7-amino-4-bromo-2-methyl-3H-isoindol-1-one

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:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-Amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (100.0 mg, 0.4148 mmol), zinc cyanide (48.71 mg, 0.4148 mmol) and Pd(PPh3)4 (71.90 mg, 0.06222 mmol) in DMF (1.5 mL, 19 mmol) was evacuated and purged with N2 three times. The mixture was heated in microwave at 150° C. for 5 minutes. The crude mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was evaporated and purified on an ISCO Combiflash unit to isolate the title compound (50.0 mg, 64% yield). MS (ES+): m/z 188.14 (100) [MH+]; HPLC: tR=1.00 min (UPLC, analytical). was evacuated purged with N2 three times The crude mixture was diluted with ethyl acetate washed with water and brine The organic layer was evaporated purified on an ISCO Combiflash unit

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-Amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (100.0 mg, 0.4148 mmol), zinc cyanide (48.71 mg, 0.4148 mmol) and Pd(PPh3)4 (71.90 mg, 0.06222 mmol) in DMF (1.5 mL, 19 mmol) was evacuated and purged with N2 three times. The mixture was heated in microwave at 150° C. for 5 minutes. The crude mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was evaporated and purified on an ISCO Combiflash unit to isolate the title compound (50.0 mg, 64% yield). MS (ES+): m/z 188.14 (100) [MH+]; HPLC: tR=1.00 min (UPLC, analytical). was evacuated purged with N2 three times The crude mixture was diluted with ethyl acetate washed with water and brine The organic layer was evaporated purified on an ISCO Combiflash unit

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

Procedure: A mixture of [A] 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (1.0 g, 4.1 mmol), and 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole [US 2007265272] (1.6 g, 5.0 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.17 g, 0.21 mmol) in a microwave tube was taken up in 1,4-Dioxane (12 mL). The mixture was treated with a solution of Potassium carbonate (1.7 g, 12 mmol) in H2O (3.0 mL, 170 mmol), flushed with N2, sealed and irradiated in the CEM for 30 minutes at 100° C. Another 1 g of boronic ester was added as well as another 0.05 eq of catalyst. The mixture was sparged with N2, sealed and irradiated for 45 min. This was worked up and purified. 1H NMR (400 MHz, DMSO-d6) δ 1.36-1.50 (m, 4H), 1.57 (td, J=9.22, 3.03 Hz, 1H), 1.63-1.71 (m, 1H), 3.03 (s, 3H), 3.35-3.41 (m, 1H), 3.57 (ddd, J=11.31, 8.40, 3.03 Hz, 1H), 3.75 (dt, J=10.80, 5.34 Hz, 1H), 3.91-3.99 (m, 1H), 4.27-4.33 (m, 2H), 4.44 (s, 2H), 4.55 (t, J=3.28 Hz, 1H), 6.06 (s, 2H), 6.62 (d, J=8.34 Hz, 1H), 7.43 (d, J=8.34 Hz, 1H), 7.74 (d, J=0.51 Hz, 1H), 7.95 (d, J=0.51 Hz, 1H). flushed with N2 sealed irradiated in the CEM for 30 minutes at 100° C The mixture was sparged with N2 sealed irradiated for 45 min purified

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

Procedure: The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (50.0 mg, 0.118 mmol) and 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (34.14 mg, 0.1416 mmol). The reaction mixture was concentrated under reduced pressure to yield a yellow oil which was purified on an ISCO Combiflash system using (DCM/MeOH 100:0→95:5) as eluent to isolate 28.1 mg of the title compound (38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t, J=7.07 Hz, 6 H), 3.09 (s, 3 H), 3.18-3.27 (m, 2 H), 3.92-4.03 (m, 4 H), 4.43 (s, 2 H), 7.23-7.33 (m, 8 H), 7.55 (br. s., 5 H), 7.63 (d, J=8.84 Hz, 4 H), 8.50 (s, 4 H), 9.95 (s, 4 H), 10.54 (br. s., 3 H). MS (ES+): m/z 627.95/629.93 (91/100) [MH+]. HPLC: tR=3.72 min (ZQ3, polar—5 min). The title compound was prepared The reaction mixture was concentrated under reduced pressure to yield a yellow oil which was purified on an ISCO Combiflash system

