2-amino-3-methoxybenzaldehyde

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

Procedure: 8-Methoxy-quinazolin-2-ylamine. To a solution of 3-methoxy-2-nitro-benzaldehyde (14.8 g, 81 mmol, Aldrich) and NH4Cl (4.4 g, 82 mmol, Aldrich) in 80% aq. MeOH (250 mL) was added iron dust (20.5 g, 367 mmol, Aldrich) and the reaction mixture was heated at 60° C. with stirring for 2 h. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite®. The filter cake was washed with MeOH and the solution was concentrated in vacuum. The concentrated aq. solution was extracted with CH2Cl2 and the combined organic layers were washed with brine and dried over Na2SO4. Purification with EtOAc/Hexanes (0:1→1:4) as eluant gave 3.84 g (31%) of 2-amino-3-methoxy-benzaldehyde as a yellow oil. This oil was heated at 190° C. for 2.5 h in the presence of guanidine hydrochloride (4.9 g, 51 mmol, Aldrich), Na2CO3 (5.4 g, 51 mmol) and decalin (55 mL). The reaction was decanted while hot and the solution was allowed to cool to room temperature. The resultant precipitate was stirred with hexanes, filtered, washed with hexanes, and dried in vacuum to give the title compound as a yellow amorphous solid. MS (ESI, pos ion.) m/z: 176 (M+1). to cool to room temperature filtered through a pad of Celite® The filter cake was washed with MeOH the solution was concentrated in vacuum The concentrated aq. solution was extracted with CH2Cl2 the combined organic layers were washed with brine dried over Na2SO4 Purification with EtOAc/Hexanes (0:1→1:4) as eluant

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8-Methoxy-quinazolin-2-ylamine. To a solution of 3-methoxy-2-nitro-benzaldehyde (14.8 g, 81 mmol, Aldrich) and NH4Cl (4.4 g, 82 mmol, Aldrich) in 80% aq. MeOH (250 mL) was added iron dust (20.5 g, 367 mmol, Aldrich) and the reaction mixture was heated at 60° C. with stirring for 2 h. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite®. The filter cake was washed with MeOH and the solution was concentrated in vacuum. The concentrated aq. solution was extracted with CH2Cl2 and the combined organic layers were washed with brine and dried over Na2SO4. Purification with EtOAc/Hexanes (0:1→1:4) as eluant gave 3.84 g (31%) of 2amino-3-methoxy-benzaldehyde as a yellow oil. This oil was heated at 190° C. for 2.5 h in the presence of guanidine hydrochloride (4.9 g, 51 mmol, Aldrich), Na2CO3 (5.4 g, 51 mmol) and decalin (55 mL). The reaction was decanted while hot and the solution was allowed to cool to room temperature. The resultant precipitate was stirred with hexanes, filtered, washed with hexanes, and dried in vacuum to give the title compound as a yellow amorphous solid. MS (ESI, pos ion.) m/z: 176 (M+1). to cool to room temperature filtered through a pad of Celite® The filter cake was washed with MeOH the solution was concentrated in vacuum The concentrated aq. solution was extracted with CH2Cl2 the combined organic layers were washed with brine dried over Na2SO4 Purification with EtOAc/Hexanes (0:1→1:4) as eluant

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8-Methoxy-quinazolin-2-ylamine. To a solution of 3-methoxy-2-nitro-benzaldehyde (14.8 g, 81 mmol, Aldrich) and NH4Cl (4.4 g, 82 mmol, Aldrich) in 80% aq. MeOH (250 mL) was added iron dust (20.5 g, 367 mmol, Aldrich) and the reaction mixture was heated at 60° C. with stirring for 2 h. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite®. The filter cake was washed with MeOH and the solution was concentrated in vacuum. The concentrated aq. solution was extracted with CH2Cl2 and the combined organic layers were washed with brine and dried over Na2SO4. Purification with EtOAc/Hexanes (0:1→1:4) as eluant gave 3.84 g (31%) of 2amino-3-methoxy-benzaldehyde as a yellow oil. This oil was heated at 190° C. for 2.5 h in the presence of guanidine hydrochloride (4.9 g, 51 mmol, Aldrich), Na2CO3 (5.4 g, 51 mmol) and decalin (55 mL). The reaction was decanted while hot and the solution was allowed to cool to room temperature. The resultant precipitate was stirred with hexanes, filtered, washed with hexanes, and dried in vacuum to give the title compound as a yellow amorphous solid. MS (ESI, pos ion.) m/z: 176 (M+1). to cool to room temperature filtered through a pad of Celite® The filter cake was washed with MeOH the solution was concentrated in vacuum The concentrated aq. solution was extracted with CH2Cl2 the combined organic layers were washed with brine dried over Na2SO4 Purification with EtOAc/Hexanes (0:1→1:4) as eluant

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

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

Procedure: The title compound was synthesized according to EXAMPLE 11 from 2-amino-3-methoxybenzaldehyde and 3-(2-methoxyphenyl)propionitrile.

