(1-aminocyclobutyl)methanol

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

Procedure: A stirred solution of ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (2.00 g, 7.57 mmol), Ac2O (4.29 mL, 45.4 mmol) and triethyl iorthoformate (2.51 mL, 15.1 mmol) was heated at 120° C. for 3 hours. The mixture was concentrated in vacuo and dried under high vacuum. The crude product was dissolved in toluene (30 mL) and a suspension of (1-aminocyclobutyl)methanol (1.04 g, 7.57 mmol) in toluene (5 mL), triethylamine (1.06 mL, 7.57 mmol) were added under ice-cooling. The mixture was stirred for 18 h at room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by column chromatography (Hexane: EtOAc 10:1→1:1) to yield the title compound (1.57 g, 55%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 0.95-1.11 (3H, m), 1.85-1.90 (1H, m), 1.91-2.07 (2H, m), 2.17-2.26 (2H, m), 2.27-2.36 (2H, m), 3.80-3.83 (2H, m), 4.00-4.10 (2H, m), 6.95-7.13 (1H, m), 8.17-8.22 (1H, m), 9.87-11.36 (1H, m). ESIMS (+): 376 [M+H]+. The mixture was concentrated in vacuo dried under high vacuum The crude product was dissolved in toluene (30 mL) were added under ice- cooling concentrated in vacuo to yield the crude product The crude product was purified by column chromatography (Hexane: EtOAc 10:1→1:1)

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

Procedure: A stirred solution of ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (2.00 g, 7.57 mmol), Ac2O (4.29 mL, 45.4 mmol) and triethyl iorthoformate (2.51 mL, 15.1 mmol) was heated at 120° C. for 3 hours. The mixture was concentrated in vacuo and dried under high vacuum. The crude product was dissolved in toluene (30 mL) and a suspension of (1-aminocyclobutyl)methanol (1.04 g, 7.57 mmol) in toluene (5 mL), triethylamine (1.06 mL, 7.57 mmol) were added under ice-cooling. The mixture was stirred for 18 h at room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by column chromatography (Hexane: EtOAc 10:1→1:1) to yield the title compound (1.57 g, 55%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 0.95-1.11 (3H, m), 1.85-1.90 (1H, m), 1.91-2.07 (2H, m), 2.17-2.26 (2H, m), 2.27-2.36 (2H, m), 3.80-3.83 (2H, m), 4.00-4.10 (2H, m), 6.95-7.13 (1H, m), 8.17-8.22 (1H, m), 9.87-11.36 (1H, m). ESIMS (+): 376 [M+H]+. The mixture was concentrated in vacuo dried under high vacuum The crude product was dissolved in toluene (30 mL) were added under ice- cooling concentrated in vacuo to yield the crude product The crude product was purified by column chromatography (Hexane: EtOAc 10:1→1:1)

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

Procedure: To a mixture containing (1-amino-cyclobutyl)-methanol (preparation described in JP 08134044) (860 mg), aza-HOBT (600 mg), TBTU (1.41 g) and Et3N (1 ml) in CH3CN (30 ml), (3-ethynyl-quinolin-6-yloxy)-methyl sulfanyl-acetic acid dissolved in Et3N (1 ml) and CH3CN (30 ml) was added over 1 hr, at room temperature, under nitrogen atmosphere. The resulting brown suspension was stirred overnight at room temperature then poured into aq NH4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 1/3) to give 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-hydroxymethyl-cyclobutyl)-2-methylsulfanyl-acetamide (1.09 g) as slightly yellow solid. extracted with ethyl acetate The combined organic layers were washed with water, brine dried over sodium sulphate anhydrous filtered concentrated under reduced pressure The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 1/3)

