3,4-dihydro-2H-chromene-2-carbonyl chloride

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

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

Procedure: A mixture of 2-chlorocarbonyl-3,4-dihydro-2H-1-benzopyran (0.47 mol) in N,N-dimethylacetamide (100 ml), a solution of thiophene (4%) (3 ml) and 2,2'-oxybispropane (400 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue, potassium acetate (20 g) and benzenemethanamine (50 g) in N,N-dimethylacetamide (2 ml) and methanol (300 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue in methanol (500 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in 1,1'-oxybisethane and washed with a NaOH-solution. The organic layer was dried (MgSO4), filtered off and evaporated. The residue (70 g) was distilled at 70° C. (0.1 mm Hg), yielding 48.7 g (63.5%) of (±)-3,4-dihydro-2H-1-benzopyran-2-methanamine (interm. 15-c). the filtrate was evaporated the filtrate was evaporated the filtrate was evaporated washed with a NaOH-solution The organic layer was dried (MgSO4) filtered off evaporated The residue (70 g) was distilled at 70° C. (0.1 mm Hg)

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

Procedure: To 0.10 mole of 2-(piperazin-1-yl)-4-amino-6-chloro-7-methoxyquinazoline in 300 ml. of methanol is added with vigorous stirring, 0.10 mole of 2,3-dihydro-4H-benzopyran-2-carboxylic acid chloride. After the addition is complete, the mixture is stirred for three hours at room temperature and the precipitated title compound is collected by filtration. After the addition the precipitated title compound is collected by filtration

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

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

Procedure: 89.0 g (0.5 mol) chroman-2-carboxylic acid and 71.4 g (0.6 mol) thionyl chloride were heated to 80° for 4-5 hours (end of gas evolution). Destillation (77°-80°/0.1 torr) yielded 96.0 g (98%) chroman-2-carboxylic acid chloride

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

Procedure: 89.0 g (0.5 mol) chroman-2-carboxylic acid and 71.4 g (0.6 mol) thionyl chloride were heated to 80° for 4-5 hours (end of gas evolution). Destillation (77°-80°/0.1 torr) yielded 96.0 g (98%) chroman-2-carboxylic acid chloride

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

Procedure: A mixture of 2-chlorocarbonyl-3,4-dihydro-2H-1-benzopyran (0.47 mol) in N,N-dimethylacetamide (100 ml), a solution of thiophene (4%) (3 ml) and 2,2'-oxybispropane (400 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue, potassium acetate (20 g) and benzenemethanamine (50 g) in N,N-dimethylacetamide (2 ml) and methanol (300 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue in methanol (500 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in 1,1'-oxybisethane and washed with a NaOH-solution. The organic layer was dried (MgSO4), filtered off and evaporated. The residue (70 g) was distilled at 70° C. (0.1 mm Hg), yielding 48.7 g (63.5%) of (±)-3,4-dihydro-2H-1-benzopyran-2-methanamine (interm. 15-c). the filtrate was evaporated the filtrate was evaporated the filtrate was evaporated washed with a NaOH-solution The organic layer was dried (MgSO4) filtered off evaporated The residue (70 g) was distilled at 70° C. (0.1 mm Hg)

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

Procedure: To 0.10 mole of 2-(piperazin-1-yl)-4-amino-6-chloro-7-methoxyquinazoline in 300 ml. of methanol is added with vigorous stirring, 0.10 mole of 2,3-dihydro-4H-benzopyran-2-carboxylic acid chloride. After the addition is complete, the mixture is stirred for three hours at room temperature and the precipitated title compound is collected by filtration. After the addition the precipitated title compound is collected by filtration

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

Procedure: To 0.10 mole of 2-(piperazin-1-yl)-4-amino-6-chloro-7-methoxyquinazoline in 300 ml. of methanol is added with vigorous stirring, 0.10 mole of 2,3-dihydro-4H-benzopyran-2-carboxylic acid chloride. After the addition is complete, the mixture is stirred for three hours at room temperature and the precipitated title compound is collected by filtration. After the addition the precipitated title compound is collected by filtration

