3-(4-methoxyphenyl)propanal

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

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

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

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

Procedure: To a solution of 964 mg (3.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 657 mg (4.0 mmol) of 3-(4-methoxyphenyl)-1-propanal in 20 ml of ethanol, 26 mg (0.3 mmol) of piperidine was added, followed by refluxing for 3.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in dichloromethane, washed with purified water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform/methanol=50/1) to yield 1.08 g (76.8%, yellow oily substance) of the desired product. by refluxing for 3.5 hours After the reaction mixture was cooled the solvent was distilled off The residue was dissolved in dichloromethane washed with purified water dried after which the solvent was distilled off The residue was purified by column chromatography (eluent, chloroform/methanol=50/1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4-Methoxy-phenyl)-propionic acid (9a, 1.80 g, 10.0 mmol) in toluene (25.0 mL) was cooled to −78° C. in dry ice-acetone bath for 5-10 minutes under N2. DIBAL-H (11.0 mmol) was slowly added by syringe and stirred for 2 hours at −78° C. Then, the reaction mixture was poured quickly into an aqueous NH4Cl solution with vigorous stirring. The solution was extracted twice with ether and the organic layer was washed with brine, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to provide 3-(4-methoxy-phenyl)-propionaldehyde (9b, 1.16 g, 7.07 mmol) as yellow oil in 70.7% yield. The solution was extracted twice with ether the organic layer was washed with brine dried over MgSO4(s) concentrated under reduced pressure The residue was purified by column chromatography on silica gel

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

Procedure: A methylene chloride solution (300 mL) of 3-(4-methoxyphenyl)-1-propanol (Aldrich, 15.0 g, 0.090 mol) was cooled to 0° C. and stirred. Pyridinium chlorochromate (Aldrich, 23.4 g, 0.108 mol) was slowly added to the solution which was then warmed to room temperature, placed under a drying tube and stirred over a weekend (approx. 72 hrs.). The reaction mixture was filtered through a pad of Florisil (Aldrich) and the filtrate was concentrated to give the crude product as a dark oil. Purification by flash chromatography (6:1 hexanes:ethyl acetate) gave the desired 3-(4-methoxyphenyl)propionaldehyde as a pale yellow oil. placed under a drying tube stirred over a weekend (approx. 72 hrs.) The reaction mixture was filtered through a pad of Florisil (Aldrich) the filtrate was concentrated to give the crude product as a dark oil Purification by flash chromatography (6:1 hexanes:ethyl acetate)

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

Procedure: 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid ((S)-2-amino-pentyl)-amide hydrochloride (400 mg, 1.467 mmol), 3-(4-methoxyphenyl)propionaldehyde (181 mg, 1.103 mmol) and sodium triacetoxyborohydride (467 mg, 2.205 mmol) are dissolved in DCM (150 mL). The reaction mixture is stirred at reflux overnight. To the reaction mixture is added 1 M NaOH solution (50 mL) and DCM (50 mL). The organic phase is separated and the aqueous phase is extracted once with DCM. The combined organic phases are washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford a yellow solid. Purification by flash column chromatography (SiO2, MeOH:DCM, gradient 2-10%+0.1% TEA) affords the title compound. [M+H]+ 421. at reflux overnight The organic phase is separated the aqueous phase is extracted once with DCM The combined organic phases are washed with brine dried (MgSO4) filtered concentrated in vacuo to afford a yellow solid Purification by flash column chromatography (SiO2, MeOH:DCM, gradient 2-10%+0.1% TEA)

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

Procedure: 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid ((S)-2-amino-pentyl)-amide hydrochloride (400 mg, 1.467 mmol), 3-(4-methoxyphenyl)propionaldehyde (181 mg, 1.103 mmol) and sodium triacetoxyborohydride (467 mg, 2.205 mmol) are dissolved in DCM (150 mL). The reaction mixture is stirred at reflux overnight. To the reaction mixture is added 1 M NaOH solution (50 mL) and DCM (50 mL). The organic phase is separated and the aqueous phase is extracted once with DCM. The combined organic phases are washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford a yellow solid. Purification by flash column chromatography (SiO2, MeOH:DCM, gradient 2-10%+0.1% TEA) affords the title compound. [M+H]+ 421. at reflux overnight The organic phase is separated the aqueous phase is extracted once with DCM The combined organic phases are washed with brine dried (MgSO4) filtered concentrated in vacuo to afford a yellow solid Purification by flash column chromatography (SiO2, MeOH:DCM, gradient 2-10%+0.1% TEA)

