(1S)-2,3-dihydro-1H-inden-1-amine

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

Procedure: To a stirred solution of (R)- or (S)-indane amine (1 eq) in DCM (0.05M) was added TEA (2 eq) and the appropriate sulfonyl chloride (2 eq.) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the pure product isolated after preparative HPLC purification. at room temperature The solvent was evaporated the pure product isolated after preparative HPLC purification

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

Procedure: To a stirred solution of (R)- or (S)-indane amine (1 eq) in DCM (0.05M) was added TEA (2 eq) and the appropriate sulfonyl chloride (2 eq.) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the pure product isolated after preparative HPLC purification. at room temperature The solvent was evaporated the pure product isolated after preparative HPLC purification

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A jacketed reactor was charged with (1S,2S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol (30.8 Kg, 115.05 mol), 2-butanol (198.5 Kg), (S)-(+)-1-aminoindane (16.95 Kg, 127.26 mol) and diisopropylethylamine (19.45 Kg, 150.50 mol). The mixture was heated to 55±5° C. and then moved to a mobile vessel. The reactor was then rinsed with 2-butanol (15.6 Kg) at 55±5° C. which was moved to the mobile vessel. The mobile vessel contents were then transferred to a pressure reactor and 2-butanol (51 L) was used to rinse the mobile vessel. The reaction mixture was then heated to 135±5° C. and adjusted to a pressure of 8 bar. The mixture was then stirred until reaction was complete by HPLC analysis. The mixture was cooled to 30±10° C. and transferred to a mobile vessel via a plate filter. The pressure reactor was rinsed with 2-butanol (43.1 L). The contents of the mobile vessel were then charged to a jacketed reactor via an in-line filter and the vessel rinsed with 2-butanol (39.2 Kg). The mixture was heated to 50±5° C. and concentrated under reduced pressure to about 50 L. The mixture was cooled to 20±5° C. and then dichloromethane (256 Kg) added over a period of about 3 hours. The mixture was stirred for a further 9.5 hours and then further cooled to 0±5° C. and stirred for about 4 hours. The solid product was isolated by filtration and washed with dichloromethane (82 Kg) at 0±5° C. The solids were then dried under reduced pressure at 40±5° C. to constant weight. A reactor was charged with water (371 Kg) and the dried solids and the mixture stirred at 20±5° C. for about 14.5 hours. The solid product was isolated by filtration and washed with water (371 Kg). The solids were then dried under reduced pressure at 50±5° C. to afford the title compound (32.4 Kg) as a white solid. 1H NMR (300 MHz, DMSO, 6): 8.15 (s, 1H), 7.71 (d, 1H), 7.07-7.29 (m, 5H), 6.61 (d, 1H), 5.88 (dd, 1H), 5.24-5.38 (m, 1H), 4.60 (d, 1H), 4.26-4.37 (m, 2H), 3.53-3.65 (m, 1H), 3.35-3.46 (m, 1H), 2.90-3.04 (m, 1H), 2.75-2.90 (m, 1H), 2.33-2.56 (m, 2H), 2.04-2.14 (m, 2H), 1.88-2.03 (m, 2H), 1.74-1.87 (m, 1H). moved to a mobile vessel The reactor was then rinsed with 2-butanol (15.6 Kg) at 55±5° C. which The mobile vessel contents were then transferred to a pressure reactor to rinse the mobile vessel The reaction mixture was then heated to 135±5° C. The mixture was cooled to 30±10° C. transferred to a mobile vessel via a plate filter The pressure reactor was rinsed with 2-butanol (43.1 L) The contents of the mobile vessel were then charged to a jacketed reactor via an in-line filter the vessel rinsed with 2-butanol (39.2 Kg) The mixture was heated to 50±5° C. concentrated under reduced pressure to about 50 L The mixture was cooled to 20±5° C. dichloromethane (256 Kg) added over a period of about 3 hours The mixture was stirred for a further 9.5 hours further cooled to 0±5° C. stirred for about 4 hours The solid product was isolated by filtration washed with dichloromethane (82 Kg) at 0±5° C The solids were then dried under reduced pressure at 40±5° C. to constant weight A reactor was charged with water (371 Kg) the dried solids and the mixture stirred at 20±5° C. for about 14.5 hours The solid product was isolated by filtration washed with water (371 Kg) The solids were then dried under reduced pressure at 50±5° C.

