(1-hydroxy-2-methylpropan-2-yl)thiourea

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

Procedure: A mixture of 0.67 g (5.0 mmol) of 1-(1-hydroxy-2-methylpropan-2-yl)thiourea and 1.60 g (5.00 mmol) of 4,8-dibromo-3,4-dihydro-2Hbenzo[b]oxepin-5-one in 30 ml of ethanol was heated under reflux for 3 hours. The mixture was concentrated, the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane. Yield 1.38 g (75%). MS(ESI+): 369.3 was heated under reflux for 3 hours The mixture was concentrated the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane

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

Procedure: A mixture of 0.67 g (5.0 mmol) of 1-(1-hydroxy-2-methylpropan-2-yl)thiourea and 1.60 g (5.00 mmol) of 4,8-dibromo-3,4-dihydro-2Hbenzo[b]oxepin-5-one in 30 ml of ethanol was heated under reflux for 3 hours. The mixture was concentrated, the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane. Yield 1.38 g (75%). MS(ESI+): 369.3 was heated under reflux for 3 hours The mixture was concentrated the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane

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

Procedure: A mixture of 0.67 g (5.0 mmol) of 1-(1-hydroxy-2-methylpropan-2-yl)thiourea and 1.60 g (5.00 mmol) of 4,8-dibromo-3,4-dihydro-2Hbenzo[b]oxepin-5-one in 30 ml of ethanol was heated under reflux for 3 hours. The mixture was concentrated, the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane. Yield 1.38 g (75%). MS (ESI+): 369.3 was heated under reflux for 3 hours The mixture was concentrated the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane

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

Procedure: A mixture of 0.67 g (5.0 mmol) of 1-(1-hydroxy-2-methylpropan-2-yl)thiourea and 1.60 g (5.00 mmol) of 4,8-dibromo-3,4-dihydro-2Hbenzo[b]oxepin-5-one in 30 ml of ethanol was heated under reflux for 3 hours. The mixture was concentrated, the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane. Yield 1.38 g (75%). MS(ESI+): 369.3 was heated under reflux for 3 hours The mixture was concentrated the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane

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

Procedure: A mixture of 0.67 g (5.0 mmol) of 1-(1-hydroxy-2-methylpropan-2-yl)thiourea and 1.60 g (5.00 mmol) of 4,8-dibromo-3,4-dihydro-2Hbenzo[b]oxepin-5-one in 30 ml of ethanol was heated under reflux for 3 hours. The mixture was concentrated, the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane. Yield 1.38 g (75%). MS (ESI+): 369.3 was heated under reflux for 3 hours The mixture was concentrated the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane

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

Procedure: A mixture of 0.67 g (5.0 mmol) of 1-(1-hydroxy-2-methylpropan-2-yl)thiourea and 1.60 g (5.00 mmol) of 4,8-dibromo-3,4-dihydro-2Hbenzo[b]oxepin-5-one in 30 ml of ethanol was heated under reflux for 3 hours. The mixture was concentrated, the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane. Yield 1.38 g (75%). MS (ESI+): 369.3 was heated under reflux for 3 hours The mixture was concentrated the residue purified on silica gel column eluting the product with 10% of methanol in dichloromethane

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

Procedure: This compound was prepared in the same manner as described in step 3 of Example 6. 4-(2-bromoacetyl)benzonitrile (1.7 g, 7.4 mmol) and N-(2-hydroxy-1,1-dimethylethyl)thiourea (1.1 g, 7.4 mmol), prepared in step 2 of Example 3, were heated to reflux in 45 mL of ethanol for 30 min. The reaction mixture was cooled to room temperature and the crude product was collected by suction filtration to give 4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (2.0 g, 100%), MS (ES) m/z 274 [M+H]+. No further purification was performed on this compound. This compound was prepared in the same manner were heated the crude product was collected by suction filtration

