2-methylpropanedioyl dichloride

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

Procedure: A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and 500-mL addition funnel. Under nitrogen, the flask is charged with 1-(7-amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone (Intermediate 4, 595 g, 2.61 mol), triethylamine (474 mL, 3.40 mol), and anhydrous acetonitrile (3.5 L). The solution is cooled to 0° C., then methyl malonyl chloride (364 mL, 3.40 mol) is added over 35 min. The cooling bath is removed and the mixture is stirred for 5 h. To the resultant slurry is added 25% sodium methoxide in methanol (596 mL, 2.61 mol) over 10 min. After being stirred at ambient temperature for 2 h, the now very thick yellow slurry is diluted with water (3 L). The precipitate is collected on a Buchner funnel and washed with water (3 L). The yellow solid is dried in vacuo. at 60° C. yielding 9-chloromethyl-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester as a yellow solid. This crude product is used for the next step without further purification. Recrystallization from MeOH-DMSO (1:1) gave an analytical sample: mp>300° C. (dec.). 1H NMR (DMSO-d6, 400 MHz) d 3.85 (s, 3H), 4.32 (s, 2H), 4.36. (s, 2H), 4.83 (s, 2H), 6.83 (s, 1H), 7.40 (s, 2H), 12.0 (s, 1H). Elemental analysis: Calculated for C10H10ClNO3: C, 54.29; H, 3.91; N, 4.52. Found: C, 53.68; H, 3.84; N, 4.48. HRMS (EI+): Calculated for C10H10ClNO3: 309.0404. Found: 309.0405. A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and 500-mL addition funnel The cooling bath is removed After being stirred at ambient temperature for 2 h The precipitate is collected on a Buchner funnel washed with water (3 L) The yellow solid is dried in vacuo

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

Procedure: A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and 500-mL addition funnel. Under nitrogen, the flask is charged with 1-(7-amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone (595 g, 2.61 mol), prepared as in example 13a, triethylamine (474 mL, 3.40 mol), and anhydrous acetonitrile (3.5 L). The solution is cooled to 0° C., then methyl malonyl chloride (364 mL, 3.40 mol) is added over 35 min. The cooling bath is removed and the mixture is stirred for 5 h. To the resultant slurry is added 25% sodium methoxide in methanol (596 mL, 2.61 mol) over 10 min. After being stirred at ambient temperature for 2 h, the now very thick yellow slurry is diluted with water (3 L). The precipitate is collected on a Buchner funnel and washed with water (3 L). The yellow solid is dried in vacuo. at 60° C. yielding 9-chloromethyl-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester as a yellow solid. This crude product is used for the next step without further purification. Recrystallization from MeOH-DMSO (1:1) gave an analytical sample: mp>300° C. (dec.). 1H NMR (DMSO-d6, 400 MHz) δ3.85 (s, 3H), 4.32 (s, 2H), 4.36 (s, 2H), 4.83 (s, 2H), 6.83 (s, 1H), 7.40 (s, 2H), 12.0 (s, 1H). Elemental analysis: Calculated for C10H10ClNO3 : C 54.29, H 3.91, N 4.52. Found: C 53.68, H 3.84, N 4.48. HRMS (EI+): Calculated for C10 H10ClNO3 : 309.0404. Found: 309.0405. A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and 500-mL addition funnel The cooling bath is removed After being stirred at ambient temperature for 2 h The precipitate is collected on a Buchner funnel washed with water (3 L) The yellow solid is dried in vacuo

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

Procedure: To a suspension of 2-naphthylmethyl ethanimidothioate hydrobromide (3.0 g, 0.01 mol) in THF (20.0 mL) at 0° C., is added N-methylmorpholine (2.4 mL. 0.022 mol), followed by the dropwise addition of a solution of methyl malonyl chloride (1.2 mL, 0.011 mol) in THF (5.0 mL). The resulting mixture is stirred at 0° C. for 30 min, and at room temperature for an additional 30 min. The mixture is diluted with cold water, (25 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts are washed with water, dried (Na2SO4), filtered and concentrated to dryness under reduced pressure to give a yellow syrup, which is purified by flash chromatography using 25% EtOAc in hexanes to give the title compound (1.9 g, 59%) as colorless syrup: ES-HR MS m/z 316.0993(M+H calcd for C17H18NO3SN requires 316.1002). at room temperature for an additional 30 min extracted with dichloromethane (2×20 mL) The combined organic extracts are washed with water dried (Na2SO4) filtered concentrated to dryness under reduced pressure to give a yellow syrup, which is purified by flash chromatography

