(3R)-N-methylpyrrolidin-3-amine

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

Procedure: The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (R)-3-methylaminopyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.36 (s, 3H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 437 [M+H]

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

Procedure: The title compound was prepared as a solid by the method of Example 75 step ii) using the product of Example 75 step i) and (R)—N-methylpyrrolidin-3-amine.

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

Procedure: Under nitrogen atmosphere, a dimethyl sulfoxide (3 ml) solution of (3R)-3-methylaminopyrrolidine (95 μl, 0.88 mmol) was added at 150° C. to a dimethyl sulfoxide (17 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (271 mg, 0.838 mmol) and triethylamine (156 μl, 1.09 mmol), followed by stirring at the same temperature for 30 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with chloroform. After cooling the reaction liquid was extracted with chloroform

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

Procedure: Under nitrogen atmosphere, a dimethyl sulfoxide (2 ml) solution of (3R)-3-methylaminopyrrolidine (85 μl, 660 μmol) was added at 150° C. to a dimethyl sulfoxide (11 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (180 mg, 557 μmol) and triethylamine (101 μl, 724 μmol), followed by stirring at the same temperature for 30 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with chloroform. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (53 mg, 23%) as a white amorphous substance. After cooling the reaction liquid was extracted with chloroform Next, the combined organic layer was washed with saturated brine dried over anhydrous magnesium sulfate filtered the filtrate was concentrated under reduced pressure

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

Procedure: Under nitrogen atmosphere, a dimethyl sulfoxide (3 ml) solution of (3R)-3-methylaminopyrrolidine (95 μl, 0.88 mmol) was added at 150° C. to a dimethyl sulfoxide (17 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (271 mg, 0.838 mmol) and triethylamine (156 μl, 1.09 mmol), followed by stirring at the same temperature for 30 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with chloroform. After cooling the reaction liquid was extracted with chloroform

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

Procedure: Under nitrogen atmosphere, a dimethyl sulfoxide (2 ml) solution of (3R)-3-methylaminopyrrolidine (85 μl, 660 μmol) was added at 150° C. to a dimethyl sulfoxide (11 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (180 mg, 557 μmol) and triethylamine (101 μl, 724 μmol), followed by stirring at the same temperature for 30 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with chloroform. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (53 mg, 23%) as a white amorphous substance. After cooling the reaction liquid was extracted with chloroform Next, the combined organic layer was washed with saturated brine dried over anhydrous magnesium sulfate filtered the filtrate was concentrated under reduced pressure

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added (R)—N-methylpyrrolidin-3-amine (50 mg, 0.50 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction solution was purified by preparative HPLC to afford the final product as a light color solid. The reaction solution was purified by preparative HPLC

