(2R)-3-aminopropane-1,2-diol

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

Procedure: A mixture of t-butyl 6-chloronicotinate (4.69 g, 0.0220 mol) and (R)-3-amino-1,2-propanediol (5.00 g, 0.0549 mol) in isopropanol (20 ml) was heated at 100° C. overnight. Solvent was removed under vacuum, and the residue taken up in ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated to give nearly pure product as a yellow oil. Yield 5.90 g (99%). 1H NMR. MS: 269 [M+H]+. Solvent was removed under vacuum washed with water, brine dried (MgSO4) evaporated to give nearly pure product as a yellow oil

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

Procedure: To a solution of (2R)-3-aminopropane-1,2-diol (132 mg, 1.446 mmol), 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carboxylic acid (500 mg, 1.315 mmol), and triethylamine (0.403 mL, 2.89 mmol) in N,N-dimethylformamide (8 mL) was added benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (821 mg, 1.578 mmol). After 45 minutes, water (32 mL) was added to the reaction mixture and the resulting yellow solid was collected by filtration; the solid was then purified by trituration using a mixture of methanol (2 mL), ethyl acetate (3 mL), and dichloromethane (3 mL) followed by filtration and drying in vacuo. The mother liqour from the trituration was concentrated and additional product was purified via column chromatography on silica (Biotage 50 g SNAP column, 97.5:2.5 to 85:15 dichloromethane:methanol). The combined material afforded in N-[(2R)-2,3-dihydroxypropyl]-5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carboxamide (487 mg 82% yield) as a yellow solid. MS ESI: [M+H]+ m/z 454.0. 1H NMR (500 MHz, d6-DMSO): δ 10.31 (s, 1H); 8.85 (d, J=4.9 Hz, 1H); 8.53 (t, J=5.9 Hz, 1H); 8.29 (s, 1H); 8.11 (s, 1H); 7.51 (s, 1H); 7.31 (s, 1H); 7.30 (d, J=4.9 Hz, 1H); 4.90 (d, J=5.1 Hz, 1H); 4.64 (t, J=5.7 Hz, 1H); 3.63 (m, 1H); 3.42 (m, 1H); 3.35 (m, 2H); 3.23 (m, 1H); 2.34 (s, 3H). rhSYK activity=+++ the resulting yellow solid was collected by filtration the solid was then purified by trituration a mixture of methanol (2 mL), ethyl acetate (3 mL), and dichloromethane (3 mL) followed by filtration drying in vacuo The mother liqour from the trituration was concentrated additional product was purified via column chromatography on silica (Biotage 50 g SNAP column, 97.5:2.5 to 85:15 dichloromethane:methanol)

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

Procedure: Triethylamine (1.83 mL, 13.2 mmol) was added to a solution of (R)-3-amino-1,2-propanediol (1.00 g, 11.0 mmol) in a mixture CH3CN/MeOH (36 mL/16 mL) at −10° C. under nitrogen. Chloroacetyl chloride (0.98 ml, 12.0 mmol) was added dropwise at −10° C. over 30 min. The reaction mixture was allowed to reach room temperature and stirred for 16 h. The mixture was concentrated and purified by flash column chromatography on silica gel, eluting with methanol/ethyl acetate (8/92), to give the title compound as a white solid (1.43 g, 78%). to reach room temperature The mixture was concentrated purified by flash column chromatography on silica gel eluting with methanol/ethyl acetate (8/92)

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

Procedure: The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using (R)-(+)-3-amino-1,2-propanediol (0.162 g 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (374.5 mg, 40%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.92 (dd, 1H, J=2 Hz), 7.77 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8.4 Hz), 7.04 (m, 2H), 5.60 (q, 2H, J=12.4 Hz), 3.80 (m, 1H), 3.53 (m, 3H), 3.39 (m, 1H), 2.19 (s, 3H); ES-HRMS m/z 524.0649 (M+H C22H21BrF2N3O5 requires 524.0627). The title compound was prepared by a procedure similar to the one After reverse phase HPLC purification the organic extracts were concentrated under reduced pressure dried in vacuo

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

Procedure: To a solution of (2R)-3-aminopropane-1,2-diol (132 mg, L446 mmol), 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carboxylic acid (500 mg, 1.315 mmol), and triethylamine (0.403 mL, 2.89 mmol) in N,N-dimethylformamide (8 mL) was added benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (821 mg, 1.578 mmol). After 45 minutes, water (32 mL) was added to the reaction mixture and the resulting yellow solid was collected by filtration; the solid was then purified by trituration using a mixture of methanol (2 mL), ethyl acetate (3 mL), and dichloromethane (3 mL) followed by filtration and drying in vacuo. The mother liquor from the trituration was concentrated and additional product was purified via column chromatography on silica (Biotage 50 g SNAP column, 97.5:2.5 to 85:15 dichloromethane:methanol). The combined material afforded in N-[(2R)-2,3-dihydroxypropyl]-5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carboxamide (487 mg 82% yield) as a yellow solid. MS ESI: [M+H]+ m/z 454.0. 1H NMR (500 MHz, d6-DMSO): δ 10.31 (s, 1H); 8.85 (d, J=4.9 Hz, 1H); 8.53 (t, J=5.9 Hz, 1H); 8.29 (s, 1H); 8.11 (s, 1H); 7.51 (s, 1H); 7.31 (s, 1H); 7.30 (d, J=4.9 Hz, 1H); 4.90 (d, J=5.1 Hz, 1H); 4.64 (t, J=5.7 Hz, 1H); 3.63 (m, 1H); 3.42 (m, 1H); 3.35 (m, 2H); 3.23 (m, 1H); 2.34 (s, 3H). rhSYK activity=+++ the resulting yellow solid was collected by filtration the solid was then purified by trituration a mixture of methanol (2 mL), ethyl acetate (3 mL), and dichloromethane (3 mL) followed by filtration drying in vacuo The mother liquor from the trituration was concentrated additional product was purified via column chromatography on silica (Biotage 50 g SNAP column, 97.5:2.5 to 85:15 dichloromethane:methanol)