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

Procedure: A solution of 0.59 ml of methyl malonyl chloride in 5 ml of THF was added dropwise at -10° C. to a solution of 731 mg of p-(2-aminoethyl)-benzonitrile and 1.39 ml of triethylamine in 10 ml of THF. The mixture was then allowed to warm to room temperature, and was then poured into ice water and adjusted to pH 2 with 1N hydrochloric acid. The THF was evaporated and the aqueous extracts were extracted with ethyl acetate. After drying and concentrating, 380 mg of methyl (p-cyanophenethyl)-malonamate, m.p. 125° C., were obtained. The THF was evaporated the aqueous extracts were extracted with ethyl acetate After drying concentrating

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

Procedure: A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and 500-mL addition funnel. Under nitrogen, the flask is charged with 1-(7-amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone (Intermediate 4, 595 g, 2.61 mol), triethylamine (474 mL, 3.40 mol), and anhydrous acetonitrile (3.5 L). The solution is cooled to 0° C., then methyl malonyl chloride (364 mL, 3.40 mol) is added over 35 min. The cooling bath is removed and the mixture is stirred for 5 h. To the resultant slurry is added 25% sodium methoxide in methanol (596 mL, 2.61 mol) over 10 min. After being stirred at ambient temperature for 2 h, the now very thick yellow slurry is diluted with water (3 L). The precipitate is collected on a Buchner funnel and washed with water (3 L). The yellow solid is dried in vacuo. at 60° C. yielding 9-chloromethyl-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester as a yellow solid. This crude product is used for the next step without further purification. Recrystallization from MeOH-DMSO (1:1) gave an analytical sample: mp>300° C. (dec.). 1H NMR (DMSO-d6, 400 MHz) d 3.85 (s, 3H), 4.32 (s, 2H), 4.36 (s, 2H), 4.83 (s, 2H), 6.83 (s, 1H), 7.40 (s, 2H), 12.0 (s, 1H). Elemental analysis: Calculated for C10H10ClNO3 : C 54.29, H 3.91, N 4.52. Found: C 53.68, H 3.84, N 4.48. HRMS (El+): Calculated for C10H10ClNO3 : 309.0404. Found: 309.0405. A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and 500-mL addition funnel The cooling bath is removed After being stirred at ambient temperature for 2 h The precipitate is collected on a Buchner funnel washed with water (3 L) The yellow solid is dried in vacuo

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

Procedure: A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and 500-mL addition funnel. Under nitrogen, the flask is charged with 1-(7-amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone (Intermediate 4, 595 g, 2.61 mol), triethylamine (474 mL, 3.40 mol), and anhydrous acetonitrile (3.5 L). The solution is cooled to 0° C., then methyl malonyl chloride (364 mL, 3.40 mol) is added over 35 min. The cooling bath is removed and the mixture is stirred for 5 h. To the resultant slurry is added 25% sodium methoxide in methanol (596 mL, 2.61 mol) over 10 min. After being stirred at ambient temperature for 2 h, the now very thick yellow slurry is diluted with water (3 L). The precipitate is collected on a Buchner funnel and washed with water (3 L). The yellow solid is dried in vacuo. at 60° C. yielding 9-chloromethyl-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester as a yellow solid. This crude product is used for the next step without further purification. Recrystallization from MeOH-DMSO (1:1) gave an analytical sample: mp>300° C. (dec.). 1H NMR (DMSO-d6, 400 MHz) d 3.85 (s, 3H), 4.32 (s, 2H), 4.36 (s, 2H), 4.83 (s, 2H), 6.83 (s, 1H), 7.40 (s, 2H), 12.0 (s, 1H). Elemental analysis: Calculated for C10H10ClNO3 : C 54.29, H 3.91, N 4.52. Found: C 53.68, H 3.84, N 4.48. HRMS (El+): Calculated for C10H10ClNO3 : 309.0404. Found: 309.0405. A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and 500-mL addition funnel The cooling bath is removed After being stirred at ambient temperature for 2 h The precipitate is collected on a Buchner funnel washed with water (3 L) The yellow solid is dried in vacuo

