6-ethyl-1,2,3,4,4a,5,7,7a-octahydropyrrolo[3,4-b]pyridine

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (0.80 g), K2CO3 (3.00 g) and 6-ethyloctahydro-1H-pyrrolo[3,4-b]pyridine (0.40 g) in 25 mL of DMF was stirred at 80° C. for 7 h, then cooled to rt, poured into 50 mL of ice-water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (0.36 g, 35.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 515.4 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.93 (t, J=4.6 Hz, 3H), 2.21-2.33 (m, 4H), 2.43-2.50 (m, 5H), 2.54-2.60 (m, 2H), 2.98-3.02 (m, 2H), 3.17-3.20 (m, 3H), 3.35-3.41 (m, 1H), 3.48-3.52 (m, 1H), 4.29 (s, 3H), 4.34 (t, J=8.6 Hz, 2H), 7.20 (s, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.43 (s, 2H), 7.91 (t, J=4.2 Hz, 1H), 8.47 (s, 1H) ppm. cooled to rt extracted with CH2Cl2 (50 mL×3) The combined organic phases were dried over anhydrous Na2SO4 filtered The filtrate was concentrated in vacuo the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (2.00 g) in glycol monomethyl ether was added a catalytic amount of 10% Pd/C. The suspension was heated to 70° C. and stirred for 6 h under H2 (2 MPa), then cooled to rt, and poured into 100 mL of water. The mixture was extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound as yellow oil (1.50 g, 70.00%). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 155.0 (M+1). cooled to rt The mixture was extracted with CH2Cl2 (50 mL×3) The combined organic phases were dried over anhydrous Na2SO4 filtered The filtrate was concentrated in vacuo

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (2.00 g) in glycol monomethyl ether was added a catalytic amount of 10% Pd/C. The suspension was heated to 70° C. and stirred for 6 h under H2 (2 MPa), then cooled to rt, and poured into 100 mL of water. The mixture was extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound as yellow oil (1.50 g, 70.00%). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 155.0 (M+1). cooled to rt The mixture was extracted with CH2Cl2 (50 mL×3) The combined organic phases were dried over anhydrous Na2SO4 filtered The filtrate was concentrated in vacuo

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (0.80 g), K2CO3 (3.00 g) and 6-ethyloctahydro-1H-pyrrolo[3,4-b]pyridine (0.40 g) in 25 mL of DMF was stirred at 80° C. for 7 h, then cooled to rt, poured into 50 mL of ice-water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (0.36 g, 35.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 515.4 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.93 (t, J=4.6 Hz, 3H), 2.21-2.33 (m, 4H), 2.43-2.50 (m, 5H), 2.54-2.60 (m, 2H), 2.98-3.02 (m, 2H), 3.17-3.20 (m, 3H), 3.35-3.41 (m, 1H), 3.48-3.52 (m, 1H), 4.29 (s, 3H), 4.34 (t, J=8.6 Hz, 2H), 7.20 (s, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.43 (s, 2H), 7.91 (t, J=4.2 Hz, 1H), 8.47 (s, 1H) ppm. cooled to rt extracted with CH2Cl2 (50 mL×3) The combined organic phases were dried over anhydrous Na2SO4 filtered The filtrate was concentrated in vacuo the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 6-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (2.00 g) in glycol monomethyl ether was added a catalytic amount of 10% Pd/C. The suspension was heated to 70° C. and stirred for 6 h under H2 (2 MPa), then cooled to rt, and poured into 100 mL of water. The mixture was extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound as yellow oil (1.50 g, 70.00%). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 155.0 (M+1). cooled to rt The mixture was extracted with CH2Cl2 (50 mL×3) The combined organic phases were dried over anhydrous Na2SO4 filtered The filtrate was concentrated in vacuo