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

Procedure: A solution of 3-(4-methoxyphenyl)propan-1-ol (15.02 g) in dichloromethane (100 ml) was added to a stirred suspension of pyridinium chlorochromate (29 g) in dichloromethane (250 ml). The mixture was stirred for 2 hours then filtered through a kieselguhr pad. The residue was washed with ether (3×500 ml) and the combined liquors were evaporated under reduced pressure. The residual oil was purified by vacuum distillation to give the subtitle compound (6.81 g) as an oil. then filtered through a kieselguhr pad The residue was washed with ether (3×500 ml) the combined liquors were evaporated under reduced pressure The residual oil was purified by vacuum distillation

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

Procedure: N-Chlorosuccinimide (980 mg, 0.0073 mol) was added to a mixture of 3-(4-methoxyphenyl)propanal (1.0 g, 6.1 mmol) and D-proline (40 mg, 0.3 mmol) in dichloromethane (10 mL, 200 mmol) at 0° C. The reaction mixture was warmed to RT after 1 h, quenched with water, and extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes to give the desired product (860 mg). 1H NMR (400 MHz, CDCl3): 9.52 (s, 1H), 7.18 (dd, 2H), 6.84 (dd, 2H), 4.36 (m, 1H), 3.80 (s, 3H), 3.32 (m, 1H), 3.02 (m, 1H). quenched with water extracted with dichloromethane The organic extracts were washed with brine dried over magnesium sulfate filtered concentrated under reduced pressure The residue was purified by flash chromatography eluting with ethyl acetate in hexanes

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

Procedure: N-Chlorosuccinimide (980 mg, 0.0073 mol) was added to a mixture of 3-(4-methoxyphenyl)propanal (1.0 g, 6.1 mmol) and D-proline (40 mg, 0.3 mmol) in dichloromethane (10 mL, 200 mmol) at 0° C. The reaction mixture was warmed to RT after 1 h, quenched with water, and extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes to give the desired product (860 mg). 1H NMR (400 MHz, CDCl3): 9.52 (s, 1H), 7.18 (dd, 2H), 6.84 (dd, 2H), 4.36 (m, 1H), 3.80 (s, 3H), 3.32 (m, 1H), 3.02 (m, 1H). quenched with water extracted with dichloromethane The organic extracts were washed with brine dried over magnesium sulfate filtered concentrated under reduced pressure The residue was purified by flash chromatography eluting with ethyl acetate in hexanes

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of dimethyl sulfoxide (5.1 mL) in dichloromethane (10 ml) was added to a stirred solution of oxalyl chloride (3.0 mL, 36 mmol) in dichloromethane (40 ml) at −78° C. over 30 min. Upon completion of the addition, the mixture was stirred at −78° C. for 5 min, followed by addition of a solution of 4-methoxybenzenepropanol (3.0 g, 18 mmol) in dichloromethane (20 ml) at −78° C. over 30 min. The resulting mixture was stirred at −78° C. for 40 min. Next, triethylamine (15 mL, 110 mmol) was added dropwise over 10 min. The resulting mixture was allowed to warm to 0° C. and stirred at this temperature for 1 hour. It was diluted with dichloromethane (30 mL) and quenched with water (15 mL). The organic extracts were separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in hexanes (gradient: 3 min: 0/100 to 23 min: 20/80) to afford the desired product (1.50 g, 51%). Upon completion of the addition The resulting mixture was stirred at −78° C. for 40 min to warm to 0° C. stirred at this temperature for 1 hour quenched with water (15 mL) The organic extracts were separated washed with water and brine dried over magnesium sulfate filtered concentrated under reduced pressure The residue was purified by flash chromatography eluting with ethyl acetate in hexanes (gradient: 3 min: 0/100 to 23 min: 20/80)