2-chlorooxane

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

Procedure: The compound is prepared in analogy to compound (204) from tert-butyl-(dimethyl-tert-butylaminocarbonyl-methyl)-hydroxylamine and 2-chlor-tetrahydropyrane in 33% yield as colorless oil.

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of imidazole (81.6 g, 1.2 mol) in dry THF (2.5 L) was slowly added NaH (86.4 g, 3.6 mol) in small portions at −78° C. After all NaH was added, the mixture was stirred at −78° C. for 30 min, and 2-chloro-tetrahydropyran solution, prepared by hydrogen chloride gas treatment of dihydropyran, was added to the reaction mixture dropwise. The mixture was slowly warmed to r.t. and it was stirred at r.t. for 2 h. Methanol was added to quench the excess NaH. The mixture was concentrated with a rotary evaporator. Water was added and it was extract with EtOAc (500 mL×3), dried over MgSO4, and purified by neutral Al2O3 column chromatography (petroleum ether 5 L, petroleum ether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc). The last four fractions were pooled and concentrated to give 1-(tetrahydro-pyran-2-yl)-1H-imidazole (140 g, 76%). 1H NMR (CDCl3): δ 7.65 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 5.20 (dd, J=2.6, 9.5 Hz, 1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.01-1.89 (m, 3H), 1.69-1.60 (m, 3H) at −78° C was added to the reaction mixture dropwise The mixture was slowly warmed to r.t. it was stirred at r.t. for 2 h to quench the excess NaH The mixture was concentrated with a rotary evaporator Water was added it was extract with EtOAc (500 mL×3) dried over MgSO4 purified by neutral Al2O3 column chromatography (petroleum ether 5 L, petroleum ether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc) concentrated

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

Procedure: 3,5-Bis(trimethylsilyloxy)-1,2,4-triazine (2.5 g) and 2-chlorotetrahydropyran (1.8 g) are dissolved in dimethylformamide (1 ml), and the mixture is stirred overnight at room temperature and concentrated in vacuo. The residue is column-chromatographed over silica gel using a mixture of acetone/n-hexane (1/3) as an eluent. The first major fraction gives 1.0 g (40%) of 2,4-bis(tetrahydro-2-pyranyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 87) (yield, 1.0 g; 36%), the second gives 4-(tetrahydro-2-pyranyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 88) (yield, 0.8 g; 40%) and the third gives 2-(tetrahydro-2-pyranyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 100) (yield, 0.6 g; 30%). Compound Nos. 87 and 88 melt at 32° C. and 116° C., respectively. concentrated in vacuo The residue is column-chromatographed over silica gel using a mixture of acetone/n-hexane (1/3) as an eluent

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

Procedure: 3,5-Bis(trimethylsilyloxy)-1,2,4-triazine (2.5 g) and 2-chlorotetrahydropyran (1.8 g) are dissolved in dimethylformamide (1 ml), and the mixture is stirred overnight at room temperature and concentrated in vacuo. The residue is column-chromatographed over silica gel using a mixture of acetone/n-hexane (1/3) as an eluent. The first major fraction gives 1.0 g (40%) of 2,4-bis(tetrahydro-2-pyranyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 87) (yield, 1.0 g; 36%), the second gives 4-(tetrahydro-2-pyranyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 88) (yield, 0.8 g; 40%) and the third gives 2-(tetrahydro-2-pyranyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 100) (yield, 0.6 g; 30%). Compound Nos. 87 and 88 melt at 32° C. and 116° C., respectively. concentrated in vacuo The residue is column-chromatographed over silica gel using a mixture of acetone/n-hexane (1/3) as an eluent