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Thionylchloride (109.21 g, 918 mmol) was added under nitrogen atmosphere at 20-25° C. to a suspension of 6-fluorochroman-2-carboxylic acid (90.00 g, 459 mmol) and DMF (1.68 g, 23 mmol) in toluene (635 ml). Afterwards, the suspension was heated to an internal temperature of 60-70° C., whereupon a clear yellow solution was obtained under simultaneous evolution of a gas. The reaction was completed within 70 min at this temperature, and the mixture was then concentrated in vacuum (bath temperature 45-50° C., pressure≦35 mbar) to yield the chroman-2-carboxylic acid chloride as a yellow oil (112.65 g). The crude product was dissolved in methylene chloride (65 ml) and added slowly under nitrogen atmosphere to a solution of Meldrum's acid (70.90 g, 482 mmol) and pyridine (72.62 g, 918 mmol) in methylene chloride (261 ml) at an internal temperature of 0-10° C. The reaction mixture was allowed to warm to 20-25° C. within 50 min. and stirred at this temperature for additional 30 min. Methylene chloride (325 ml) and water (325 ml) were then added to the formed brown suspension. The two phase mixture was stirred for 5 min, separated, and the organic layer was subsequently extracted twice with water (200 ml each), then with 2N aqueous HCl solution (250 ml) and finally with water (250 ml). After drying over Na2SO4, the organic layer was filtrated and concentrated in vacuo (≦50 mbar) to give a brown, viscous oil (170.76 g), which crystallized after 10 min at room temperature. The solid was slurried at 20-25° C. in diisopropyl ether (500 ml) for 2 h. After filtration of the suspension, the wet product was washed with diisopropyl ether (70 ml) and dried in vacuo (13 h at 40° C.) to give a yellow-ocher colored solid (yield: 114.71 g, HPLC-purity: 96.98%). was obtained under simultaneous evolution of a gas the mixture was then concentrated in vacuum (bath temperature 45-50° C., pressure≦35 mbar)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Thionylchloride (109.21 g, 918 mmol) was added under nitrogen atmosphere at 20-25° C. to a suspension of 6-fluorochroman-2-carboxylic acid (90.00 g, 459 mmol) and DMF (1.68 g, 23 mmol) in toluene (635 ml). Afterwards, the suspension was heated to an internal temperature of 60-70° C., whereupon a clear yellow solution was obtained under simultaneous evolution of a gas. The reaction was completed within 70 min at this temperature, and the mixture was then concentrated in vacuum (bath temperature 45-50° C., pressure≦35 mbar) to yield the chroman-2-carboxylic acid chloride as a yellow oil (112.65 g). The crude product was dissolved in methylene chloride (65 ml) and added slowly under nitrogen atmosphere to a solution of Meldrum's acid (70.90 g, 482 mmol) and pyridine (72.62 g, 918 mmol) in methylene chloride (261 ml) at an internal temperature of 0-10° C. The reaction mixture was allowed to warm to 20-25° C. within 50 min. and stirred at this temperature for additional 30 min. Methylene chloride (325 ml) and water (325 ml) were then added to the formed brown suspension. The two phase mixture was stirred for 5 min, separated, and the organic layer was subsequently extracted twice with water (200 ml each), then with 2N aqueous HCl solution (250 ml) and finally with water (250 ml). After drying over Na2SO4, the organic layer was filtrated and concentrated in vacuo (≦50 mbar) to give a brown, viscous oil (170.76 g), which crystallized after 10 min at room temperature. The solid was slurried at 20-25° C. in diisopropyl ether (500 ml) for 2 h. After filtration of the suspension, the wet product was washed with diisopropyl ether (70 ml) and dried in vacuo (13 h at 40° C.) to give a yellow-ocher colored solid (yield: 114.71 g, HPLC-purity: 96.98%). was obtained under simultaneous evolution of a gas the mixture was then concentrated in vacuum (bath temperature 45-50° C., pressure≦35 mbar)

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

Procedure: A mixture of 2-chlorocarbonyl-3,4-dihydro-2H-1-benzopyran (0.47 mol) in N,N-dimethylacetamide (100 ml), a solution of thiophene (4%) (3 ml) and 2,2'-oxybispropane (400 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue, potassium acetate (20 g) and benzenemethanamine (50 g) in N,N-dimethylacetamide (2 ml) and methanol (300 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue in methanol (500 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in 1,1'-oxybisethane and washed with a NaOH-solution. The organic layer was dried (MgSO4), filtered off and evaporated. The residue (70 g) was distilled at 70° C. (0.1 mm Hg), yielding 48.7 g (63.5%) of (±)-3,4-dihydro-2H-1-benzopyran-2-methanamine (interm. 15-c). the filtrate was evaporated the filtrate was evaporated the filtrate was evaporated washed with a NaOH-solution The organic layer was dried (MgSO4) filtered off evaporated The residue (70 g) was distilled at 70° C. (0.1 mm Hg)