(1S)-1-phenylethanamine

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

Procedure: 1,4-Dioxaspiro[4.5]decan-8-one (10 g, 64.03 mmol) was dissolved in dry dichloroethane (300 mL) under an atmosphere of nitrogen. (1S)-1-phenylethylamine (8.96 mL, 70.43 mmol) was added neat at room temperature followed by sodium triacetoxyborohydride (20.36 g, 96.04 mmol) neat in small portions. The reaction was stirred at room temperature overnight. The reaction was quenched by the addition of distilled water (200 mL). The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate. The filtrate was concentrated under reduced pressure. A yellow oil was obtained of satisfactory purity based on (11.2 g, 67% yield). M+1: 262. The reaction was quenched by the addition of distilled water (200 mL) The phases were separated the aqueous phase was extracted with dichloromethane The combined organic phases were dried over sodium sulfate The filtrate was concentrated under reduced pressure A yellow oil was obtained of satisfactory purity

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

Procedure: The method described in Part A of Example 1 was used to treat 2,4-dichloro-3-nitroquinoline (19.4 g, 78.5 mmol) in DMF (100 mL) with triethylamine (32 mL, 0.235 mol) and (S)-(−)-α-methylbenzylamine (11.5 g, 94.2 mmol) with the modification that the reaction was allowed to warm to room temperature and stirred for two hours. After the isolated precipitate was washed with water, it was dried under high vacuum overnight to provide 25.1 g of 2-chloro-3-nitro-N-[(1S)-1-phenylethyl]quinolin-4-amine as an orange solid. After the isolated precipitate was washed with water, it was dried under high vacuum overnight

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

Procedure: In a flame dried roundbottomflask (E)-but-2-enoic acid methoxy-methyl-amide (Einhorn et al., Synth. Commun. 20 (8), 1105-1112 (1990)) (8.0 g, 61.9 mmol) was dissolved in 150 ml of THF. A 1M solution of vinylmagnesium bromide in Et2O (68.1 ml, 68.1 mmol) was added at 0° C. and then the mixture was stirred for 1 h at rt. (S)-(−)-alpha-methylbenzylamin (15.8 ml, 124 mmol) was added at rt, followed by water (15 ml). The reaction was stirred at rt for 1 h. THF was evaporated and 150 ml of water was added. Then the mixture was extracted three times with CH2Cl2 The organic layer was washed with brine, dried over Na2 SO4 and evaporated. The crude product was purified by flash chromatography (silica gel, 20% EtOAc/cyclohexane) which furnished the (S,S) product as the first fraction (confirmed by x-ray). The reaction was stirred at rt for 1 h THF was evaporated 150 ml of water was added Then the mixture was extracted three times with CH2Cl2 The organic layer was washed with brine dried over Na2 SO4 evaporated The crude product was purified by flash chromatography (silica gel, 20% EtOAc/cyclohexane) which furnished the (S,S) product as the first fraction (confirmed by x-ray)

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

Procedure: A solution of 2-(1-methyl-3-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-ylamino) acetic acid (0.035 g, 0.095 mmol), DIC (0.018 g, 0.143 mmol) and HOBt (0.020 g, 0.143 mmol) in THF (5 ml) was stirred at rt for 10 min. (S)-(−)-α-methyl benzyl amine (0.013 g, 0.104 mmol) was added to the reaction mixture dropwise at rt and stirring was continued for 16 h. The reaction mixture was poured into ice cold water and the precipitated product was collected by filtration and dried under vacuum. The crude product was purified by preparative HPLC using acetonitrile/water as mobile phase to yield the title compound as a white solid (0.018 g, 42%). [1H-NMR (CDCl3, 300 MHz) δ 7.52-7.38 (m, 4H), 7.32-7.21 (m, 6H), 6.66 (s, 1H), 6.39 (d, 1H), 5.51 (t, 1H), 5.30-5.15 (m, 1H), 4.20 (dd, 2H), 3.95 (s, 3H), 1.52 (d, 3H); HPLC RtA=5.294 (98%) min; LCMS RtA=1.682 min; [M+H]+=454.1] was added to the reaction mixture dropwise at rt The reaction mixture was poured into ice cold water the precipitated product was collected by filtration dried under vacuum The crude product was purified by preparative HPLC

