2,2-dimethylpropanimidamide;hydrochloride

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

Procedure: In ethanol (40 mL) was placed t-butylcarbamidine hydrochloride (3.71 g, 27.2 mmol). This was treated with 21% sodium ethoxide in ethanol (8.80 g, 27.2 mmol) and stirred at RT for 15 min. To this was added the diethyl ethoxymethylenemalonate (5.87 g, 27.2 mmol) and the reaction mixture was stirred overnight at RT. The reaction mixture was refluxed for 1 hour and then cooled to RT. The solution was evaporated, the residue dissolved in water (100 mL) and the pH adjusted to 3-4 (wet litmus) with acetic acid. The mixture formed a precipitate. The solid collected by filtration, washed with water (50 mL) and dried in vacuo to obtain ethyl 2-tert-butyl-4-hydroxypyrimidine-5-carboxylate (2.18 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.6 (brs, 1H), 8.44 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 1.25 (s, 9H), 1.23 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 225.0 (M+H+). the reaction mixture was stirred overnight at RT The reaction mixture was refluxed for 1 hour cooled to RT The solution was evaporated the residue dissolved in water (100 mL) The mixture formed a precipitate The solid collected by filtration washed with water (50 mL) dried in vacuo

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

Procedure: In ethanol (40 mL) was placed t-butylcarbamidine hydrochloride (3.71 g, 27.2 mmol). This was treated with 21% sodium ethoxide in ethanol (8.80 g, 27.2 mmol) and stirred at RT for 15 min. To this was added the diethyl ethoxymethylenemalonate (5.87 g, 27.2 mmol) and the reaction mixture was stirred overnight at RT. The reaction mixture was refluxed for 1 hour and then cooled to RT. The solution was evaporated, the residue dissolved in water (100 mL) and the pH adjusted to 3-4 (wet litmus) with acetic acid. The mixture formed a precipitate. The solid collected by filtration, washed with water (50 mL) and dried in vacuo to obtain ethyl 2-tert-butyl-4-hydroxypyrimidine-5-carboxylate (2.18 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.6 (brs, 1H), 8.44 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 1.25 (s, 9H), 1.23 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 225.0 (M+H+). the reaction mixture was stirred overnight at RT The reaction mixture was refluxed for 1 hour cooled to RT The solution was evaporated the residue dissolved in water (100 mL) The mixture formed a precipitate The solid collected by filtration washed with water (50 mL) dried in vacuo

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

Procedure: A single-necked flask containing 80 ml of ethanol is cooled down to 0° C. by an ice bath, 4 g (55.6 mmoles) of sodium ethylate and 3.8 g (27.8 mmoles) of tert-butylcarbamidine hydrochloride are added. The reaction mixture is left to return to ambient temperature, then 5 ml (27.8 mmoles) of diethyl ester methylmalonate is added dropwise. Stirring is maintained at ambient temperature overnight. The ethanol is then condensed under reduced pressure (2 kPa). The crude product obtained is solubilized in a minimum amount of water (approximately 40 ml), then acidified at 0° C. with pure acetic acid until a pH comprised between 4 and 5 is achieved. The white precipitate formed is filtered, rinsed successively with water, ethyl ether and with pentane. Then the white powder obtained is dried over P2O5 under reduced pressure (0.2 kPa). 2.4 g of expected product is obtained. The reaction mixture is left to return to ambient temperature is maintained at ambient temperature overnight condensed under reduced pressure (2 kPa) The crude product obtained The white precipitate formed is filtered rinsed successively with water, ethyl ether and with pentane Then the white powder obtained is dried over P2O5 under reduced pressure (0.2 kPa)

