5-(Aminomethyl)-1-methyl-1H-pyrazole 97%

A solution of the Example 5 (12 mg, 0.021 mmol), diphenylcarbonate (5 mg, 0.023 mmol)) and DMAP (15 mg, 0.123 mmol) in 3 mL acetonitrile was allowed to stir at rt for 16 hrs. (1-Methyl-1H-pyrazol-5-yl)methanamine (6.8 mg, 0.062 mmol) was added and the mixture was further stirred at rt for 1 hr. LC/MS showed completion of the reaction. The solvent was evaporated under reduced pressure and the residue was dissolved in 3 mL methanol and purified using HPLC to afford Example 75. 1H NMR (400 MHz, Methanol-d4) delta 7.74 (d, J=8.5 Hz, 1H), 7.49-7.20 (m, 3H), 7.20-7.03 (m, 2H), 6.87 (d, J=8.2 Hz, 1H), 6.37 (d, J=1.9 Hz, 1H), 6.00-5.68 (m, 2H), 5.38-5.16 (m, 2H), 4.21-3.90 (m, 2H), 3.82-3.47 (m, 3H), 3.46-3.18 (m, 11H), 3.10 (dd, J=15.0, 10.7 Hz, 1H), 2.93-2.60 (m, 3H), 2.58-2.15 (m, 3H), 2.15-1.64 (m, 6H), 1.52-1.17 (m, 2H). LCMS-ESI+(m/z): [M+H]+ calcd for C37H45ClN6O5S: 721.29; found: 721.91.General procedure: To a solutionof the corresponding aldehyde (1.2 eq.; unless stated otherwise) in DMF (2 inL per 0.3 mmol of aldehyde; unless stated otherwise) was added the corresponding amine (2.5 eq.; unless stated otherwise) and the resulting solution was stirred at 25 C to form the corresponding inline. Then, the corresponding isocyano(tosyl)methyl)arene reagent (1 eq.; unless stated otherwise) and K2CO3 (1.5 eq.; unless stated otherwise*) were added and the reaction mixture was stirred at 25 C (unless stated otherwise). The reaction was stopped after the time indicated for each particular reaction. The reaction progress was monitored by TLC. (0083) A saturated aqueous solution of NH4CI (10 mL per 1 mmol of aldehyde) was added to the reaction mixture, which was then extracted with EtOAc (2 x 30 mL per 1 mmol of aldehyde). The combined organic extracts were washed with H2O (2 x 25 mL per 1 mmol of aldehyde), dried over MgSCC, filtered, and the solvent was evaporated in vacuo to provide the crude product. The residue obtained after the workup was purified using column chromatography or preparative TLC (unless stated otherwise). (0084) * note: in cases when the amine was used as HC1 salt, 4 eq. of K2CO3 were usedGeneral procedure: N, N-Diisopropylethylamine (3.0-4.0 eq) was added to 8-methoxyquinoline-3-carboxylic acid (1.0 eq) in solvent (dichloromethane, tetrahydrofuran, or N, N-dimethylformamide, 0.05 to 0.2 M) at room temperature. Then, 1-((dimethylamino)(dimethyliminio)methyl)-1H-[1, 2, 3]triazolo[4, 5-b]pyridine 3-oxide hexafluorophosphate(V)(1.0-1.5 eq) was added and the reaction mixture was stirred for five minutes. Then, amine (1.0 - 2.0 eq) was added and the reaction mixture was stirred for one to sixteen hours. 