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

Procedure: A mixture containing 3-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}-5-[(methyloxy)carbonyl]benzoic acid (0.34 g, 1.0 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.51 g, 1.6 mmol), (S)-(+)-1-aminoindan (0.17 g, 1.3 mmol), diisopropylethylamine (0.6 mL, 3.4 mmol) and DMF (70 mL) were stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted 3' with ethyl acetate and 3× with 5% aqueous lithium chloride, and dried over sodium sulfate. Filtration, concentration, and purification by reverse phase HPLC gave the product as a yellow solid (0.41 g, 90% yield). 1H NMR (400 MHz, d6-DMSO): δ 9.09 (d, 1H), 8.91 (s, 1H), 8.83 (d, 1H), 8.75 (t, 1H), 8.70 (t, 1H), 8.45 (t, 1H), 7.73 (br, 2H), 7.28 (d, 2H), 7.24-7.17 (m, 2H), 5.64-5.58 (q, 1H), 3.91 (s, 3H), 3.04-3.00 (m, 1H), 3.00-2.87 (m, 1H), 2.83 (d, 3H), 2.53-2.51 (m, 1H), 2.06-1.96 (m, 1H). MS (EI) for C24H23N5O4: 446 (MH+). extracted 3' with ethyl acetate and 3× with 5% aqueous lithium chloride dried over sodium sulfate Filtration, concentration, and purification by reverse phase HPLC

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

Procedure: The 3-amino-6-[3-(bromomethyl)phenyl]-N-ethylpyrazine-2-carboxamide (112 mg, 1.0 eq) was dissolved in acetonitrile (5 mL) and treated with (1S)-2,3-dihydro-1H-inden-1-amine (133.8 mg, 3.0 eq), diisopropylethylamine (69.3 mg, 1.6 eq) at ambient temperature. After being stirred for 7 h, the white suspension was filtered on Celite and concentrated in vacuo. The resulting residue was purified by flash column chromatography to give the 3-amino-6-(3-{[(1S)-2,3-dihydro-1H-inden-1-ylamino]methyl}phenyl)-N-ethylpyrazine-2-carboxamide (50.2 mg, 39% yield): 1H NMR (400 MHz, CD3OD): δ 8.72 (s, 1H), 8.21 (s, 1H), 8.11 (d, 1H), 7.61 (d, 1H), 7.58 (t, 1H), 7.49 (d, 1H), 7.39 (d, 2H), 7.39 (d, 2H), 7.37 (m, 1H), 4.38 (s, 2H), 3.47 (m 1H), 3.23 (m, 1H), 3.01 (m, 1H), 2.64 (m, 1H), 2.39 (m, 1H); MS (EI) for C23H25N5O: 388.22 (MH+). the white suspension was filtered on Celite concentrated in vacuo The resulting residue was purified by flash column chromatography

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

Procedure: The 3-amino-6-[3-(bromomethyl)phenyl]-N-ethylpyrazine-2-carboxamide (112 mg, 1.0 eq) was dissolved in acetonitrile (5 mL) and treated with (1S)-2,3-dihydro-1H-inden-1-amine (133.8 mg, 3.0 eq), diisopropylethylamine (69.3 mg, 1.6 eq) at ambient temperature. After being stirred for 7 h, the white suspension was filtered on Celite and concentrated in vacuo. The resulting residue was purified by flash column chromatography to give the 3-amino-6-(3-{[(1S)-2,3-dihydro-1H-inden-1-ylamino]methyl}phenyl)-N-ethylpyrazine-2-carboxamide (50.2 mg, 39% yield): 1H NMR (400 MHz, CD3OD): δ 8.72 (s, 1H), 8.21 (s, 1H), 8.11 (d, 1H), 7.61 (d, 1H), 7.58 (t, 1H), 7.49 (d, 1H), 7.39 (d, 2H), 7.39 (d, 2H), 7.37 (m, 1H), 4.38 (s, 2H), 3.47 (m 1H), 3.23 (m, 1H), 3.01 (m, 1H), 2.64 (m, 1H), 2.39 (m, 1H); MS (EI) for C23H25N5O: 388.22 (MH+). the white suspension was filtered on Celite concentrated in vacuo The resulting residue was purified by flash column chromatography

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

Procedure: 3-bromo-N-[(1S)-2,3-dihydro-1H-indene-1-yl]benzenesulfonamide was synthesized according to the procedure described above from (S)-1-aminoindan and 3-bromobenzensulfonyl chloride. Yield 52%. 1H NMR (400 MHz, CDCl3): 7.20 (m, 1H), 7.90 (dd, 1H), 7.80 (dd, 1H), 7.50 (t, 1H), 7.20 (m, 2H), 7.15 (m, 1H), 7.02 br d, 1H), 4.80 (t, 1H), 2.90(m, 1H), 2.70 (m, 1H), 2.20 (m, 1H), 1.70 (m, 1H).