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

Procedure: A solution of 2,4′-dibromoacetophenone (4.17 g, 15.0 mmol) in N,N-dimethylformamide (60.0 mL) was treated with t-butylcarbamidine hydrochloride (2.05 g, 15.0 mmol) and K2CO3 (4.15 g, 30.0 mmol) and heated to 50° C. for 4 h. Following cooling, the reaction was quenched with water, diluted with brine, and extracted thrice with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification via flash column chromatography (10-40% EtOAc/hexanes) gave the title compound as a light yellow solid (3.38 g; 81%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=8.1 Hz, 2 H) 7.46 (d, J=8.6 Hz, 2 H) 7.18 (s, 1 H) 1.42 (s, 9 H). MS(ES+) m/e 279/281 [M+H]+. Following cooling the reaction was quenched with water diluted with brine extracted thrice with EtOAc The organic layer was dried over MgSO4 filtered concentrated in vacuo Purification via flash column chromatography (10-40% EtOAc/hexanes)

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

Procedure: In ethanol (40 mL) was placed t-butylcarbamidine hydrochloride (3.71 g, 27.2 mmol). This was treated with 21% sodium ethoxide in ethanol (8.80 g, 27.2 mmol) and stirred at RT for 15 min. To this was added the diethyl ethoxymethylenemalonate (5.87 g, 27.2 mmol) and the reaction mixture was stirred overnight at RT. The reaction mixture was refluxed for 1 hour and then cooled to RT. The solution was evaporated and the residue was dissolved in water (100 mL) and the pH adjusted to 3-4 (wet litmus) with acetic acid. The mixture formed a precipitate. The solid collected by filtration, washed with water (50 mL) and dried under vacuum to obtain ethyl 2-tert-butyl-4-hydroxypyrimidine-5-carboxylate (2.18 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.6 (brs, 1H), 8.44 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 1.25 (s, 9H), 1.23 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 225.0 (M+H+). the reaction mixture was stirred overnight at RT The reaction mixture was refluxed for 1 hour cooled to RT The solution was evaporated the residue was dissolved in water (100 mL) The mixture formed a precipitate The solid collected by filtration washed with water (50 mL) dried under vacuum

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

Procedure: In ethanol (40 mL) was placed t-butylcarbamidine hydrochloride (3.71 g, 27.2 mmol). This was treated with 21% sodium ethoxide in ethanol (8.80 g, 27.2 mmol) and stirred at RT for 15 min. To this was added the diethyl ethoxymethylenemalonate (5.87 g, 27.2 mmol) and the reaction mixture was stirred overnight at RT. The reaction mixture was refluxed for 1 hour and then cooled to RT. The solution was evaporated and the residue was dissolved in water (100 mL) and the pH adjusted to 3-4 (wet litmus) with acetic acid. The mixture formed a precipitate. The solid collected by filtration, washed with water (50 mL) and dried under vacuum to obtain ethyl 2-tert-butyl-4-hydroxypyrimidine-5-carboxylate (2.18 g, 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.6 (brs, 1H), 8.44 (s, 1H), 4.20 (q, J=7.2 Hz, 2H), 1.25 (s, 9H), 1.23 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 225.0 (M+H+). the reaction mixture was stirred overnight at RT The reaction mixture was refluxed for 1 hour cooled to RT The solution was evaporated the residue was dissolved in water (100 mL) The mixture formed a precipitate The solid collected by filtration washed with water (50 mL) dried under vacuum

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

Procedure: A solution of 2,4′-dibromoacetophenone (4.17 g, 15.0 mmol) in N,N-dimethylformamide (60.0 mL) was treated with t-butylcarbamidine hydrochloride (2.05 g, 15.0 mmol) and K2CO3 (4.15 g, 30.0 mmol) and heated to 50° C. for 4 h. Following cooling, the reaction was quenched with water, diluted with brine, and extracted thrice with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification via flash column chromatography (10-40% EtOAc/hexanes) gave the title compound as a light yellow solid (3.38 g; 81%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=8.1 Hz, 2H) 7.46 (d, J=8.6 Hz, 2H) 7.18 (s, 1H) 1.42 (s, 9H). MS (ES+) m/e 279/281 [M+H]+. Following cooling the reaction was quenched with water diluted with brine extracted thrice with EtOAc The organic layer was dried over MgSO4 filtered concentrated in vacuo Purification via flash column chromatography (10-40% EtOAc/hexanes)