10% Aqueous citric acid was added and the reaction mixture was extracted with dichloromethane, washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by RP HPLC or silica gel chromatography to give the quinoline-3-carboxamide (1%-95% yield).To a soluiton of 2-methyl-2H-pyrazole-3-carboxylic acid amide (crude, 3.97 mmol) in THF (50 mL) was added LiA1H4 (453 mg, 11.9 mmol). After stirred at reflux overnight, the reaction mixture was quenched by H20 (2 mL). And the mixture was then dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated in vacuum. The residue was used for next step without further purification.To a solution of General procedure: To a stirred solution of compound 11 (100 mg, 0.245 mmol) in DMF (4 mL) was added diisopropylethylamine (DiPEA) (95 mg, 0.735 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU) (112 mg, 0.294 mmol) followed by addition of aryl or aliphatic amines (12a-m) (0.279 mmol) and stirred at room temperature for 18 h. After completion reaction mixture was poured into ice cold water extracted with ethyl acetate (2 × 15 mL), combined extracts were washed with brine solution, dried over anhy. Na2SO4 and concentrated under reduced pressure to afford crude product. This crude compound was purified by column chromatography (elutent:2 % methaol: CH2Cl2) to affords pure compounds 13a-m as yields of the products varied between 80-94 %. By adapting this procedure the compounds 13a-13m were synthesized (Scheme-II).Step a. To a mixture of tert-butyl 2-chloro-4-(3-(2-oxopyrrolidin-l-yl)phenyl)-5, 7-dihydro-6H- pyrrolo[3, 4-d]pyrimidine-6-carboxylate (prepared as in step a of Example 289, 0.450 g, 1.086 mmol) and l-methyl-lH-pyrazol-5-yl)methylamine (CAS Number 863548-52-1; 0.180 g, 1.629 mmol) in 1, 4-dioxane (100 ml) was added K2C03 (0.450 g, 3.258 mmol) at rt. The reaction mixture was degassed for 10 min before addition of Pd2(dba)3 (0.099 g, 0.108 mmol) and Xanthphos (0.062 g, 0.108 mmol). The reaction mixture was heated at 90C for 16 h. The resulting mixture was cooled to rt, poured into water (20 ml) and extracted with EtOAc (3 x 30 ml). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (3.2% MeOH in DCM) yielding tert-butyl 2-(((l-methyl-lH-pyrazol-5- yl)memyl)amino)-4-(3-(2-oxopyrrolidin-l-yl)phenyl)-5, 7-dihydro-6H-pyrrolo[3, 4-d]pyrimidine-6- carboxylate (0.250 g, 0.511 mmol). LCMS: Method A, 1.858 min, MS: ES+ 490.41.Example 241 Rac-4-((4bS, 5R, 6S, 7S, 7aR)-4b, 5-dihydroxy-4-methoxy-6-((((1-methyl-1H-pyrazol-5-yl)methyl)amino)methyl)-7-phenyl-4b, 5, 6, 7-tetrahydro-7aH-cyclopenta[4, 5]furo[2, 3-c]pyridin-7a-yl)benzonitrile (Cpd. No. 241F) (1493) Synthesis of rac-(4bS, 5R, 6R, 7S, 7aR)-7a-(4-bromophenyl)-4b, 5-dihydroxy-4-methoxy-N-((1-methyl-1H-pyrazol-5-yl)methyl)-7-phenyl-4b, 6, 7, 7a-tetrahydro-5H-cyclopenta[4, 5]furo[2, 3-c]pyridine-6-carboxamide. (Cpd. No. 241F) (1494) To the solution of rac-(4bS, 5R, 6R, 7S, 7aR)-7a-(4-bromophenyl)-4b, 5-dihydroxy-4-methoxy-7-phenyl-4b, 6, 7, 7a-tetrahydro-5H-cyclopenta[4, 5]furo[2, 3-c]pyridine-6-carboxylic acid (1, 1.00 g, 2.01 mmol) in N, N-dimethylformamide (5 mL) at 0 C., HATU (1.14 g, 3.01 mmol) and N, N-diisopropylethylamine (1.04 ml, 6.02 mmol) were added and the mixture was stirred for 5 min.

Molecular Weight:111.15
XLogP3:-0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:111.079647300
Monoisotopic Mass:111.079647300
Topological Polar Surface Area:43.8
Heavy Atom Count:8
Complexity:74.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes