tert-butyl (2S)-2-aminopropanoate

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

Procedure: To a solution of 4-oxo-3,4-dihydro-quinazoline-7-carboxylic acid in tetrahydrofuran, 1.2 equivalents of 1,1′-carbonyldiimidazole are added and the mixture is stirred for 30 minutes. Then, the (S)-L-Alanine tert-butyl ester is added and the mixture is stirred for 24 hours until disappearance of starting material. The solvent is removed under reduced pressure and the crude is diluted in chloroform and brine. The organic layer is washed with water and dried over MgSO4. The filtrate is concentrated and the residue is purified by column chromatography to give the desired compound. the mixture is stirred for 24 hours until disappearance of starting material The solvent is removed under reduced pressure the crude is diluted in chloroform The organic layer is washed with water dried over MgSO4 The filtrate is concentrated the residue is purified by column chromatography

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

Procedure: To a solution of para-nitrobenzoic acid in tetrahydrofuran, 1.2 equivalents of 1,1′-carbonyldiumidazole are added and the mixture is stirred for 30 minutes. Then, 1.1 equivalents of the (S)-L-alanine tert-butyl ester are added and the mixture is stirred for 24 hours at room temperature. The solvent is removed under reduced pressure and the crude is diluted in chloroform and brine. The organic layer is washed with water and dried over MgSO4. The filtrate is concentrated under vacuum and the residue is purified by column chromatography to give the desired compound. the mixture is stirred for 24 hours at room temperature The solvent is removed under reduced pressure the crude is diluted in chloroform The organic layer is washed with water dried over MgSO4 The filtrate is concentrated under vacuum the residue is purified by column chromatography

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

Procedure: Z-Protected L-methionine (10 g) was dissolved in DMF (200 ml) and 1-[3-(diemthylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.13 g) was added followed by HOBT (5.72 g) and triethylamine (19.7 ml). The mixture was stirred for 1 h then L-alanine tert-butyl ester (7.7 g) was added and stirring continued for 18 h. The mixture was evaporated under reduced pressure and partitioned between diethyl ether and water. The separated organic phase was washed with hydrochloric acid (1M), saturated sodium bicarbonate solution and brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (11.9 g) as an orange oil which crystallised on standing. stirring continued for 18 h The mixture was evaporated under reduced pressure partitioned between diethyl ether and water The separated organic phase was washed with hydrochloric acid (1M), saturated sodium bicarbonate solution and brine dried (over magnesium sulphate) concentrated under reduced pressure

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

Procedure: Synthesized from (S)-alanin tert-butyl ester and 4-Benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid (Example A-68 c) in analogy to Example A-68 d); MS-(+)-ion: M+23=565.2.

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

Procedure: Synthesized from (S)-alanin tert-butyl ester and 4-Benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid (Example A-68 c) in analogy to Example A-68 d); MS-(+)-ion: M+23=565.2.

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

Procedure: To a solution of L-Alanine tert-butylester (1.53 g, 10.5 mmol) in tetrahydrofuran (20 mL) was added 1,3-propanesultone (1.16 g, 9.6 mmol). The solution stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×20 mL). The solid was dissolved in water (80 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (80 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (1.37 g, 54%). 1H NMR (D2O, 500 MHz) δ ppm 3.88 (m, 1H), 3.09 (m, 2H), 2.86 (t, 2H, J=7.3 Hz), 2.00 (m, 2H), 1.39 (d, 3H, J=7.3 Hz), 1.35 (s, 9H). 13C (D2O, 125 MHz) δ ppm 169.13, 86.12, 56.24, 47.94, 44.71, 27.11, 21.52, 14.17. [α]D=−1.1° (c=0.0027 in water), ES-MS 266 (M−1). at reflux for 2 hours The solid was collected by filtration washed with acetone (2×20 mL) The solid was dissolved in water (80 mL) Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution The suspension was stirred for 15 minutes before the resin was removed by filtration The filtrate was evaporated under reduced pressure filtered dried in the vacuum oven (50° C.)

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

Procedure: A mixture of 5 g of L-alanine tert-butyl ester.oxalate, 11 g of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate, 1.6 g of sodium acetate, 1.2 g of acetic acid and 100 ml of ethanol is stirred at room temperature for 1 hour, and a solution of 1.9 g of sodium cyanoborohydride in 100 ml of ethanol is added dropwise to the mixture over a period of 4 hours. After stirring at room temperaute overnight, 500 ml of water is added to the reaction mixture, and the mixture is extracted with 300 ml of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is separated and purified by silica gel column chromatography (hexane:acetone=4:1), whereby the first fraction yields 1.7 g of N-[(R)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine tert-butyl ester as a colorless oil. is added to the reaction mixture the mixture is extracted with 300 ml of ethyl acetate The extract is washed with water dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue is separated purified by silica gel column chromatography (hexane:acetone=4:1), whereby the first fraction

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

Procedure: Synthesized from (S)-alanin tert-butyl ester and 4-Benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid (Example A-68 c) in analogy to Example A-68 d); MS-(+)-ion: M+23=565.2.

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

Procedure: Synthesized from (S)-alanin tert-butyl ester and 4-Benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid (Example A-68 c) in analogy to Example A-68 d); MS-(+)-ion: M+23=565.2.

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

Procedure: Prepared from Intermediate D and L-alanine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 6.96 (1H, s), 6.33 (1H, s), 4.17 (2H, m), 3.19 (3H, m), 2.95 (2H, t, J=12.0 Hz), 2.60 (2H, m), 1.78 (4H, m), 1.50 (9H, m), 1.27 (3H, d, J=6.9 Hz), 1.23 (2H, m), 1.18 (6H, d, J=6.9 Hz). LC/MS: purity 98%, m/z 435 [M+H]+

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

Procedure: Prepared from Intermediate D and L-alanine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 6.96 (1H, s), 6.33 (1H, s), 4.17 (2H, m), 3.19 (3H, m), 2.95 (2H, t, J=12.0 Hz), 2.60 (2H, m), 1.78 (4H, m), 1.50 (9H, m), 1.27 (3H, d, J=6.9 Hz), 1.23 (2H, m), 1.18 (6H, d, J=6.9 Hz). LC/MS: purity 98%, m/z 435 [M+H]+

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

Procedure: The title compound was prepared following the protocol used for Example 91, Steps 2 and 3, but starting from (3-(5-(2′-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol (84 mg, 0.2 mmol) and (S)-tert-butyl 2-aminopropanoate (87 mg, 0.6 mmol). It was isolated as a white solid (133 mg, 96%). 1H NMR: (DMSO-d6, 400 MHz) δ 8.57 (s, 1H), 8.53 (d, J=8.1 Hz, 1H), 8.07-8.03 (m, 2H), 7.69 (d, J=8.0 Hz, 1H), 7.65-7.53 (m, 2H), 7.44-7.37 (m, 2H), 7.33 (td, J=4.0, 2.1 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 3.31 (q, J=7.2 Hz, 2H), 3.18-3.02 (m, 3H), 2.06 (s, 3H), 1.33 (d, J=7.0 Hz, 3H). LC/MS (Method B): 496 (M+H)+. HPLC (Method G) Rt 3.24 min (Purity: 99.1%).