2-(thian-4-yl)acetaldehyde

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

Procedure: 0.44 ml of 4-tert-butylbenzylamine (2.5 mmol) and 541 mg (tetrahydro-thiopyran-4-yl)-acetaldehyde (3.75 mmol) were dissolved in 7.5 ml methanol and stirred for 30 min at rt and then refluxed for 2.5 h. After cooling down to rt, 114 mg (3 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was refluxed for 2¾ h. After cooling down to rt, the reaction mixture was treated with 5 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; EtOAc/heptane 1:2 then EtOAc) to give 632 mg light yellow viscous oil (87%). MS (ISP) 292.3 (M+H)+. refluxed for 2.5 h After cooling down to rt after stirring for 15 min at rt the reaction mixture was refluxed for 2¾ h After cooling down to rt concentrated in vacuo The residue was diluted with water/EtOAc After separation of the organic phase the aqueous phase was extracted with EtOAc the combined organic phases were washed with brine dried with magnesium sulfate filtered off concentrated in vacuo The residue was purified by column chromatography (90 g silica gel

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

Procedure: 0.44 ml of 4-tert-butylbenzylamine (2.5 mmol) and 541 mg (tetrahydro-thiopyran-4-yl)-acetaldehyde (3.75 mmol) were dissolved in 7.5 ml methanol and stirred for 30 min at rt and then refluxed for 2.5 h. After cooling down to rt, 114 mg (3 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was refluxed for 2¾ h. After cooling down to rt, the reaction mixture was treated with 5 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (90 g silica gel; EtOAc/heptane 1:2 then EtOAc) to give 632 mg light yellow viscous oil (87%). MS (ISP) 292.3 (M+H)+. refluxed for 2.5 h After cooling down to rt after stirring for 15 min at rt the reaction mixture was refluxed for 2¾ h After cooling down to rt concentrated in vacuo The residue was diluted with water/EtOAc After separation of the organic phase the aqueous phase was extracted with EtOAc the combined organic phases were washed with brine dried with magnesium sulfate filtered off concentrated in vacuo The residue was purified by column chromatography (90 g silica gel

Conditions: temp:22.01; pressure:0.00; stir:

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

Procedure: To a mixed liquid of 1.40 g of methyl 3-chloro-2-hydrazino-7-methylquinoxaline-6-carboxylate and 28.0 mL of acetic acid was added 820 mg of tetrahydro-2H-thiopyran-4-ylacetaldehyde, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and to the residue was added 28.0 mL of N,N-dimethylformamide, followed by replacement with argon. Then, a mixed liquid of 706 mg of copper(II) chloride and 28.0 mL of N,N-dimethylformamide was added thereto, followed by stirring at 50° C. for 20 minutes and at 100° C. for 1 hour. To the reaction liquid were added water and chloroform, followed by extraction with chloroform, the organic layer was washed with 1 M hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine and, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 600 mg of methyl 4-chloro-8-methyl-1-(tetrahydro-2H-thiopyran-4-ylmethyl)[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate as a brown solid. The solvent was evaporated under reduced pressure to the residue was added 28.0 mL of N,N-dimethylformamide Then, a mixed liquid of 706 mg of copper(II) chloride and 28.0 mL of N,N-dimethylformamide was added by stirring at 50° C. for 20 minutes and at 100° C. for 1 hour To the reaction liquid followed by extraction with chloroform the organic layer was washed with 1 M hydrochloric acid, water a saturated aqueous sodium hydrogen carbonate solution, and saturated brine and, dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (chloroform/methanol)

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

Procedure: The title compound was prepared in analogy to Example 1, replacing (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester with (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (([CAS RN 579474-50-3]), Example 47), cyclohexanecarbaldehyde with tetrahydro-2H-thiopyran-4-acetaldehyde ([CAS RN 372159-78-9]), (3-chloro-phenyl)-acetic acid with DL-cyclohexyl-methoxy-acetic acid ([CAS RN 15540-18-8]) and cyclohexyl isocyanide with cyclopentyl isocyanide ([CAS RN 68498-54-4]). MS (ISP): 536.3 [M+H]+.