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

Procedure: A mixture of 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (1.0 g, 4.1 mmol), E-phenylethenylboronic acid (921 mg, 6.22 mmol), potassium carbonate (1.72 g, 12.4 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (169 mg, 0.207 mmol) in 10 mL 1,4-Dioxane and 2.5 mL H2O was irradiated in a microwave reactor at 100° C. for 30 minutes. The crude mixture was partitioned between EtOAc and sat. NaHCO3. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification. MS (ES+): m/z 265.31 (100) [MH+]; HPLC: tR=1.24 min (UPLC, Analytical). was irradiated in a microwave reactor at 100° C. for 30 minutes The crude mixture was partitioned between EtOAc and sat. NaHCO3 The combined organic layers were washed with brine dried over Na2SO4 filtered concentrated The crude product was used in the next step without further purification

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

Procedure: A solution of ethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)methylphosphinate (230 mg, 584 mmol) and 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (169 mg, 701 mmol) in TFE (2.0 mL) was charged with TFA (200 mg, 1.75 mmol) and the reaction mixture irradiated in a microwave reactor at 105° C. for 1 hour. The resulting mixture was concentrated under reduced pressure and the residue purified using an Isco Combiflash system eluting with 0→5% MeOH in DCM as eluent to afford the title compound, 337.5 mg (96.6% yield). 1H NMR (CDCl3, 400 MHz): δ=1.33 (t, J=6.95 Hz, 3 H), 1.45 (d, J=13.64 Hz, 3 H), 3.22 (s, 1 H), 3.24 (s, 3 H), 3.26 (s, 1 H), 4.03-4.15 (m, 2 H), 4.34 (s, 2 H), 7.36-7.41 (m, 2 H), 7.50 (d, J=8.08 Hz, 4 H), 7.54 (d, J=8.84 Hz, 1 H), 8.20 (s, 1 H), 8.30 (d, J=9.35 Hz, 1 H). MS (ES+): m/z 600.0844 [MH+] (TOF, polar). the reaction mixture irradiated in a microwave reactor at 105° C. for 1 hour The resulting mixture was concentrated under reduced pressure the residue purified eluting with 0→5% MeOH in DCM as eluent

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

Procedure: A mixture of 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (1.7 g, 7.0 mmol), 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid pinacol ester (2.2 g, 8.5 mmol) (preparation: WO 2007/141517), potassium carbonate (2.9 g, 21 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (1:1) (0.57 g, 0.69 mmol) in 1,4-dioxane (40 mL) and H2O (10 mL) was evacuated and refilled with nitrogen (3×) and irradiated in the microwave at 100° C. for 30 min. The reaction mixture was partitioned between EtOAc and brine and separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated. The compound was purified on an Isco Combiflash eluting with 30 to 100% EtOAc in heptane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, J=8.34 Hz, 1H), 6.55 (d, J=8.59 Hz, 1H), 6.08 (s, 2H), 5.60-5.66 (m, 1H), 4.39 (s, 2H), 3.91 (s, 4H), 2.98 (s, 3H), 2.50 (td, J=1.86, 3.60 Hz, 1H), 2.42-2.48 (m, 2H), 2.31-2.37 (m, 2H), 1.77 (t, J=6.44 Hz, 2H); MS (ES+): m/z: 302.1621 [MH+]. HPLC: tR=1.21 min (UPLC TOF MS: polar—3 min). was evacuated refilled with nitrogen (3×) irradiated in the microwave at 100° C. for 30 min The reaction mixture was partitioned between EtOAc and brine separated The aqueous layer was extracted with EtOAc (3×) the combined organic fractions were dried over sodium sulfate filtered concentrated The compound was purified on an Isco Combiflash eluting with 30 to 100% EtOAc in heptane

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

Procedure: NBS (2.3 g, 12.96) was added to a cold (−8° C. to −10° C.) solution of 7-amino-2-methyl-2,3-dihydro-1H-isoindol-1-one (2 g, 12.4 mmol) in DCM (40 mL) and the mixture stirred at −8° C. to −10° C. for 1 h. A solution of 10% aq. sodium thiosulfate (30 mL) was then added to the reaction mixture and stirring was continued for another 20 minutes. The layers were separated and the aqueous layer was extracted with DCM (2×20 mL). The combined organic extracts were washed with water (3×40 mL) and brine (30 mL), and the organic layer was dried (Na2SO4) and concentrated in vacuo to yield 3.2 g of crude product. This material was triturated with ethyl acetate (10 mL) to give 2.2 g of pure 7-amino-4-bromo-2-methyl-2,3-dihydro-1H-isoindol-1-one (XXXIX, yield: 74%). stirring was continued for another 20 minutes The layers were separated the aqueous layer was extracted with DCM (2×20 mL) The combined organic extracts were washed with water (3×40 mL) and brine (30 mL) the organic layer was dried (Na2SO4) concentrated in vacuo to yield 3.2 g of crude product This material was triturated with ethyl acetate (10 mL)