sodium;acetate;hydrate

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

Procedure: To a solution of 0.85 g of allyl alcohol of step C in 20 mL of anhydrous THF was added a solution of 15 mL of 0.5 N 9-BBN. The reaction was stirred for 2 days. Water (0.5 mL) was added followed with 1 mL of 30% H2O2 and 1 mL of NaOAc/water. After being stirred for 1 h, the organic phase was separated. The water solution was neutralized with HCl and extracted with EtOAc twice. The combined organic phase was dried over Na2SO4. Solvent was removed under vacuum. Column chromatography on silica gel using pure EtOAc as eluent provided 0.80 g of the title compound. MS (M+H)+ 395. After being stirred for 1 h the organic phase was separated extracted with EtOAc twice The combined organic phase was dried over Na2SO4 Solvent was removed under vacuum

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 309c (120 mg, 0.30 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (240 mg, 0.60 mmol), K3PO4 (127 mg, 0.60 mmol), sodium acetate monohydrate (82 mg, 0.60 mmol), Pd(dppf)Cl2 (12 mg, 0.015 mmol), and acetonitrile/water (8/0.5 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 2 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane (20 mL) and water (10 mL). The water layer was extracted with dichloromethane (2×10 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 309d (150 mg, 74%) as yellow solid. MS-ESI: [M+H]+ 668.9 A 25-mL round-bottomed flask equipped with a reflux condenser flush The reaction mixture was cooled to room temperature concentrated under reduced pressure The residue was partitioned between dichloromethane (20 mL) and water (10 mL) The water layer was extracted with dichloromethane (2×10 mL) The combined organic extract was dried over Na2SO4 filtered concentrated under reduced pressure The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1)

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

Procedure: To a solution of 0.85 g of allyl alcohol of step C in 20 mL of anhydrous THF was added a solution of 15 mL of 0.5 N 9-BBN. The reaction was stirred for 2 days. Water (0.5 mL) was added followed with 1 mL of 30% H2O2 and 1 mL of NaOAc/water. After being stirred for 1 h, the organic phase was separated. The water solution was neutralized with HCl and extracted with EtOAc twice. The combined organic phase was dried over Na2SO4. Solvent was removed under vacuum. Column chromatography on silica gel using pure EtOAc as eluent provided 0.80 g of the title compound. MS (M+H)+ 395. After being stirred for 1 h the organic phase was separated extracted with EtOAc twice The combined organic phase was dried over Na2SO4 Solvent was removed under vacuum

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

Procedure: To a solution of 0.85 g of allyl alcohol of step C in 20 mL of anhydrous THF was added a solution of 15 mL of 0.5 N 9-BBN. The reaction was stirred for 2 days. Water (0.5 mL) was added followed with 1 mL of 30% H2O2 and 1 mL of NaOAc/water. After being stirred for 1 h, the organic phase was separated. The water solution was neutralized with HCl and extracted with EtOAc twice. The combined organic phase was dried over Na2SO4. Solvent was removed under vacuum. Column chromatography on silica gel using pure EtOAc as eluent provided 0.80 g of the title compound. MS (M+H)+ 395. After being stirred for 1 h the organic phase was separated extracted with EtOAc twice The combined organic phase was dried over Na2SO4 Solvent was removed under vacuum

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

Procedure: A mixture of 6.5 ml (70 mmol) of phosphorus oxychloride and 9.3 ml (70 mmol) of N-methylformanilide was stirred at ambient temperature. The resulting mixture was diluted with 90 ml of 1,2-dichloroethane, treated with 15.0 g (59.8 mmol) of benzyl indole-2-carboxylate, and heated at reflux for 1 h. After being allowed to cool for 5 min, the warm solution was poured into an ice-cold solution of 60 g of sodium acetate hydrate in 200 ml of water. The resulting mixture was stirred for 1 h, filtered, and the yellow solid was washed twice with water and twice with ether, and air-dried. The filtrate was treated with 400 ml of hexane and filtered. The combined solids were digested with hot ethyl acetate, cooled to 0° C., and filtered to give 13.41 g (80%) of the desired compound as an off-white solid. 1H NMR (CDCl3 /CD3OD) δ 5.50 (s,2H), 7.3-7.55 (m, 8H), 8.38 (d,J=9 Hz,1H). Mass spectrum: (M+H)+ =280. heated at reflux for 1 h to cool for 5 min The resulting mixture was stirred for 1 h filtered the yellow solid was washed twice with water and twice with ether air-dried The filtrate was treated with 400 ml of hexane filtered cooled to 0° C. filtered

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

Procedure: To 56.4 g (0.323 mole) of benzamidine hydrochloride hydrate in 200 ml of warm water is added with vigorous stirring 40 ml of biacetyl. Within a few minutes a heavy precipitate forms and 150 ml of isopropyl alcohol is added followed by 5.0 g of sodium acetate hydrate dissolved in 15 ml of warm water. Stirring is continued for 4 hours after which time the product, 4,5-dimethyl-2-phenylimidazoline-4,5-diol hydrochloride, is filtered off and washed with isopropyl alcohol. Recrystallization from 95% ethanol gives the pure product, m.p. 162°-165° C (dec.). after which time the product, 4,5-dimethyl-2-phenylimidazoline-4,5-diol hydrochloride, is filtered off washed with isopropyl alcohol Recrystallization from 95% ethanol gives the pure product, m.p. 162°-165° C (dec.)