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

Procedure: Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (S)-(+)-1-aminoindan. Prepared

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

Procedure: Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (S)-(+)-1-aminoindan. Prepared

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

Procedure: To a solution of (S)-(+)-1-aminoindan (176 mg, 1.29 mmol) in THF (10.0 mL) was added Et3N (0.200 mL, 1.43 mmol) followed by di-tert-butyldicarbonate (286 mg, 1.31 mmol). The mixture was stirred under an atmosphere of nitrogen for 3 days, concentrated, diluted with DCM (100 mL), and washed with 0.1 N aq hydrochloric acid (50.0 mL) and aq NaCl. The organic layer was dried (MgSO4), filtered and concentrated. The tan solid was taken up in tetrahydrofuran (10.0 mL) and to this was added with a 1.00 M solution of lithium aluminum hydride (1.0 M in THF, 5.80 mL). The mixture was heated at reflux for 6 hours, quenched with water (0.300 mL), 15% aq NaOH solution (0.300 mL) and water (0.900 mL). This was stirred for 10 minutes, filtered through celite, diluted with EtOAc (100 mL), dried (MgSO4), filtered and concentrated. The residue was purified via flash chromatography (0 to 100% EtOAc/hexanes to 10% MeOH/DCM) to afford the title compound as a black solid (146 mg, 77%). concentrated diluted with DCM (100 mL) washed with 0.1 N aq hydrochloric acid (50.0 mL) and aq NaCl The organic layer was dried (MgSO4) filtered concentrated to this was added with a 1.00 M solution of lithium aluminum hydride (1.0 M in THF, 5.80 mL) The mixture was heated at reflux for 6 hours quenched with water (0.300 mL), 15% aq NaOH solution (0.300 mL) and water (0.900 mL) This was stirred for 10 minutes filtered through celite diluted with EtOAc (100 mL) dried (MgSO4) filtered concentrated The residue was purified via flash chromatography (0 to 100% EtOAc/hexanes to 10% MeOH/DCM)

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

Procedure: To a solution of (S)-(+)-1-aminoindan (176 mg, 1.29 mmol) in THF (10.0 mL) was added Et3N (0.200 mL, 1.43 mmol) followed by di-tert-butyldicarbonate (286 mg, 1.31 mmol). The mixture was stirred under an atmosphere of nitrogen for 3 days, concentrated, diluted with DCM (100 mL), and washed with 0.1 N aq hydrochloric acid (50.0 mL) and aq NaCl. The organic layer was dried (MgSO4), filtered and concentrated. The tan solid was taken up in tetrahydrofuran (10.0 mL) and to this was added with a 1.00 M solution of lithium aluminum hydride (1.0 M in THF, 5.80 mL). The mixture was heated at reflux for 6 hours, quenched with water (0.300 mL), 15% aq NaOH solution (0.300 mL) and water (0.900 mL). This was stirred for 10 minutes, filtered through celite, diluted with EtOAc (100 mL), dried (MgSO4), filtered and concentrated. The residue was purified via flash chromatography (0 to 100% EtOAc/hexanes to 10% MeOH/DCM) to afford the title compound as a black solid (146 mg, 77%). concentrated diluted with DCM (100 mL) washed with 0.1 N aq hydrochloric acid (50.0 mL) and aq NaCl The organic layer was dried (MgSO4) filtered concentrated to this was added with a 1.00 M solution of lithium aluminum hydride (1.0 M in THF, 5.80 mL) The mixture was heated at reflux for 6 hours quenched with water (0.300 mL), 15% aq NaOH solution (0.300 mL) and water (0.900 mL) This was stirred for 10 minutes filtered through celite diluted with EtOAc (100 mL) dried (MgSO4) filtered concentrated The residue was purified via flash chromatography (0 to 100% EtOAc/hexanes to 10% MeOH/DCM)

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

Procedure: A solution of (1S,2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(6-chloro-9H-purin-9-yl)cyclopentanol (0.091 g, 0.24 mmol), triethylamine (0.1 mL, 0.72 mmol) and (S)-1-aminoindane (0.0662 g, 0.48 mmol) in ethanol (5 mL) was refluxed at 95° C. for 14 h and then concentrated under reduced pressure. The residue was purified by flash chromatography (0 to 60% EtOAc/DCM) to afford the title compound (0.09 g, 80%). concentrated under reduced pressure The residue was purified by flash chromatography (0 to 60% EtOAc/DCM)