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

Procedure: To a solution of 4-piperidone monohydrate, hydrochloride (30.7 g; 0.2 mol), sodium carbonate (42 g; 0.4 mol) in water (160 mL) was added dichloromethane (500 mL). The mixture was stirred at room temperature and a solution of methyl malonylchloride (26 ml; 1.2 eq) in dichloromethane (100 mL) was added dropwise at room temperature, keeping the temperature of the reaction mixture below 30° C. The pH was maintained at 8 at the end of the addition. The mixture was stirred 4 hours at room temperature. The residue was extracted twice with dichloromethane, dried over magnesium sulfate and evaporate to yield the title compound (37.4 g). the temperature of the reaction mixture below 30° C The pH was maintained at 8 at the end of the addition The mixture was stirred 4 hours at room temperature The residue was extracted twice with dichloromethane dried over magnesium sulfate evaporate

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

Procedure: To a solution of 4-piperidone monohydrate, hydrochloride (30.7 g; 0.2 mol), sodium carbonate (42 g; 0.4 mol) in water (160 mL) was added dichloromethane (500 mL). The mixture was stirred at room temperature and a solution of methyl malonylchloride (26 ml; 1.2 eq) in dichloromethane (100 mL) was added dropwise at room temperature, keeping the temperature of the reaction mixture below 30° C. The pH was maintained at 8 at the end of the addition. The mixture was stirred 4 hours at room temperature. The residue was extracted twice with dichloromethane, dried over magnesium sulfate and evaporate to yield the title compound (37.4 g). the temperature of the reaction mixture below 30° C The pH was maintained at 8 at the end of the addition The mixture was stirred 4 hours at room temperature The residue was extracted twice with dichloromethane dried over magnesium sulfate evaporate

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

Procedure: A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and 500-mL addition funnel. Under nitrogen, the flask is charged with 1-(7-amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone (Intermediate 4, 595 g, 2.61 mol), triethylamine (474 mL, 3.40 mol), and anhydrous acetonitrile (3.5 L). The solution is cooled to 0° C., then methyl malonyl chloride (364 mL, 3.40 mol) is added over 35 min. The cooling bath is removed and the mixture is stirred for 5 h. To the resultant slurry is added 25% sodium methoxide in methanol (596 mL, 2.61 mol) over 10 min. After being stirred at ambient temperature for 2 h, the now very thick yellow slurry is diluted with water (3 L). The precipitate is collected on a Buchner funnel and washed with water (3 L). The yellow solid is dried in vacuo. at 60° C. yielding 9-chloromethyl-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester as a yellow solid. This crude product is used for the next step without further purification. Recrystallization from MeOH-DMSO (1:1) gave an analytical sample: mp>300 ° C. (dec.). 1H NMR (DMSO-d6, 400 MHz) d 3.85 (s, 3H), 4.32 (s, 2H), 4.36. (s, 2H), 4.83 (s, 2H), 6.83 (s, 1H), 7.40 (s, 2H), 12.0 (s, 1H). Elemental analysis: Calculated for C10H10CINO3: C 54.29, H 3.91, N 4.52. Found: C 53.68, H 3.84, N 4.48. HRMS (EI+): Calculated for C10H10CINO3: 309.0404. Found: 309.0405. A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and 500-mL addition funnel The cooling bath is removed After being stirred at ambient temperature for 2 h The precipitate is collected on a Buchner funnel washed with water (3 L) The yellow solid is dried in vacuo