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of imidazole (81.6 g, 1.2 mol) in dry THF (2.5 L) was slowly added NaH (86.4 g, 3.6 mol) in small portions at −78° C. After all NaH was added, the mixture was stirred at −78° C. for 30 min, and 2-chloro-tetrahydropyran solution, prepared by hydrogen chloride gas treatment of dihydropyran, was added to the reaction mixture dropwise. The mixture was slowly warmed to r.t. and it was stirred at r.t. for 2 h. Methanol was added to quench the excess NaH. The mixture was concentrated with a rotary evaporator. Water was added and it was extract with EtOAc (500 mL×3), dried over MgSO4, and purified by neutral Al2O3 column chromatography (petroleum ether 5 L, petroleum ether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc). The last four fractions were pooled and concentrated to give 1-(tetrahydro-pyran-2-yl)-1H-imidazole (140 g, 76%). 1H NMR (CDCl3): δ 7.65 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 5.20 (dd, J=2.6, 9.5 Hz, 1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.01-1.89 (m, 3H), 1.69-1.60 (m, 3H) at −78° C was added to the reaction mixture dropwise The mixture was slowly warmed to r.t. it was stirred at r.t. for 2 h to quench the excess NaH The mixture was concentrated with a rotary evaporator Water was added it was extract with EtOAc (500 mL×3) dried over MgSO4 purified by neutral Al2O3 column chromatography (petroleum ether 5 L, petroleum ether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc) concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of imidazole (81.6 g, 1.2 mol) in dry THF (2.5 L) was slowly added NaH (86.4 g, 3.6 mol) in small portions at −78° C. After all NaH was added, the mixture was stirred at −78° C. for 30 min, and 2-chloro-tetrahydropyran solution, prepared by hydrogen chloride gas treatment of dihydropyran, was added to the reaction mixture dropwise. The mixture was slowly warmed to r.t. and it was stirred at r.t. for 2 h. Methanol was added to quench the excess NaH. The mixture was concentrated with a rotary evaporator. Water was added and it was extract with EtOAc (500 mL×3), dried over MgSO4, and purified by neutral Al2O3 column chromatography (petroleum ether 5 L, petroleum ether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc). The last four fractions were pooled and concentrated to give 1-(tetrahydro-pyran-2-yl)-1H-imidazole (140 g, 76%). 1H NMR (CDCl3): δ 7.65 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 5.20 (dd, J=2.6, 9.5 Hz, 1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.01-1.89 (m, 3H), 1.69-1.60 (m, 3H) at −78° C was added to the reaction mixture dropwise The mixture was slowly warmed to r.t. it was stirred at r.t. for 2 h to quench the excess NaH The mixture was concentrated with a rotary evaporator Water was added it was extract with EtOAc (500 mL×3) dried over MgSO4 purified by neutral Al2O3 column chromatography (petroleum ether 5 L, petroleum ether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc) concentrated

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

Procedure: The compound is prepared in analogy to compound (204) from tert-butyl-(dimethyl-tert-butylaminocarbonyl-methyl)-hydroxylamine and 2-chlor-tetrahydropyrane in 33% yield as colorless oil.

