methyl butanoate

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

Procedure: The procedure according to Example 17 was repeated, but using the same amount of the polymer obtained from Example 10 instead of the polymer obtained from Example 1; 1,4-cyclohexane dicarboxaldehyde (1.4 g) as a cross-linker instead of glutaric dialdehyde, and methyl 3-methylpropionate (25 ml) as a solvent, to obtain a negative pattern with a resolution of 0.15 μm (FIG. 3).

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

Procedure: The procedure according to Example 17 was repeated, but using the same amount of the polymer obtained from Example 10 instead of the polymer obtained from Example 1; 1,4-cyclohexane dicarboxaldehyde (1.4 g) as a cross-linker instead of glutaric dialdehyde, and methyl 3-methylpropionate (25 ml) as a solvent, to obtain a negative pattern with a resolution of 0.15 μm (FIG. 3).

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

Procedure: To a suspension of NaH (7.99 g, 200 mmol) in DME (100 mL) was added a mixture of methyl butyrate (5.1 g, 49.9 mmol) and methyl formate (17.99 g, 300 mmol) in DME (100 mL) dropwise at 0° C. under nitrogen. The mixture was stirred at room temperature overnight, and then filtered through a pad of celite. To the filtrate was added ether (200 mL), and let the suspension stand for 4 h. The solid was collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound (3 g, 23.05 mmol). LCMS: rt=1.108 min, [M+H+]=130 was added filtered through a pad of celite To the filtrate was added ether (200 mL) stand for 4 h The solid was collected by filtration washed with diethyl ether dried in vacuo

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

Procedure: To a round bottom flask was combined 7-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (0.461 g, 0.722 mmol), methanol ethyl acetate (12 ml), THF (3 ml), methanol (3 ml), and Pd on C/10%. The mixture was put under a balloon of hydrogen and stirred over night. The mixture was purged with nitrogen followed by addition of methylene chloride. The resultant mixture was filtered through a pad of celite. The celite was washed with additional methylene chloride. The organics were combined and concentrated to a residue. The residue was purified by silica gel chromotography which gave 7-Cyclopentyl-2-[5-(3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (338 mg, 0.67 mmol) in 93% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.82 (s, 1H), 8.63 (d, J=8.6 Hz, 1H), 8.56 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 7.87 (dd, J1=8.78 Hz, J2=2.26 Hz, 1H), 6.51 (s, 1H), 4.83 (m, 1H), 4.47 (s, 1H), 4.09 (m, 4H), 3.77 (s, 1H), 3.45-3.21 (m, 4H), 3.19 (s, 6H), 2.59 (m, 2H), 2.11 (m, 5H), 1.77 (m, 2H); HRMS m/z 505.2665 (M+H)+. To a round bottom flask was combined The mixture was purged with nitrogen followed by addition of methylene chloride The resultant mixture was filtered through a pad of celite The celite was washed with additional methylene chloride concentrated to a residue The residue was purified by silica gel chromotography which

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

Procedure: Using analogous procedures to those described in Example 1 pentafluorophenyl p-{N-[1-(2,7-dimethyl-4-oxo-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-6-yl)ethyl]-N-(prop-2-ynyl)amino}benzoate was reacted with methyl (2S)-2-amino-4-(tetrazol-5-yl)butyrate and the resultant methyl butyrate was hydrolysed to give 2- {p-{N-[1-(2,7-dimethyl-4-oxo-3,4-dihydroquinazolin-6-yl)ethyl]-N-(prop-2-ynyl)amino}benzamido}-4-(tetrazol-5-yl)butyric acid in 25% yields m.p. 207° C.

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

Procedure: This compound (720 mg, 1.75 mmol, 31% yield) obtained as an off-white solid was prepared according to procedure described for Intermediate 51, using methyl butanoate (1.89 mL, 16.65 mmol) and tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (50) (2.00 g, 5.55 mmol) as the starting materials. m/z (ESI, +ve ion) 413.0 (M+1)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.62 (1H, s), 7.47-7.55 (2H, m), 7.39-7.46 (1H, m), 7.29 (1H, d, J=1.4 Hz), 6.92 (1H, dd, J=7.8, 1.0 Hz), 6.57 (1H, br. s.), 2.66 (2H, q, J=7.4 Hz), 2.19 (3H, s), 1.50 (9H, s), 1.23-1.31 (3H, m). was prepared