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

Procedure: Ethyl 4-chloro-3-oxo-2-n-propoxyiminobutyrate (syn isomer) (15.4 g.), thiourea (4.97 g.) and sodium acetate hydrate (8.89 g.) were dissolved in a mixture of water (40 ml.) and ethanol (50 ml.), and stirred at 40° C. for an hour. The reaction mixture was adjusted to pH6.5 with a saturated aqueous solution of potassium carbonate under cooling and stirred at the same temperature for half an hour. The precipitating crystals were collected by filtration, washed with water and diisopropyl ether, and then dried to give crystalline ethyl 2-n-propoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (10.55 g.), mp 142° to 144° C. under cooling stirred at the same temperature for half an hour The precipitating crystals were collected by filtration washed with water and diisopropyl ether dried

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

Procedure: Ethyl 4-chloro-3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.), thiourea (4.97 g.) and sodium acetate hydrate (8.89 g.) were dissolved in a mixture of water (40 ml.) and ethanol (50 ml.), and stirred at 40° C. for an hour. The reaction mixture was adjusted to pH 6.5 with a saturated aqueous solution of potassium carbonate under cooling and stirred at the same temperature for half an hour. The precipitating crystals were collected by filtration, washed with water and diisopropyl ether, and then dried to give crystalline ethyl 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetate (syn isomer, 10.55 g.), mp 142°-144° C. under cooling stirred at the same temperature for half an hour The precipitating crystals were collected by filtration washed with water and diisopropyl ether dried

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

Procedure: Ethyl 4-chloro-3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.), thiourea (4.97 g.) and sodium acetate hydrate (8.89 g.) were dissolved in a mixture of water (40 ml.) and ethanol (50 ml.), and stirred at 40° C. for an hour. The reaction mixture was adjusted to pH 6.5 with a saturated aqueous solution of potassium carbonate under cooling and stirred at the same temperature for half an hour. The precipitating crystals were collected by filtration, washed with water and diisopropyl ether, and then dried to give crystalline ethyl 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetate (syn isomer, 10.55 g.), mp 142°-144° C. under cooling stirred at the same temperature for half an hour The precipitating crystals were collected by filtration washed with water and diisopropyl ether dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 309c (120 mg, 0.30 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (240 mg, 0.60 mmol), K3PO4 (127 mg, 0.60 mmol), sodium acetate monohydrate (82 mg, 0.60 mmol), Pd(dppf)Cl2 (12 mg, 0.015 mmol), and acetonitrile/water (8/0.5 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 2 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane (20 mL) and water (10 mL). The water layer was extracted with dichloromethane (2×10 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 309d (150 mg, 74%) as yellow solid. MS-ESI: [M+H]+ 668.9 A 25-mL round-bottomed flask equipped with a reflux condenser flush The reaction mixture was cooled to room temperature concentrated under reduced pressure The residue was partitioned between dichloromethane (20 mL) and water (10 mL) The water layer was extracted with dichloromethane (2×10 mL) The combined organic extract was dried over Na2SO4 filtered concentrated under reduced pressure The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 309c (120 mg, 0.30 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (240 mg, 0.60 mmol), K3PO4 (127 mg, 0.60 mmol), sodium acetate monohydrate (82 mg, 0.60 mmol), Pd(dppf)Cl2 (12 mg, 0.015 mmol), and acetonitrile/water (8/0.5 mL). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 2 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane (20 mL) and water (10 mL). The water layer was extracted with dichloromethane (2×10 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1) to afford 309d (150 mg, 74%) as yellow solid. MS-ESI: [M+H]+ 668.9 A 25-mL round-bottomed flask equipped with a reflux condenser flush The reaction mixture was cooled to room temperature concentrated under reduced pressure The residue was partitioned between dichloromethane (20 mL) and water (10 mL) The water layer was extracted with dichloromethane (2×10 mL) The combined organic extract was dried over Na2SO4 filtered concentrated under reduced pressure The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 30:1)

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

Procedure: Ethyl 4-chloro-3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.), thiourea (4.97 g.) and sodium acetate hydrate (8.89 g.) were dissolved in a mixture of water (40 ml.) and ethanol (50 ml.), and stirred at 40° C. for an hour. The reaction mixture was adjusted to pH 6.5 with a saturated aqueous solution of potassium carbonate under cooling and stirred at the same temperature for half an hour. The precipitating crystals were collected by filtration, washed with water and diisopropyl ether, and then dried to give crystalline ethyl 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetate (syn isomer, 10.55 g.), mp 142°-144° C. under cooling stirred at the same temperature for half an hour The precipitating crystals were collected by filtration washed with water and diisopropyl ether dried