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

Procedure: The title compound was prepared in analogy to Example 1, replacing (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester with (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (([CAS RN 579474-50-3]), Example 47), cyclohexanecarbaldehyde with tetrahydro-2H-thiopyran-4-acetaldehyde ([CAS RN 372159-78-9]), (3-chloro-phenyl)-acetic acid with DL- -methoxyphenylacetic acid ([CAS RN 7021-09-2]) and cyclohexyl isocyanide with cyclopentyl isocyanide ([CAS RN 68498-54-4]). MS (ISP): 530.3 [M+H]+.

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

Procedure: The title compound was prepared in analogy to Example 1, replacing (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester with (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (([CAS RN 579474-50-3]), Example 47), cyclohexanecarbaldehyde with tetrahydro-2H-thiopyran-4-acetaldehyde ([CAS RN 372159-78-9]) and (3-chloro-phenyl)-acetic acid with DL-cyclohexyl-methoxy-acetic acid ([CAS RN 15540-18-8]). MS (ISP): 590.3 [M+H]+.

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

Procedure: The title compound was prepared in analogy to Example 1, replacing (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester with (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (([CAS RN 579474-50-3]), Example 47), cyclohexanecarbaldehyde with tetrahydro-2H-thiopyran-4-acetaldehyde ([CAS RN 372159-78-9]) and (3-chloro-phenyl)-acetic acid with DL- -methoxyphenylacetic acid ([CAS RN 7021-09-2]). MS (ISP): 544.3 [M+H]+.

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

Procedure: To a mixed liquid of 1.40 g of methyl 3-chloro-2-hydrazino-7-methylquinoxaline-6-carboxylate and 28.0 mL of acetic acid was added 820 mg of tetrahydro-2H-thiopyran-4-ylacetaldehyde, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and to the residue was added 28.0 mL of N,N-dimethylformamide, followed by replacement with argon. Then, a mixed liquid of 706 mg of copper(II) chloride and 28.0 mL of N,N-dimethylformamide was added thereto, followed by stirring at 50° C. for 20 minutes and at 100° C. for 1 hour. To the reaction liquid were added water and chloroform, followed by extraction with chloroform, the organic layer was washed with 1 M hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine and, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 600 mg of methyl 4-chloro-8-methyl-1-(tetrahydro-2H-thiopyran-4-ylmethyl)[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate as a brown solid. The solvent was evaporated under reduced pressure to the residue was added 28.0 mL of N,N-dimethylformamide Then, a mixed liquid of 706 mg of copper(II) chloride and 28.0 mL of N,N-dimethylformamide was added by stirring at 50° C. for 20 minutes and at 100° C. for 1 hour To the reaction liquid followed by extraction with chloroform the organic layer was washed with 1 M hydrochloric acid, water a saturated aqueous sodium hydrogen carbonate solution, and saturated brine and, dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (chloroform/methanol)

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

Procedure: The title compound was prepared in analogy to Example 1, replacing (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester with (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (([CAS RN 579474-50-3]), Example 47), cyclohexanecarbaldehyde with tetrahydro-2H-thiopyran-4-acetaldehyde ([CAS RN 372159-78-9]), (3-chloro-phenyl)-acetic acid with DL-cyclohexyl-methoxy-acetic acid ([CAS RN 15540-18-8]) and cyclohexyl isocyanide with cyclopentyl isocyanide ([CAS RN 68498-54-4]). MS (ISP): 536.3 [M+H]+.

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

Procedure: The title compound was prepared in analogy to Example 1, replacing (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester with (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (([CAS RN 579474-50-3]), Example 47), cyclohexanecarbaldehyde with tetrahydro-2H-thiopyran-4-acetaldehyde ([CAS RN 372159-78-9]), (3-chloro-phenyl)-acetic acid with DL-α-methoxyphenylacetic acid ([CAS RN 7021-09-2]) and cyclohexyl isocyanide with cyclopentyl isocyanide ([CAS RN 68498-54-4]). MS (ISP): 530.3 [M+H]+.

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

Procedure: The title compound was prepared in analogy to Example 1, replacing (2-amino-4,5-difluoro-phenyl)-carbamic acid tert-butyl ester with (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (([CAS RN 579474-50-3]), Example 47), cyclohexanecarbaldehyde with tetrahydro-2H-thiopyran-4-acetaldehyde ([CAS RN 372159-78-9]) and (3-chloro-phenyl)-acetic acid with DL-cyclohexyl-methoxy-acetic acid ([CAS RN 15540-18-8]). MS (ISP): 590.3 [M+H]+.