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

Procedure: A mixture of 5-amino-6-nitroisoindoline-1,3-dione (2.27 g, 10.98 mmol), (R)-3-aminopropane-1,2-diol (1.0 g, 10.98 mmol), and imidazole (0.75 g, 10.98 mmol) in 100 mL of pentanol was heated to reflux and maintained for 8 h and allowed to cool down to rt. The precipitate was filtered and washed with heptanes and dried to give a yellow crystalline solid (2.57 g, 9.14 mmol, 83%). 1H NMR (500 MHz, DMSO-d6) δ58.38 (s, 2H), 8.31 (s, 1H), 7.45 (1, 1H), 4.90 (d, J=5.0 Hz, 1H), 4.66 (t, J=5.5 Hz, 1H), 3.82-3.74 (m, 1H), 3.55 (d, J=6.5 Hz, 2H), 3.42-3.18 (m, 2H). ESI MS: m/z 279.8 (M−1). was heated to reflux maintained for 8 h The precipitate was filtered washed with heptanes dried

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

Procedure: A mixture of t-butyl 6chloronicotinate (4.69 g, 0.0220 mol) and (R)-3-amino-1,2-propanediol (5.00 g, 0.0549 mol) in isopropanol (20 ml) was heated at 100° C. overnight. Solvent was removed under vacuum, and the residue taken up in ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated to give nearly pure product as a yellow oil. Yield 5.90 g (99%). 1H NMR. MS: 269 [M+H]+. Solvent was removed under vacuum washed with water, brine dried (MgSO4) evaporated to give nearly pure product as a yellow oil

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

Procedure: 50 mg (0.12 mmol) of 3-({[6-amino-3,5-dicyano-4-(4-fluorophenyl)pyridin-2-yl]sulfanyl}methyl)-benzenecarboxylic acid Example 14 were initially charged in 1.2 ml of DMF. The reaction solution was cooled to 0° C. After addition of 94 mg (0.25 mmol) of HATU, the mixture was stirred at 0° C. for 20 min. 22.5 mg (0.25 mmol) of (R)-3-amino-1,2-propanediol and 32 mg (0.25 mmol) of N,N-diisopropylethylamine were added, and the reaction solution was stirred at RT overnight. Water and tetrahydrofuran were added to the reaction mixture until a clear solution had formed. The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid). the reaction solution was stirred at RT overnight had formed The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid)

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

Procedure: 61.5 mg (0.15 mmol) of 3-{[(6-chloro-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methyl}benzenecarboxylic acid (Example 72A) were initially charged in 1.6 ml of THF. After addition of 27.6 mg (0.30 mmol) of (2R)-3-aminopropane-1,2-diol, the mixture was stirred at RT overnight. 2 ml of water were added, and the reaction mixture was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid). the reaction mixture was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid)

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

Procedure: The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acid obtained in step B of Example 2-2-1 and (R)-3-amino-1,2-propanediol (produced by Wako Pure Chemical Industries) in accordance with the same procedure as in the methods described in step C of Example 1-2-3.

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

Procedure: The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzoic acid obtained in step B of Example 2-2-1 and (R)-3-amino-1,2-propanediol (produced by Wako Pure Chemical Industries) in accordance with the same procedure as in the methods described in step C of Example 1-2-3.

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

Procedure: A mixture of 6-(bromomethyl)-5-(3-chlorobenzoyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (2 g, 5.38 mmol), (R)-3-aminopropane-1,2-diol (0.490 g, 5.38 mmol) and triethylamine (0.750 ml, 5.38 mmol) in EtOH (17.94 ml) was heated under microwave irradiation at 100° C. for 1 hour. The mixture was evaporated under vacuum and the residue partitioned between DCM (20 mL) and 1M HCl (20 mL). The phases were separated and the organic phase was washed with water (2×20 mL). The organic phase was passed through a hydrophobic frit and evaporate under vacuum to afford the title compound. The mixture was evaporated under vacuum the residue partitioned between DCM (20 mL) and 1M HCl (20 mL) The phases were separated the organic phase was washed with water (2×20 mL) evaporate under vacuum