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of 2-chloro-4-bromopyridine (4.3 g, 22.1 mmol) in toluene (100 mL) was added (R)-methyl-pyrrolidin-3-yl-amine (1.7 g, 17.0 mmol) and sodium tert-butoxide (2.5 g, 26.0 mmol). The flask was evacuated and flushed with N2(g) twice. A mixture of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 590 mg, 1.0 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (Pd2(dba)3; 310 mg, 0.34 mmol) was added in one portion and the mixture was heated at 85° C. for 20 h. The mixture was cooled to room temperature (rt), diluted with H2O (75 mL), and extracted with ethyl acetate (EtOAc; 3×). The combined organic layers were dried and concentrated to give a clear brown oil. The oil was purified by FCC (0 to 5% 2 M NH3 in MeOH/CH2Cl2) to give the title compound as a brown solid (1.1 g, 30%). MS (ESI): mass calcd. for C10H14ClN3, 211.09 m/z found, 212.1 [M+H]. 1H NMR (DMSO-d6): 7.86 (d, J=5.9, 1H), 6.47-6.38 (m, 2H), 3.45-3.17 (m, 4H), 3.11-3.01 (m, 1H), 2.29 (s, 3H), 2.15-2.00 (m, 1H), 1.82 (br s, 1H), 1.79-1.65 (m, 1H). Bicyclo[2.2.1]hept-2-yl-[(3R)-4-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine. To a stirring mixture of [(3R)-1-(2-chloro-pyridin-4-yl)-pyrrolidin-3-yl]-methyl-amine (97 mg, 0.46 mmol), exo-2-aminonorbornane (164 μL, 1.4 mmol) in ethylene glycol dimethyl ether (DME; 4 mL) in a scintillation vial was added sodium tert-butoxide (245 mg, 2.6 mmol). To the stirring mixture was added in one portion Pd(OAc)2 (16 mg, 0.024 mmol) and racemic 2,2′-bis(diphenylphosphino)-1,1′-bihaphthyl (BINAP; 19 mg, 0.031 mmol). The mixture was heated at 65° C. for 20 h, then was cooled to rt and filtered through a plug of diatomaceous earth. The plug was washed with MeOH (2 mL) and the filtrate was purified directly by FCC (5% 2 M NH3 in MeOH/CH2Cl2) to give a clear light golden oil (70 mg, 54%). Bicyclo[2.2.1]hept-2-yl-[(3R)-4-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine. To a stirring solution of bicyclo[2.2.1]hept-2-yl-[(3R)-4-(3-methylamino-pyrrolidin-1-yl)-pyridin-2-yl]-amine in 1:1 Et2O/CH2Cl2 (8 mL) was added 1 N HCl in Et2O (1 mL). The organic layers was separated and concentrated to give the desired product (89 mg, 100%) as a beige solid. MS (ESI): mass calcd. for C17H26N4, 286.2; m/z found, 287.3 [M+H]+. 1H NMR (DMSO-d6): 12.07 (s, 1H), 9.57 (br s, 1H), 9.46 (br s, 1H), 7.81 (d, J=5.1, 1H), 7.66 (d, J=4.6, 1H), 6.28 (d, J=7.4, 1H), 5.64 (s, 1H), 3.89 (br s, 1H), 3.85-3.61 (m, 3H), 3.49 (br s, 2H), 2.60 (s, 3H), 2.35-2.20 (m, 3H), 2.18 (s, 1H), 1.95-1.85 (m, 1H), 1.55-1.46 (m, 3H), 1.37-1.25 (m, 2H), 1.21-1.09 (m, 2H). The compounds in Example 2 through Example 15 were prepared using methods analogous to those described for Example 1. The flask was evacuated flushed with N2(g) twice was added in one portion The mixture was cooled to room temperature (rt) extracted with ethyl acetate (EtOAc; 3×) The combined organic layers were dried concentrated to give a clear brown oil The oil was purified by FCC (0 to 5% 2 M NH3 in MeOH/CH2Cl2)

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

Procedure: The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (R)-3-methylaminopyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.36 (s, 3H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 437 [M+H]

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

Procedure: The title compound was prepared as a solid by the method of Example 75 step ii) using the product of Example 75 step i) and (R)—N-methylpyrrolidin-3-amine.

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

Procedure: Under nitrogen atmosphere, a dimethyl sulfoxide (3 ml) solution of (3R)-3-methylaminopyrrolidine (95 μl, 0.88 mmol) was added at 150° C. to a dimethyl sulfoxide (17 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (271 mg, 0.838 mmol) and triethylamine (156 μl, 1.09 mmol), followed by stirring at the same temperature for 30 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with chloroform. After cooling the reaction liquid was extracted with chloroform

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

Procedure: Under nitrogen atmosphere, a dimethyl sulfoxide (2 ml) solution of (3R)-3-methylaminopyrrolidine (85 μl, 660 μmol) was added at 150° C. to a dimethyl sulfoxide (11 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (180 mg, 557 μmol) and triethylamine (101 μl, 724 μmol), followed by stirring at the same temperature for 30 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with chloroform. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (53 mg, 23%) as a white amorphous substance. After cooling the reaction liquid was extracted with chloroform Next, the combined organic layer was washed with saturated brine dried over anhydrous magnesium sulfate filtered the filtrate was concentrated under reduced pressure