1-[4-(3-hydroxypropyl)piperazin-1-yl]ethanone

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: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:; See reaction.notes.procedure_details.

Procedure: Diethyl azodicarboxylate (991 mg, 5.7 mmol) was added dropwise to a solution of 4-chloro-6-hydroxy-7-methoxyquinazoline (1 g, 4.75 mmol), 3-(4-acetylpiperazin-1-yl)propan-1-ol (972 mg, 5.22 mmol), (prepared as described for the starting material in Example 1 or Example 7), and triphenylphosphine (1.74 g, 6.65 mmol) in methylene chloride (25 ml). The mixture was stirred at ambient temperature for 2 hours. The solution was poured onto silica and eluted with methylene chloride, followed by methylene chloride/methanol (97/3 followed by 92/8). The fractions containing the expected product were combined and evaporated to give 6-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-7-methoxyquinazoline (1.3 g, 72%). (prepared The solution was poured onto silica eluted with methylene chloride The fractions containing the expected product evaporated

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

Procedure: Diethyl azodicarboxylate (991 mg, 5.7 mmol) was added dropwise to a solution of 4-chloro-6-hydroxy-7-methoxyquinazoline (1 g, 4.75 mmol), 3-(4-acetylpiperazin-1-yl)propan-1-ol (972 mg, 5.22 mmol), (prepared as described for the starting material in Example 1 or Example 7), and triphenylphosphine (1.74 g, 6.65 mmol) in methylene chloride (25 ml). The mixture was stirred at ambient temperature for 2 hours. The solution was poured onto silica and eluted with methylene chloride, followed by methylene chloride/methanol (97/3 followed by 92/8). The fractions containing the expected product were combined and evaporated to give 6-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-7-methoxyquinazoline (1.3 g, 72%). (prepared The solution was poured onto silica eluted with methylene chloride The fractions containing the expected product evaporated

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

Procedure: Diethyl azodicarboxylate (117 μl, 0.738 mmol) was added dropwise to a solution of 4-(4-fluoroindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.2 g, 0.615 mmol), triphenylphosphine (0.242 g, 0.92 mmol) and 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.137 g, 0.738 mmol), (prepared as described for the starting material in Example 1 or Example 7), in methylene chloride (5 ml). After stirring at ambient temperature for 1 hour, triphenylphosphine (0.032 g), 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.022 g) and diethyl azodicarboxylate (20 μl) were added. The mixture was stirred for 1 hour at ambient temperature and evaporated under vacuum. The residue was purified by column chromatography, eluting with increasingly polar mixtures of methylene chloride and ethyl acetate followed by methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was repurified by preparative LC/MS eluting with increasingly polar mixtures of acetonitrile and water (containing 1% acetic acid). The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and pentane and the residue was filtered, washed with diethyl ether and dried under vacuum to give 6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoroindol-5-yloxy)-7-methoxyquinazoline (0.057 g, 19%). (prepared The mixture was stirred for 1 hour at ambient temperature evaporated under vacuum The residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and ethyl acetate The fractions containing the expected product evaporated The residue was repurified by preparative LC/MS eluting with increasingly polar mixtures of acetonitrile and water (containing 1% acetic acid) The fractions containing the expected product evaporated The residue was triturated under diethyl ether pentane and the residue was filtered washed with diethyl ether dried under vacuum

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

Procedure: Diethyl azodicarboxylate (117 μl, 0.738 mmol) was added dropwise to a solution of 4-(4-fluoroindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.2 g, 0.615 mmol), triphenylphosphine (0.242 g, 0.92 mmol) and 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.137 g, 0.738 mmol), (prepared as described for the starting material in Example 1 or Example 7), in methylene chloride (5 ml). After stirring at ambient temperature for 1 hour, triphenylphosphine (0.032 g), 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.022 g) and diethyl azodicarboxylate (20 μl) were added. The mixture was stirred for 1 hour at ambient temperature and evaporated under vacuum. The residue was purified by column chromatography, eluting with increasingly polar mixtures of methylene chloride and ethyl acetate followed by methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was repurified by preparative LC/MS eluting with increasingly polar mixtures of acetonitrile and water (containing 1% acetic acid). The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and pentane and the residue was filtered, washed with diethyl ether and dried under vacuum to give 6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoroindol-5-yloxy)-7-methoxyquinazoline (0.057 g, 19%). (prepared The mixture was stirred for 1 hour at ambient temperature evaporated under vacuum The residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and ethyl acetate The fractions containing the expected product evaporated The residue was repurified by preparative LC/MS eluting with increasingly polar mixtures of acetonitrile and water (containing 1% acetic acid) The fractions containing the expected product evaporated The residue was triturated under diethyl ether pentane and the residue was filtered washed with diethyl ether dried under vacuum

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

Procedure: 4-Chloro-7-hydroxy-6-methoxyquinazoline (3 g, 14.2 mmol), (prepared as described for the starting material in Example 4), 3-(4-acetylpiperazin-1-yl)propan-1-ol (3.2 g, 17.1 mmol), (prepared as described for the starting material in this example hereinbefore), and triphenylphosphine (4.5 g, 17.1 mmol) were stirred together in dichloromethane (140 ml). Diisopropyl azodicarboxylate (3.4 ml, 17.1 mmol) was added dropwise and an ice/water bath used to keep the temperature of the reaction mixture below 10° C. After the addition, the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was concentrated under reduced pressure. Column chromatography of the residue (2:1 iso-hexane:ethyl acetate then 3%-5% methanol/dichloromethane) gave 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (3.96 g, 74%) as a white solid. (prepared an ice/water bath used the temperature of the reaction mixture below 10° C After the addition The mixture was concentrated under reduced pressure