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

Procedure: A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and 500-mL addition funnel. Under nitrogen, the flask is charged with 1-(7-amino-2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-chloro-ethanone (Intermediate 4, 595 g, 2.61 mol), triethylamine (474 mL, 3.40 mol), and anhydrous acetonitrile (3.5 L). The solution is cooled to 0° C., then methyl malonyl chloride (364 mL, 3.40 mol) is added over 35 min. The cooling bath is removed and the mixture is stirred for 5 h. To the resultant slurry is added 25% sodium methoxide in methanol (596 mL, 2.61 mol) over 10 min. After being stirred at ambient temperature for 2 h, the now very thick yellow slurry is diluted with water (3 L). The precipitate is collected on a Buchner funnel and washed with water (3 L). The yellow solid is dried in vacuo. at 60° C. yielding 9-chloromethyl-7-oxo-2,3,6,7-tetrahydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester as a yellow solid. This crude product is used for the next step without further purification. Recrystallization from MeOH-DMSO (1:1) gave an analytical sample: mp>300 ° C. (dec.). 1H NMR (DMSO-d6, 400 MHz) d 3.85 (s, 3H), 4.32 (s, 2H), 4.36. (s, 2H), 4.83 (s, 2H), 6.83 (s, 1H), 7.40 (s, 2H), 12.0 (s, 1H). Elemental analysis: Calculated for C10H10CINO3: C 54.29, H 3.91, N 4.52. Found: C 53.68, H 3.84, N 4.48. HRMS (EI+): Calculated for C10H10CINO3: 309.0404. Found: 309.0405. A 4-necked 12-L round-bottom flask is equipped with a mechanical stirrer and 500-mL addition funnel The cooling bath is removed After being stirred at ambient temperature for 2 h The precipitate is collected on a Buchner funnel washed with water (3 L) The yellow solid is dried in vacuo

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

Procedure: A solution of (852 μl, 7.9 mmol) of methyl-malonyl chloride in DCM (5 ml) was added dropwise, with vigorous stirring and while cooling (ice-bath), to a solution of (1.5 g, 7.6 mmol) of 1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (A2) and (1.27 ml, 9.1 mmol) of NEt3 in DCM (35 ml). Stirring was then carried out for 60 min at RT. The mixture was then washed with water and brine, and the organic phase was dried over MgSO4, filtered and concentrated in vacuo. CC (chloroform/ethyl acetate 10:1) yielded 1.26 g (4.2 mmol, 55%) of 3-oxo-3-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)propanoic acid methyl ester. while cooling (ice-bath) Stirring The mixture was then washed with water and brine the organic phase was dried over MgSO4 filtered concentrated in vacuo

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

Procedure: 4-Fluoro-1-(3-methyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (Example 14g, 0.24 g, 0.944 mmol) was dissolved in anhydrous 1,4-dioxane (10 mL) and methyl malonyl chloride was added under a nitrogen atmosphere. The reaction mixture was heated to 100° C. for 1 h. Upon cooling to 25° C., saturated aqueous sodium bicarbonate solution was added and the product was extracted with 50% ethyl acetate/hexanes. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude desired product, 1-[(2-ethoxycarbonyl-acetyl)-(3-methyl-butyl)-amino]-4-fluoro-1H-pyrrole-2-carboxylic acid allyl ester (0.335 g, 0.944 mmol, 100% yield) as a pale yellow oil, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ: 0.90 (3H, d, J=4.6 Hz), 0.92 (3H, d, J=5.2 Hz), 1.37-1.46 (1H, m), 1.54-1.64 (1H, m), 1.69-1.78 (1H, m), 3.13 (2H, d, J=3.1 Hz), 3.70 (3H, s), 4.16-4.26 (2H, m), 4.73 (2H, d, J=5.5 Hz), 5.28-5.31 (1H, m), 5.37 (1H, dd, J1=17.2 Hz, J2=1.6 Hz), 5.91-6.01 (1H, m), 6.69-6.76 (2H, m). Upon cooling to 25° C. the product was extracted with 50% ethyl acetate/hexanes The combined organic layers were dried over sodium sulfate filtered concentrated in vacuo