1,4-dithiane-2,5-diol

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

Procedure: 100.0 g of dimethyl 1,3-acetonedicarboxylate was dissolved in 2,800 ml of dioxane, and added thereto were 52.5 g of 2,5-dihydroxy-1,4-dithiane and 5.0 g of lithium bromide. The resulting mixture was refluxed for 15 hours, cooled to room temperature, and concentrated by evaporation. To the residue, 1,000 ml of n-hexane was added, stirred, and the hexane layer was separated. This extraction procedure was repeated twice using 500 ml portions of n-hexane. The separated n-hexane layers were combined and concentrated under reduced pressure to obtain 60.9 g (yield of 49%) of the title compound as an oil, which was directly used in the next step without any purification. An analytical sample of the title compound could be obtained by vacuum distillation. added The resulting mixture was refluxed for 15 hours concentrated by evaporation To the residue, 1,000 ml of n-hexane was added the hexane layer was separated This extraction procedure concentrated under reduced pressure

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

Procedure: 100.0 g of dimethyl 1,3-acetonedicarboxylate was dissolved in 2,800 ml of dioxane, and added thereto were 52.5 g of 2,5-dihydroxy-1,4-dithiane and 5.0 g of lithium bromide. The resulting mixture was refluxed for 15 hours, cooled to room temperature, and concentrated by evaporation. To the residue, 1,000 ml of n-hexane was added, stirred, and the hexane layer was separated. This extraction procedure was repeated twice using 500 ml portions of n-hexane. The separated n-hexane layers were combined and concentrated under reduced pressure to obtain 60.9 g (yield of 49%) of the title compound as an oil, which was directly used in the next step without any purification. An analytical sample of the title compound could be obtained by vacuum distillation. added The resulting mixture was refluxed for 15 hours concentrated by evaporation To the residue, 1,000 ml of n-hexane was added the hexane layer was separated This extraction procedure concentrated under reduced pressure

Conditions: temp:37.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,5-Dihydroxy-1,4-dithiane (76 g) and cyanoacetamide (84 g) were added to a mixture of methanol (180 mL), water (10 mL) and triethylamine (10 g). The resulting mixture was heated at 35-40° C. for about 30 minutes while stirring, and then heated to 50-60° C. for an additional 30 minutes with stirring. The reaction mixture was then cooled to room temperature and poured into a mixture of ice (100 g)/water (360 mL). A fine precipitate formed upon addition, which was filtered and dried overnight to give 100.6 g of the title compound as a pale gray powder ((M+H)+=143, M.P.=159.0-159.6° C.). heated to 50-60° C. for an additional 30 minutes with stirring The reaction mixture was then cooled to room temperature A fine precipitate formed upon addition, which was filtered dried overnight

Conditions: temp:37.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2,5-Dihydroxy-1,4-dithiane (76 g) and cyanoacetamide (84 g) were added to a mixture of methanol (180 mL), water (10 mL) and triethylamine (10 g). The resulting mixture was heated at 35-40° C. for about 30 minutes while stirring, and then heated to 50-60° C. for an additional 30 minutes with stirring. The reaction mixture was then cooled to room temperature and poured into a mixture of ice (100 g)/water (360 mL). A fine precipitate formed upon addition, which was filtered and dried overnight to give 100.6 g of the title compound as a pale gray powder ((M+H)+=143, M.P.=159.0-159.6° C.). heated to 50-60° C. for an additional 30 minutes with stirring The reaction mixture was then cooled to room temperature A fine precipitate formed upon addition, which was filtered dried overnight

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-fluorobenzoylacetonitrile (2.84 g), 2,5-dihydroxy-1,4-dithian (1.31 g), triethylamine (2.2 ml) and ethanol (15 ml) was stirred for 40 minutes at 50° C. The reaction mixture was cooled to give 2-amino-3-(4-fluorobenzoyl)thiophene as yellow crystals (2.22 g). The reaction mixture was cooled

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl cyanoacetate (3.25 g, 32.3 mmol), 1,4 dithiane-2,5 diol (5 g, 32.8 mmol), triethylamine (1 mL, 7.71 mmol) in EtOH (50 mL) is stirred at 40° C. for 1 h. The cooled solution is eluted through a silica plug with CH2Cl2. The filtrate is stripped to dryness to give crude methyl 2-aminothiophene-3-carboxylate which is carried on to the next reaction. 1H NMR (DMSO) δ 7.26 (1H, s), 6.82 (1H, d, J=5.8 Hz), 6.28 (1H, d, J=5.8 Hz), 3.69 (3H, s). The cooled solution is eluted through a silica plug with CH2Cl2

