addition of 1 uL DMSO to each reaction well, followed by dispense mixing. The reactions were quenched with 1 uL saturated aqueous NaHCO3. The reactions were quenched with 1 uL water. The reactions were diluted to approximately 10 mM. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC.

Conditions: temp:22.01; pressure:0.00; stir:

Procedure: The next morning, the Mosquito(R) was used to dilute the 100 mM reactions to 50 mM via addition of 1 uL DMSO to each reaction well, followed by dispense mixing. The reactions were quenched with 1 uL saturated aqueous NaHCO3. The reactions were quenched with 1 uL water. The reactions were diluted to approximately 10 mM. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC.

Conditions: temp:22.01; pressure:0.00; stir:

Procedure: The next morning, the Mosquito(R) was used to dilute the 100 mM reactions to 50 mM via addition of 1 uL DMSO to each reaction well, followed by dispense mixing. The reactions were quenched with 1 uL saturated aqueous NaHCO3. The reactions were quenched with 1 uL water. The reactions were diluted to approximately 10 mM. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC.

Conditions: temp:22.01; pressure:0.00; stir:

Procedure: The next morning, the Mosquito(R) was used to dilute the 100 mM reactions to 50 mM via addition of 1 uL DMSO to each reaction well, followed by dispense mixing. The reactions were quenched with 1 uL saturated aqueous NaHCO3. The reactions were quenched with 1 uL water. The reactions were diluted to approximately 10 mM. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC.

Conditions: temp:22.01; pressure:0.00; stir:

Procedure: The next morning, the Mosquito(R) was used to dilute the 100 mM reactions to 50 mM via addition of 1 uL DMSO to each reaction well, followed by dispense mixing. The reactions were quenched with 1 uL saturated aqueous NaHCO3. The reactions were quenched with 1 uL water. The reactions were diluted to approximately 10 mM. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC. Mosquito(R) was used to transfer 1 uL of each quenched reaction from the 1,536-well reaction plate to 384-well analytical plates containing 60 uL DMSO for analysis by UPLC.

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

Procedure: To a solution of 6-dimethylamino-2-fluoro-3-formyl-benzonitrile (69 mg, 0.36 mmol) in CH3OH (7 mL) was added 2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (11 mg, 0.34 mmol). The reaction mixture was stirred overnight at RT. NaBH4 (19 mg, 0.50 mmol) was then added and the suspension was stirred for 30 min at RT. The reaction mixture was diluted with a few drops of H2O, and the solvents were removed under reduced pressure. The crude material was purified by basic reverse phase to provide 70 mg (44%) of the title compound. MS (ESI): exact mass calculated for C26H26FN7O, 471.22; m/z found, 472.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.09 (s, 1H), 8.75 (d, J=5.1, 1H), 8.26 (d, J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.38 (t, J=8.7, 1H), 7.18 (d, J=9.1, 1H), 6.58 (d, J=8.7, 1H), 4.75 (br s, 1H), 4.10 (s, 3H), 3.86 (s, 2H), 3.08 (s, 6H), 3.02-2.97 (m, 3H), 2.84-2.77 (m, 1H), 2.52 (dd, J=16.6, 9.9, 1H), 2.15-2.11 (m, 1H). the suspension was stirred for 30 min at RT the solvents were removed under reduced pressure The crude material was purified by basic reverse phase

Conditions: temp:22.01; pressure:0.00; stir:

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

Procedure: To a solution of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (200 mg, 0.4 mmol) in THF (10 mL) and triethylamine (0.1643 mL, 1.179 mmol) was added 6-(dimethylamino)-2-fluoro-3-formylbenzonitrile (75.52 mg, 0.3929 mmol). The solution was stirred at room temperature for 30 minutes before the addition of sodium triacetoxyborohydride (249.8 mg, 1.179 mmol). The mixture was stirred at room temperature overnight. After addition of aqueous NaHCO3, and EtOAc, the organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated. Purification by HPLC afforded 150 mg of the product 3-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile as a white solid. LC/MS: 669.2 (M+H)+. the organic layer was separated washed with brine dried over anhydrous Na2SO4 concentrated Purification by HPLC

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

Procedure: To a solution of 6-dimethylamino-2-fluoro-3-formyl-benzonitrile (69 mg, 0.36 mmol) in CH3OH (7 mL) was added 2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamine (11 mg, 0.34 mmol). The reaction mixture was stirred overnight at RT. NaBH4 (19 mg, 0.50 mmol) was then added and the suspension was stirred for 30 min at RT. The reaction mixture was diluted with a few drops of H2O, and the solvents were removed under reduced pressure. The crude material was purified by basic reverse phase to provide 70 mg (44%) of the title compound. MS (ESI): exact mass calculated for C26H26FN7O, 471.22; m/z found, 472.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.09 (s, 1H), 8.75 (d, J=5.1, 1H), 8.26 (d, J=9.1, 1H), 8.14 (d, J=5.1, 1H), 7.38 (t, J=8.7, 1H), 7.18 (d, J=9.1, 1H), 6.58 (d, J=8.7, 1H), 4.75 (br s, 1H), 4.10 (s, 3H), 3.86 (s, 2H), 3.08 (s, 6H), 3.02-2.97 (m, 3H), 2.84-2.77 (m, 1H), 2.52 (dd, J=16.6, 9.9, 1H), 2.15-2.11 (m, 1H). the suspension was stirred for 30 min at RT the solvents were removed under reduced pressure The crude material was purified by basic reverse phase