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

Procedure: To a solution of (3-ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid (1.10 g) in CH3CN (40 ml) was added Et3N (2.25 ml), AHOBT (0.06 g), TBTU (1.50 g) and (1-amino-cyclobutyl)-methanol (0.06 g) at room temperature, under nitrogen atmosphere. The mixture was stirred at the same temperature during 1 hour, then poured into sat aq NH4Cl and extracted with ethyl acetate (2×20 ml). The organic phase was separated and washed with aq Na2S2O3 and sat. aq. NaCl then dried over anhydrous sodium sulphate, filtered and evaporated under vacuum. Purification by flash chromatography (ethyl acetate/cyclohexane, 2/1) gave 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-hydroxymethyl-cyclobutyl)-2-methylsulfanyl-acetamide (0.70 g) as a yellow oil. poured extracted with ethyl acetate (2×20 ml) The organic phase was separated washed with aq Na2S2O3 and sat. aq. NaCl then dried over anhydrous sodium sulphate filtered evaporated under vacuum Purification by flash chromatography (ethyl acetate/cyclohexane, 2/1)

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

Procedure: Method as described for example 58 using intermediate 32 (100 mg, 0.18 mmol) and (1-aminocyclobutyl)methanol (27 mg, 0.267 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound. (54 mg, 53%) The reaction mixture was purified by prep HPLC at low pH

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

Procedure: The title compound was synthesized in analogy to Example 8e, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and 1-amino-cyclobutanemethanol (CAN 180205-34-9, 66.02 mg, 0.64 mmol) as starting materials, and isolated (50 mg, 36.86%) as off white solid; LC-MS (UV peak area, ESI) 97.56%, 318.4 (M+H). isolated (50 mg, 36.86%) as off white solid

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

Procedure: A stirred solution of ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (2.00 g, 7.57 mmol), Ac2O (4.29 mL, 45.4 mmol) and triethyl orthoformate (2.51 mL, 15.1 mmol) was heated at 120° C. for 3 hours. The mixture was concentrated in vacuo and dried under high vacuum. The crude product was dissolved in toluene (30 mL) and a suspension of (1-aminocyclobutyl)methanol (1.04 g, 7.57 mmol) in toluene (5 mL), triethylamine (1.06 mL, 7.57 mmol) were added under ice-cooling. The mixture was stirred for 18 h at room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by column chromatography (Hexane:EtOAc 10:1→1:1) to yield the title compound (1.57 g, 55%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 0.95-1.11 (3H, m), 1.85-1.90 (1H, m), 1.91-2.07 (2H, m), 2.17-2.26 (2H, m), 2.27-2.36 (2H, m), 3.80-3.83 (2H, m), 4.00-4.10 (2H, m), 6.95-7.13 (1H, m), 8.17-8.22 (1H, m), 9.87-11.36 (1H, m). ESIMS (+): 376 [M+H]+. The mixture was concentrated in vacuo dried under high vacuum The crude product was dissolved in toluene (30 mL) were added under ice- cooling concentrated in vacuo to yield the crude product The crude product was purified by column chromatography (Hexane:EtOAc 10:1→1:1)

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

Procedure: A stirred solution of ethyl 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (2.00 g, 7.57 mmol), Ac2O (4.29 mL, 45.4 mmol) and triethyl iorthoformate (2.51 mL, 15.1 mmol) was heated at 120° C. for 3 hours. The mixture was concentrated in vacuo and dried under high vacuum. The crude product was dissolved in toluene (30 mL) and a suspension of (1-aminocyclobutyl)methanol (1.04 g, 7.57 mmol) in toluene (5 mL), triethylamine (1.06 mL, 7.57 mmol) were added under ice-cooling. The mixture was stirred for 18 h at room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by column chromatography (Hexane: EtOAc 10:1→1:1) to yield the title compound (1.57 g, 55%) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 0.95-1.11 (3H, m), 1.85-1.90 (1H, m), 1.91-2.07 (2H, m), 2.17-2.26 (2H, m), 2.27-2.36 (2H, m), 3.80-3.83 (2H, m), 4.00-4.10 (2H, m), 6.95-7.13 (1H, m), 8.17-8.22 (1H, m), 9.87-11.36 (1H, m). ESIMS (+): 376 [M+H]+. The mixture was concentrated in vacuo dried under high vacuum The crude product was dissolved in toluene (30 mL) were added under ice- cooling concentrated in vacuo to yield the crude product The crude product was purified by column chromatography (Hexane: EtOAc 10:1→1:1)