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

Procedure: A solution of 2-(1-methyl-3-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yloxy)acetic acid (0.14 g, 0.494 mmol), DIC (0.094 g, 0.744 mmol) and HOBt (0.087 g mg, 0.644 mmol) in DMF (4.0 ml) was stirred at rt for 15 min. (S)-(−)-α methyl benzyl amine (0.072 g, 0.594 mmol) was added to the reaction mixture at rt and stirring was continued overnight. The reaction mixture was concentrated. Diethyl ether was added and the mixture was washed with water, followed by brine and dried over Na2SO4. Concentration of the organic layer furnished the crude product as an off-white solid. The product was purified by preparative HPLC using acetonitrile/water as mobile phase to yield the title compound as a white solid (0.133 g, 68%). [1H-NMR (CDCl3, 300 MHz) δ 8.22 (d, 1H), 7.96-7.89 (m, 2H), 7.55-7.38 (m, 3H), 7.37-7.21 (m, 5H), 6.73 (d, 1H), 6.61 (d, 1H), 5.35-5.21 (m, 1H), 4.99 (s, 2H), 4.03 (s, 3H), 1.53 (d, 3H); HPLC RtA=5.273 min (98%) LCMS RtE=1.921 min; [M+H]+=387.1; Mp=55-56° C.] was added to the reaction mixture at rt The reaction mixture was concentrated Diethyl ether was added the mixture was washed with water dried over Na2SO4 Concentration of the organic layer furnished the crude product as an off-white solid The product was purified by preparative HPLC

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

Procedure: A solution of 2-(3-(2-fluorophenyl)-1-methyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yloxy)acetic acid (70 mg, 0.189 mmol), DIC (31.1 mg, 0.246 mmol) and HOBt (38.4 mg, 0.285 mmol) in DMF (3 ml) was stirred at rt for 15 min. (S)-(−)-α-methyl benzyl amine (25.3 mg, 0.208 mmol) was added dropwise to the reaction mixture at rt and then the mixture was heated at 100° C. for 1 h. After completion of the reaction, ice-cold water was added and the reaction mixture was stirred for 10 min. The resulting precipitate was collected by filtration. The crude product was re-crystallized from diethyl ether to yield 46 mg (51%) of the title compound. [1H-NMR (CDCl3, 300 MHz) δ 7.55-7.05 (m, 9H), 7.01 (s, 1H), 6.55 (d, 1H), 5.23 (m, 1H), 5.01 (s, 2H), 4.03 (s, 3H), 1.60 (d, 3H); HPLC RtA=5.384 min (98%); LCMS RtD=3.055; [M+H]+=473.1]. was added dropwise to the reaction mixture at rt After completion of the reaction, ice-cold water was added The resulting precipitate was collected by filtration The crude product was re-crystallized from diethyl ether

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-Fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)-5-(4-tert.butoxycarbonyl-1-piperazinyl)imidazo[4,5-b]pyridine (106 mg, 0.2 mmol) is dissolved in CH2Cl2/HOAc 1:1 (10 ml), combined with mCPBA (113 mg 70%, 0.24 mmol) and stirred for 15 min. The reaction mixture is poured on water and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4. filtered and evaporated to dryness to yield the crude sulfoxide (100 mg), which is dissolved in 1-(S)-phenylethylamine (0.2 ml) and heated to 120° C. for 1 h. Purification over SiO2 (acetone/hexanes 1:1) yielded the title compound as colorless foam (45 mg 35%) The reaction mixture is poured on water extracted with CH2Cl2 three times The combined organic phases are dried over Na2SO4 filtered evaporated to dryness to yield the crude sulfoxide (100 mg), which Purification over SiO2 (acetone/hexanes 1:1)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-Fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)-5-aminoimidazo[4,5-b]pyridine (110 mg, 0.31 mmol) is dissolved in CH2Cl2/HOAc 1:1 (6.2 ml), combined at 0° C. with mCPBA (84 mg 70% 0.34 mmol) and stirred for 30 min. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crude sulfoxide (110 mg). 50 mg are dissolved in 1-(S)-phenylethylamine (0.5 ml) and heated to 120° C. for 1 h. Purification over RP18 (CH3CN/Water 70/30 to 10/90) yielded the title compound as light brown foam (30 mg 52%) extracted with ethyl acetate three times The combined organic phases are dried over Na2SO4 filtered evaporated to dryness to yield the crude sulfoxide (110 mg) Purification over RP18 (CH3CN/Water 70/30 to 10/90)

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

Procedure: 4-(4-Fluorophenyl)-2-(1-ethoxycarbonylpiperidin-4-yl)-5-(2-fluoro-4-pyridinyl)thiazole (2.4 g. 5.5 mmol) and 1-(S)-phenylethylamine (5.5 ml are heated to 195° C. for 5 h. The reaction mixture is evaporated and purified by SiO2 chromatography (ethyl acetate/cyclohexane 20/80 to 30/70) to yield the title compound as a white foam (2.0 g 67.3%) The reaction mixture is evaporated purified by SiO2 chromatography (ethyl acetate/cyclohexane 20/80 to 30/70)