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

Procedure: To a solution of 2-picoline (10 g) in THF (75 mL) was added n-BuLi (113 mmol) at −40° C. Further, methyl butanoate (15.8 mL) was added and the mixture was stirred for 1 hour, and the mixture quenched with water. The mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 2-(2-oxopentanyl)pyridine (4.8 g) as a yellow oil. A solution of 2-bromo-3-cyanobenzaldehyde (1.5 g), Meldrum's acid (1.0 g), 2-(2-oxopentanyl)pyridine (1.2 g) and ammonium acetate (0.6 g) in acetic acid (7 mL) was heated under reflux for 11 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) and the obtained residue was crystallized from ethyl acetate to give colorless crystals (520 mg). To a solution of dimethylformamide (384 mg) in chloroform (5 mL) were added phosphorus oxychloride (805 mg) and a solution of the obtained crystals (520 mg) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (3.4 g) solution was added and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give oil. The obtained oil was purified by silica gel column chromatography (eluent: chloroform-methanol (9:1)) to give a yellow solid (530 mg). To a solution of the obtained solid in pyridine (10 mL) was added hydrazine (120 mg), and the mixture was stirred with heating for 4 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give oil. To the obtained oil was added water and the mixture was extracted with ethyl acetate. The extract was washed a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give the title compound (145 mg) as a pale-yellow crystal. the mixture quenched with water The mixture was extracted with ethyl acetate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1))

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

Procedure: To a solution of 2-picoline (10 g) in THF (75 mL) was added n-BuLi (113 mmol) at −40° C. Further, methyl butanoate (15.8 mL) was added and the mixture was stirred for 1 hour, and the mixture quenched with water. The mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 2-(2-oxopentanyl)pyridine (4.8 g) as a yellow oil. A solution of 2-bromo-3-cyanobenzaldehyde (1.5 g), Meldrum's acid (1.0 g), 2-(2-oxopentanyl)pyridine (1.2 g) and ammonium acetate (0.6 g) in acetic acid (7 mL) was heated under reflux for 11 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate (1:1)) and the obtained residue was crystallized from ethyl acetate to give colorless crystals (520 mg). To a solution of dimethylformamide (384 mg) in chloroform (5 mL) were added phosphorus oxychloride (805 mg) and a solution of the obtained crystals (520 mg) under ice-cooling, and the mixture was stirred overnight. Under ice-cooling, an aqueous sodium acetate (3.4 g) solution was added and the mixture was stirred for 1 hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give oil. The obtained oil was purified by silica gel column chromatography (eluent: chloroform-methanol (9:1)) to give a yellow solid (530 mg). To a solution of the obtained solid in pyridine (10 mL) was added hydrazine (120 mg), and the mixture was stirred with heating for 4 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure to give oil. To the obtained oil was added water and the mixture was extracted with ethyl acetate. The extract was washed a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give the title compound (145 mg) as a pale-yellow crystal. the mixture quenched with water The mixture was extracted with ethyl acetate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1))

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

Procedure: To a suspension of NaH (7.99 g, 200 mmol) in DME (100 mL) was added a mixture of methyl butyrate (5.1 g, 49.9 mmol) and methyl formate (17.99 g, 300 mmol) in DME (100 mL) dropwise at 0° C. under nitrogen. The mixture was stirred at room temperature overnight, and then filtered through a pad of celite. To the filtrate was added ether (200 mL), and let the suspension stand for 4 h. The solid was collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound (3 g, 23.05 mmol). LCMS: rt=1.108 min, [M+H+]=130 was added filtered through a pad of celite To the filtrate was added ether (200 mL) stand for 4 h The solid was collected by filtration washed with diethyl ether dried in vacuo

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The autoclave was charged with 0.3 gms of palladium chloride, 5 gms o-trifluoromethylphenyldiphenylphosphine, 10 mls of methanol and 50 ml of p-dioxane. After flushing with nitrogen, the autoclave was pressurized with carbon monoxide to 800 psig and heated to 120 degrees C. with stirring. 10 gms of liquid propylene was added and the reaction continued at 120° C. and 100 psig for 3 hours. The autoclave was then cooled and the reaction fluid analyzed by gas chromatography. A methyl isobutyrate:methyl n-butyrate ratio of 7.1:1 was obtained. After flushing with nitrogen 10 gms of liquid propylene was added continued at 120° C. The autoclave was then cooled

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The autoclave was charged with 0.3 gms of palladium chloride, 5 gms o-trifluoromethylphenyldiphenylphosphine, 10 mls of methanol and 50 ml of p-dioxane. After flushing with nitrogen, the autoclave was pressurized with carbon monoxide to 800 psig and heated to 120 degrees C. with stirring. 10 gms of liquid propylene was added and the reaction continued at 120° C. and 100 psig for 3 hours. The autoclave was then cooled and the reaction fluid analyzed by gas chromatography. A methyl isobutyrate:methyl n-butyrate ratio of 7.1:1 was obtained. After flushing with nitrogen 10 gms of liquid propylene was added continued at 120° C. The autoclave was then cooled

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The procedure in Example 5 is followed but using 4,6-diphenyl-2-pyridinone (2.8 g) (prepared by analogy with the method described in Patent EP 108 592 from methyl butanoate), methyl 6-bromo-2-ethylhexanoate (5.4. g), silver carbonate (1.6 g) and dimethylformamide (100 cc). The reaction mixture is heated at 100° C. for 31 hours then at 120° C. for 40 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1). (yellow oil) prepared by analogy with the method The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1)