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

Procedure: To a 1:1 mixture of ethanol and acetic acid was added 3-methoxy-2-nitrobenzaldehyde (1 eq) and Fe dust (3 eq) was added in portions. The reduction was complete in 3 h. The reaction mixture was filtered and then concentrated and partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate and dried and concentrated to give 2-amino-3-methoxybenzaldehyde in 85% yield. ES/MS m/z 151 (MH+). was added in portions The reaction mixture was filtered concentrated partitioned between ethyl acetate and water The organic layer was washed with saturated sodium bicarbonate dried concentrated

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Solid 2-amino-3-methoxybenzaldehyde (37.2 g, 0.246 mole), urea (158 g, 2.5 mole) and catalytic NH4OAc (1 g) were thoroughly mixed together in a roundbottom flask. The solid mixture was heated in a 160° C. bath. The solids quickly melted and stirring was commenced. After about 15 minutes, solids start to precipitate from the hot solution. After adding NMP (150 mL) to dissolve the solids, the reaction was heated with stirring for an additional 30-45 minutes until complete as judged by LCMS. The hot reaction mixture was poured into vigorously stirred water (400 mL). The reaction flask was washed out with water (3×100 mL) and EtOAc (4×50 mL). After stirring ca. 30 minutes, mixture was filtered to collect the light solid precipitate. The solid filter cake was washed with portions of water and EtOAc to give a white solid. The solid was dried on the frit and in vacuo to give the product in 99% purity and 95% yield (41 g, 233 mmole). to precipitate from the hot solution After adding NMP (150 mL) to dissolve the solids the reaction was heated with stirring for an additional 30-45 minutes until complete The hot reaction mixture was poured into vigorously stirred water (400 mL) The reaction flask was washed out with water (3×100 mL) and EtOAc (4×50 mL) After stirring ca. 30 minutes mixture was filtered to collect the light solid precipitate The solid filter cake was washed with portions of water and EtOAc to give a white solid The solid was dried on the frit and in vacuo to give the product in 99% purity and 95% yield (41 g, 233 mmole)

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

Procedure: Iron powder (40 g) was slowly added to a stirred solution of 3-methoxy-2-nitrobenzaldehyde (1) (70 g, 386 mmole) in AcOH gal. (100 mL) and EtOH abs. (400 mL). The reaction was cooled using an ice bath followed by addition of con. HCL (1 mL). The reaction became exothermic. After stabilization of the reaction temperature, the reaction was heated to reflux. The reaction reached completion after ca. 20 minutes according to LCMS. The reaction mixture was cooled to RT and filtered. The filtrate was evaporated to a thick brown syrup. The dark residue was dissolved in EtOAc (500 mL) and water (200 mL). The mixture was basified with NaOH 6M to ca. pH 10. The mixture was filtered over celite and the layers separated. The organic layer was washed with NaHCO3 (2×100 mL), water (2×100 mL), brine (100 mL), dried (Na2SO4), filtered and evaporated to a dark amber oil. The oil was dried in vacuo to give 95% pure product 2-amino-3-methoxybenzaldehyde in 64% yield (37.2 g, 246 mmole). The reaction was cooled followed by addition of con After stabilization of the reaction temperature, the reaction was heated to reflux after ca. 20 minutes filtered The filtrate was evaporated to a thick brown syrup The dark residue was dissolved in EtOAc (500 mL) The mixture was filtered over celite the layers separated The organic layer was washed with NaHCO3 (2×100 mL), water (2×100 mL), brine (100 mL) dried (Na2SO4) filtered evaporated to a dark amber oil The oil was dried in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 8-Methoxy-quinazolin-2-ylamine. To a solution of 3-methoxy-2-nitro-benzaldehyde (14.8 g, 81 mmol, Aldrich) and NH4Cl (4.4 g, 82 mmol, Aldrich) in 80% aq. MeOH (250 mL) was added iron dust (20.5 g, 367 mmol, Aldrich) and the reaction mixture was heated at 60° C. with stirring for 2 h. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite®. The filter cake was washed with MeOH and the solution was concentrated in vacuum. The concentrated aq. solution was extracted with CH2Cl2 and the combined organic layers were washed with brine and dried over Na2SO4. Purification with EtOAc/Hexanes (0:1→1:4) as eluant gave 3.84 g (31%) of 2-amino-3-methoxy-benzaldehyde as a yellow oil. This oil was heated at 190C for 2.5 h in the presence of guanidine hydrochloride (4.9 g, 51 mmol, Aldrich), Na2CO3 (5.4 g, 51 mmol) and decalin (55 mL). The reaction was decanted while hot and the solution was allowed to cool to room temperature. The resultant precipitate was stirred with hexanes, filtered, washed with hexanes, and dried in vacuum to give the title compound as a yellow amorphous solid. MS (ESI, pos ion.) m/z: 176 (M+1). to cool to room temperature filtered through a pad of Celite® The filter cake was washed with MeOH the solution was concentrated in vacuum The concentrated aq. solution was extracted with CH2Cl2 the combined organic layers were washed with brine dried over Na2SO4 Purification with EtOAc/Hexanes (0:1→1:4) as eluant