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

Procedure: The above prepared 2:1 mixture of 5-(2-bromo-acetyl)-1-methyl-1H-pyrrole-3-carbonitrile and 5-acetyl-1-methyl-1H-pyrrole-3-carbonitrile in ethanol (50 mL) was treated with N-(2-Hydroxy-1,1-dimethylethyl)thiourea, prepared in step 2 of Example 52, and heated under reflux. The mixture was filtered while still hot, and the precipitate washed with ethanol, and then partitioned between 1 N sodium carbonate and ethyl acetate. The organic layer was washed with water, dried (anhydrous MgSO4) and evaporated to afford 5-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}-1-methyl-1H-pyrrole-3-carbonitrile (1.10 g, 3.98 mmol), as a yellow oil. ANLC 100% at 210-370 nm, 7.8 min; 100% at 248 nm, 7.8 min, the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C13H16N4OS [M+H]+, 277.11176; found (ESI, [M+H]+), 277.1126. The above prepared prepared in step 2 of Example 52 heated under reflux The mixture was filtered while still hot, and the precipitate washed with ethanol partitioned between 1 N sodium carbonate and ethyl acetate The organic layer was washed with water dried (anhydrous MgSO4) evaporated

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

Procedure: N-(2-Hydroxy-1,1-dimethylethyl)thiourea (0.75 g, 5 mmol), prepared in step 2 of Example 52, was added to 4-(2-bromo-acetyl)-1-methyl-1H-pyrrole-2-carbonitrile (1.15 g, 5 mmol), prepared in the previous step, in ethanol (20 mL) and the mixture was heated under reflux. After 2 h, the reaction was cooled to room temperature, the precipitate was collected, washed with ethanol, suspended in water and made basic with a 1 N sodium carbonate solution. The mixture was extracted with ethyl acetate, the organic layer was then washed with a 1 N sodium carbonate solution, water, dried (anhydrous MgSO4) and evaporated to afford 4-[2-(2-hydroxy-1,1-dimethyl-ethylamino)-thiazol-4-yl]-1-methyl-1H-pyrrole-2-carbonitrile (0.92 g, 67%), which was used without further characterization. the mixture was heated under reflux the precipitate was collected washed with ethanol The mixture was extracted with ethyl acetate the organic layer was then washed with a 1 N sodium carbonate solution, water dried (anhydrous MgSO4) evaporated

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

Procedure: This compound was prepared in the same manner as described in step 3 of Example 81. 4-(2-bromoacetyl)benzonitrile (1.7 g, 7.4 mmol) and N-(2-hydroxy-1,1-dimethylethyl)thiourea (1.1 g, 7.4 mmol), prepared in step 2 of Example 52, were heated to reflux in 45 mL of ethanol for 30 min. The reaction mixture was cooled to room temperature and the crude product was collected by suction filtration to give 4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}benzonitrile (2.0 g, 100%), MS (ES) m/z 274 [M+H]+. No further purification was performed on this compound. This compound was prepared in the same manner were heated the crude product was collected by suction filtration

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

Procedure: A mixture of 4-(chloroacetyl)thiophene-2-carbonitrile (500.5 mg, 2.73 mmol), prepared in step 1 of Example 59, and N-(2-hydroxy-1,1-dimethylethyl)thiourea (399.4 mg, 2.69 mmol), prepared in step 2 of Example 52, in 20 mL of ethanol was stirred under nitrogen at room temperature overnight. The solid was collected by filtration and dried under reduced pressure to give 4-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}thiophene-2-carbonitrile hydrochloride (738.1 mg, 86%) as a light tan solid, mp 197-201° C.; MS (ES) m/z 277.9 [M−H]−. The solid was collected by filtration dried under reduced pressure

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

Procedure: A mixture of 4-bromo-5-(chloroacetyl)thiophene-2-carbonitrile (430 mg, 1.6 mmol), prepared in the previous step, and N-(2-hydroxy-1,1-dimethylethyl)thiourea (241.2 mg, 1.6 mmol), prepared in step 2 of Example 52, in 10 mL of absolute ethanol was refluxed under nitrogen for 2.5 h. The solvent was concentrated to approximately two thirds its volume. The solid present was collected by filtration and dried under reduced pressure to give 4-bromo-5-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}thiophene-2-carbonitrile hydrochloride (367.8 mg, 58%) as a yellow solid, mp 177.5-178.5° C.; MS (ESI) m/z 358 [M+H]+. was refluxed under nitrogen for 2.5 h The solvent was concentrated to approximately two thirds its volume The solid present was collected by filtration dried under reduced pressure