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,4-dithian-2,5-diol (4.56 g, 30 mmole) and 2-cyanoacetamide (2.52 g, 30 mmole) were combined in ethanol (50 ml). Triethylamine (6 ml) was added and heated to 70° C. for 1 hour. The volume of solvent was reduced under vacuum, and the product was isolated by filtration. Product was recrystallized from ethanol to give 2.71 g of product (yield 64%). the product was isolated by filtration Product was recrystallized from ethanol

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,4-dithian-2,5-diol (4.56 g, 30 mmole) and 2-cyanoacetamide (2.52 g, 30 mmole) were combined in ethanol (50 ml). Triethylamine (6 ml) was added and heated to 70° C. for 1 hour. The volume of solvent was reduced under vacuum, and the product was isolated by filtration. Product was recrystallized from ethanol to give 2.71 g of product (yield 64%). the product was isolated by filtration Product was recrystallized from ethanol

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2,5-dihydroxy-1,4-dithiane (25 g) and cyanoacetamide (19.3 g) in ethanol (120 mL) was stirred and heated to 50° C. Triethylamine (9.2 ml) was added over 15 minutes and the mixture was stirred at 50° C. for a further 2 h. After ice cooling the solid was filtered off and dried (21.4 g). the mixture was stirred at 50° C. for a further 2 h After ice cooling the solid was filtered off dried (21.4 g)

Conditions: temp:37.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,4-Dithiane-2,5-diol (50 g, 328 mmol), and cyanoacetamide (55.2 g, 657 mmol) were added to a mixture of MeOH (150 mL), water (9 mL) and TEA (6.5 g, 50 mmol). The resulting mixture was heated at about 35-40° C. for 30 minutes while stirring, and then heated to about 50-60° C. for an additional 30 minutes with stirring. The reaction mixture was then cooled to RT and poured into a mixture of ice (70 g)/water (200 mL). A fine precipitate formed upon addition, which was filtered and dried overnight to give (66.7 g) of the title compound. MS (ES+): 143 (M+H)+. heated to about 50-60° C. for an additional 30 minutes with stirring The reaction mixture was then cooled to RT A fine precipitate formed upon addition, which was filtered dried overnight

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (1.331 mL, 9.55 mmol) was added with stirring to a solution of methyl 4-(2-cyanoacetyl)benzoate (4.85 g, 23.87 mmol) and 1,4-dithiane-2,5-diol (1.817 g, 11.93 mmol) in dimethylformamide (10 mL), to give a yellow solution. After 15 min, the solution was heated to 60° C. for 2 hours and stirred at room temperature overnight. Water (50 mL), ethyl acetate (50 mL), and glacial acetic acid (ca. 1-3 mL) were added to the oily residue until the organic layer became clear. After separation of the organic layer and further extraction of the aqueous layer with ethyl acetate (50 mL), the combined organic layers were washed subsequently with 5% aqueous NaHCO3 and H2O, dried over anhydrous MgSO4. The solvent was removed and the residue was purified via ISCO (0-50% EtOAc/Hexanes; 80 g silica gel column) to afford title compound 491 (3.7 g, 59%) as a yellow solid. MS (m/z): 357.4 (M+H). to give a yellow solution After separation of the organic layer and further extraction of the aqueous layer with ethyl acetate (50 mL) the combined organic layers were washed subsequently with 5% aqueous NaHCO3 and H2O dried over anhydrous MgSO4 The solvent was removed the residue was purified via ISCO (0-50% EtOAc/Hexanes; 80 g silica gel column)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2,5-dihydroxy-1,4-dithiane (11.8 g, 155 mmol), cyanoacetamide (17.0 g, 202 mmol) and triethylamine (20 ml) in ethanol (100 mL) was stirred under heating at 70° C. for 4 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to an about half volume. Water was added to the residue, the precipitated insoluble material was collected by filtration, and the solid was washed with water to give 2-amino-3-thiophenecarboxamide as a brown powder (15.3 g, 69%). The reaction mixture was cooled to room temperature concentrated under reduced pressure to an about half volume Water was added to the residue the precipitated insoluble material was collected by filtration the solid was washed with water