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

Procedure: To a solution of 6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid (Example 157) (6.75 g, 24.3 mmol) in ethyl acetate (25 mL) was added (S)-(−)-α-methylbenzylamine (1.50 g, 12.2 mmol). To the resulting solution was added hexanes (50 mL) with mixing. Stirring was discontinued and the reaction held static at room temperature for 16 hours during which time yellow crystals formed. The crystals were collected and washed with ethyl acetate-hexanes (100 mL, 1:2). The resulting yellow solid (932 mg) was dissolved in ethyl acetate (20 mL) and extracted with 1 N HCl (3×10 mL). The organic layer was dried over sodium sulfate and solvent removed at reduced pressure. The (s)-6-chloro-1,2-dihydro-2-(trifluoromethyl)-3-quinolinecarboxylic acid was obtained as a yellow solid (648 mg, 10% yield). mp 173-176° C. 1H NMR (acetone-d6, 300 MHz) 7.80 (s, 1H), 7.35 (d, 1H, J=2.2 Hz), 7.18 (d, 1H, J=8.0, J=2.2 Hz), 6.86 (d, 1H, J=8.0 Hz), 6.60 (brs, 1H), 5.20 (m, 1H). Anal. Calc'd. for C11H7NO2F3Cl: C, 47.40; H, 2.54; N, 5.40. Found C, 47.49; H, 2.60; N, 4.98. The compound was determined to have an optical purity greater than 90% ee. Optical purity was determined by HPLC as described in Example 66. with mixing formed The crystals were collected washed with ethyl acetate-hexanes (100 mL, 1:2) The resulting yellow solid (932 mg) was dissolved in ethyl acetate (20 mL) extracted with 1 N HCl (3×10 mL) The organic layer was dried over sodium sulfate and solvent removed at reduced pressure

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

Procedure: A mixture of (3R,4S,5S), and (3S,4R,5R), -N-tert-Butyloxycarbonyl-4-hydroxy-piperidine-3,5-dicarboxylic acid 3-methyl ester (96% ee) (78 g, 0.26 mol) is dissolved in MeOH (500 mL) and (S)-(−)1-phenylethylamine (33 mL, 0.26 mol) at room temperature is added. The mixture is stirred for 30 min at room temperature and concentrated under reduced pressure to provide a salt as a colorless amorphous. The resulting residue is dissolved in CH3CN (1.3 L) at 70° C. and stirred vigorously at room temperature for 20 h. A white crystalline salt is collected by filtration, washed with Et2O. After repeating the same recrystallization procedure (dissolution in CH3CN and stirring at room temperature) two or three times the resulting salt is dissolved in water, acidified to pH 3 with 5N and 1N HCl, and extracted with AcOEt. The combined organic phases are dried over Na2SO4. Concentration under reduced pressure gives enantiomeric pure (3R,4S,5S)-starting material-G as a white solid: ES-MS: M+H=304: CtRet=2.37 min. chiral HPLC: >99.9% ee, AD-H, 7.5% i-PrOH/Hexane/0.1% TFA, flow 0.75 mL/min, 210 nm, tRet=24 min A mixture of (3R,4S,5S), and (3S,4R,5R) concentrated under reduced pressure to provide a salt as a colorless amorphous stirred vigorously at room temperature for 20 h A white crystalline salt is collected by filtration washed with Et2O the same recrystallization procedure (dissolution in CH3CN and stirring at room temperature) two or three times the resulting salt is dissolved in water extracted with AcOEt The combined organic phases are dried over Na2SO4 Concentration under reduced pressure gives enantiomeric pure (3R,4S,5S)-starting material-G as a white solid CtRet=2.37 min. chiral HPLC tRet=24 min

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

Procedure: The known method by T. Inaba, A. G. Birchler, Y. Yamada, S. Sagawa, K. Yokata, K. Ando and I. Uchida, J. Org. Chem., 1998, 63, 7582 for the preparation of the enantiomer of the title compound was followed. (S)-1-Phenylethanamine (30.4 ml, 236 mmol) and 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (34 g, 236 mmol) were dissolved in iPrOH (16 ml) and heated under reflux for 16 h. The mixture was stirred and cooled in an ice bath. Hexanes (90 ml) was added. After 1 h the colourless crystalline solid was filtered off, washed with hexanes and dried to give (5S,6R)-2,2-dimethyl-6-((S)-1-phenylethylamino)-1,3-dioxepan-5-ol (21.9 g, 35%). The 1H NMR was in agreement with that described for the enantiomer of the title compound by T. Inaba, A. G. Birchler, Y. Yamada, S. Sagawa, K. Yokata, K. Ando and I. Uchida, J. Org. Chem., 1998, 63, 7582. [α]D 20 −96.6 (c, 1.01, MeOH). Lit. (T. Inaba, A. G. Birchler, Y. Yamada, S. Sagawa, K. Yokata, K. Ando and I. Uchida, J. Org. Chem., 1998, 63, 7582) [α]D 25 +96.2 (c 1.00, MeOH) for the enantiomer. heated under reflux for 16 h cooled in an ice bath After 1 h the colourless crystalline solid was filtered off washed with hexanes dried