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of imidazole (81.6 g, 1.2 mol) in dry THF (2.5 L) was slowly added NaH (86.4 g, 3.6 mol) in small portions at −78° C. After all NaH was added, the mixture was stirred at −78° C. for 30 min, and 2-chloro-tetrahydropyran solution, prepared by hydrogen chloride gas treatment of dihydropyran, was added to the reaction mixture dropwise. The mixture was slowly warmed to r.t. and it was stirred at r.t. for 2 h. Methanol was added to quench the excess NaH. The mixture was concentrated with a rotary evaporator. Water was added and it was extract with EtOAc (500 mL×3), dried over MgSO4, and purified by neutral Al2O3 column chromatography (petroleum ether 5 L, petroleum ether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc). The last four fractions were pooled and concentrated to give 1-(tetrahydro-pyran-2-yl)-1H-imidazole (140 g, 76%). 1H NMR (CDCl3): δ 7.65 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 5.20 (dd, J=2.6, 9.5 Hz, 1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.01-1.89 (m, 3H), 1.69-1.60 (m, 3H) at −78° C was added to the reaction mixture dropwise The mixture was slowly warmed to r.t. it was stirred at r.t. for 2 h to quench the excess NaH The mixture was concentrated with a rotary evaporator Water was added it was extract with EtOAc (500 mL×3) dried over MgSO4 purified by neutral Al2O3 column chromatography (petroleum ether 5 L, petroleum ether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc) concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of imidazole (81.6 g, 1.2 mol) in dry THF (2.5 L) was slowly added NaH (86.4 g, 3.6 mol) in small portions at −78° C. After all NaH was added, the mixture was stirred at −78° C. for 30 min, and 2-chloro-tetrahydropyran solution, prepared by hydrogen chloride gas treatment of dihydropyran, was added to the reaction mixture dropwise. The mixture was slowly warmed to r.t. and it was stirred at r.t. for 2 h. Methanol was added to quench the excess NaH. The mixture was concentrated with a rotary evaporator. Water was added and it was extract with EtOAc (500 mL×3), dried over MgSO4, and purified by neutral Al2O3 column chromatography (petroleum ether 5 L, petroleum ether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc). The last four fractions were pooled and concentrated to give 1-(tetrahydro-pyran-2-yl)-1H-imidazole (140 g, 76%). 1H NMR (CDCl3): δ 7.65 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 5.20 (dd, J=2.6, 9.5 Hz, 1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.01-1.89 (m, 3H), 1.69-1.60 (m, 3H) at −78° C was added to the reaction mixture dropwise The mixture was slowly warmed to r.t. it was stirred at r.t. for 2 h to quench the excess NaH The mixture was concentrated with a rotary evaporator Water was added it was extract with EtOAc (500 mL×3) dried over MgSO4 purified by neutral Al2O3 column chromatography (petroleum ether 5 L, petroleum ether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc) concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6.3 g of 55% NaH are added, at 0° C., under an argon atmosphere, to 20 g of 5-nitroindole in solution in 200 ml of dimethylformamide. After stirring for 15 minutes at 0° C., 27.1 g of tetrahydropyranyl chloride are added to the reaction mixture. After stirring for 24 hours at room temperature, the reaction mixture is poured onto 1200 ml of ice-cold water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel eluted with a 4/1 (v/v) cyclohexane/ethyl acetate mixture, to provide 19 g of 5-nitro-1-tetrahydropyran-2-ylindole. 1H NMR (DMSO): 1.34-2.12 (m, 6H), 3.67-4.48 (m, 2H), 5.70 (dd, J=2.0, 10.2, 1H), 6.75 (d, J=3.4, 1H), 7.72-7.76 (m, 2H), 8.02 (dd, J=2.2, 9.2, 1H), 8.54 (d, J=2.2, 1H). After stirring for 24 hours at room temperature extracted with ethyl acetate The combined organic phases are dried over sodium sulphate evaporated to dryness The residue is purified by chromatography on a column of silica gel eluted with a 4/1 (v/v) cyclohexane/ethyl acetate mixture

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

Procedure: The compound is prepared in analogy to compound (204) from tert-butyl-(dimethyl-tert-butylaminocarbonyl-methyl)-hydroxylamine and 2-chlor-tetrahydropyrane in 33% yield as colorless oil.

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of imidazole (81.6 g, 1.2 mol) in dry THF (2.5 L) was slowly added NaH (86.4 g, 3.6 mol) in small portions at −78° C. After all NaH was added, the mixture was stirred at −78° C. for 30 min, and 2-chloro-tetrahydropyran solution, prepared by hydrogen chloride gas treatment of dihydropyran, was added to the reaction mixture dropwise. The mixture was slowly warmed to r.t. and it was stirred at r.t. for 2 h. Methanol was added to quench the excess NaH. The mixture was concentrated with a rotary evaporator. Water was added and it was extract with EtOAc (500 mL×3), dried over MgSO4, and purified by neutral Al2O3 column chromatography (petroleum ether 5 L, petroleum ether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc). The last four fractions were pooled and concentrated to give 1-(tetrahydro-pyran-2-yl)-1H-imidazole (140 g, 76%). 1H NMR (CDCl3): δ 7.65 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 5.20 (dd, J=2.6, 9.5 Hz, 1H), 4.05-4.02 (m, 1H), 3.68-3.62 (m, 1H), 2.01-1.89 (m, 3H), 1.69-1.60 (m, 3H) at −78° C was added to the reaction mixture dropwise The mixture was slowly warmed to r.t. it was stirred at r.t. for 2 h to quench the excess NaH The mixture was concentrated with a rotary evaporator Water was added it was extract with EtOAc (500 mL×3) dried over MgSO4 purified by neutral Al2O3 column chromatography (petroleum ether 5 L, petroleum ether:CH2Cl2=10:1, petroleum ether:CH2Cl2=3:1, CH2Cl2 and EtOAc) concentrated