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

Procedure: 2,2-dimethylpropionamidine hydrochloride (0.14 g), prepared according to Example 1, was added to a solution of a 4:3 mixture of ethyl (RS)-4-dimethylamino-3-formyl-2-(1-methylethyl)-3-butenoate and ethyl (RS)-4-ethoxy-3-formyl- 2-(1-methylethyl)-3-butenoate (0.2 g), prepared according to the method of Example 10, in ethanol (2 cm3). A solution of sodium methoxide (0.06 g) in ethanol (1 cm3) was added to the stirred mixture, which was then heated at the reflux temperature for 2 hours. After cooling, the ethanol was evaporated under reduced pressure. The residual oil was purified by column chromatography on a silica gel support (Merck 7729), using dichloromethane, followed by dichloromethane containing 2% by volume ethyl acetate, as eluent, to give ethyl (RS)-2-[2-(2-methylprop-2-yl)pyrimidin-5-yl]-3-methylbutyrate (0.068 g) as a pale yellow oil. prepared was then heated at the reflux temperature for 2 hours After cooling the ethanol was evaporated under reduced pressure The residual oil was purified by column chromatography on a silica gel support (Merck 7729)

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

Procedure: A solution of 2,4′-dibromoacetophenone (4.17 g, 15.0 mmol) in N,N-dimethylformamide (60.0 mL) was treated with t-butylcarbamidine hydrochloride (2.05 g, 15.0 mmol) and K2CO3 (4.15 g, 30.0 mmol) and heated to 50° C. for 4 h. Following cooling, the reaction was quenched with water, diluted with brine, and extracted thrice with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification via flash column chromatography (10-40% EtOAc/hexanes) gave the title compound as a light yellow solid (3.38 g; 81%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=8.1 Hz, 2H) 7.46 (d, J=8.6 Hz, 2H) 7.18 (s, 1H) 1.42 (s, 9H). MS (ES+) m/e 279/281 [M+H]+. Following cooling the reaction was quenched with water diluted with brine extracted thrice with EtOAc The organic layer was dried over MgSO4 filtered concentrated in vacuo Purification via flash column chromatography (10-40% EtOAc/hexanes)

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

Procedure: 2,2-dimethylpropionamidine hydrochloride (0.14 g), prepared according to Example 1, was added to a solution of a 4:3 mixture of ethyl (RS)-4-dimethylamino-3-formyl-2-(1-methylethyl)-3-butenoate and ethyl (RS)-4-ethoxy-3-formyl- 2-(1-methylethyl)-3-butenoate (0.2 g), prepared according to the method of Example 10, in ethanol (2 cm3). A solution of sodium methoxide (0.06 g) in ethanol (1 cm3) was added to the stirred mixture, which was then heated at the reflux temperature for 2 hours. After cooling, the ethanol was evaporated under reduced pressure. The residual oil was purified by column chromatography on a silica gel support (Merck 7729), using dichloromethane, followed by dichloromethane containing 2% by volume ethyl acetate, as eluent, to give ethyl (RS)-2-[2-(2-methylprop-2-yl)pyrimidin-5-yl]-3-methylbutyrate (0.068 g) as a pale yellow oil. prepared was then heated at the reflux temperature for 2 hours After cooling the ethanol was evaporated under reduced pressure The residual oil was purified by column chromatography on a silica gel support (Merck 7729)

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

Procedure: Analogous to Scheme 1, from 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and 2,2-dimethylpropionamidine hydrochloride. Yield: 88%. Off-white solid, m/z (ISP) 302 (MH)

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

Procedure: A mixture of 3-(2-bromoacetyl)benzonitrile (500 mg, 2.23 mmol), tert-butylcarbamidine hydrochloride (610 mg, 4.46 mmol), potassium carbonate (770 mg, 5.58 mmol), and acetonitrile (10 mL) was refluxed for 1 hour. After the reaction was completed, the mixture was left to cool to room temperature. Then, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to give 3-(2-tert-butyl-1H-imidazol-4-yl)benzonitrile (500 mg, 2.22 mmol, yield: 99%). was refluxed for 1 hour the mixture was left the mixture was extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate Then, the solvent was evaporated under reduced pressure