Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:6]([N:11]2[CH:15]=[C:14]([C:16](OCC)=[O:17])[C:13]([CH3:21])=[N:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:3][N:2]([CH2:4][C:5]1[C:6]([N:11]2[CH:15]=[C:14]([CH2:16][OH:17])[C:13]([CH3:21])=[N:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: CCOC(=O)c1cn(-c2ncccc2CN(C)C)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ncccc2CN(C)C)cc1CO
Reaction time: 0.08 h
Yield: 79 %

Procedure:
To a solution of ethyl 1-[3-(dimethylaminomethyl)-2-pyridyl]-3-methyl-pyrazole-4-carboxylate (217.7 g, 0.75 mmol) in tetrahydrofuran (5 mL) cooled to 0° C. and under nitrogen, 1 M lithium aluminum hydride in tetrahydrofuran (0.9 mL, 0.9 mmol) is added and the mixture is stirred at that temperature for 5 minutes. The reaction is quenched with saturated aqueous solution of ammonium chloride and the crude is extracted with ethyl acetate. The organic layer is separated, dried on sodium sulfate and the solvent is evaporated in vacuo. In this particular example the compound is not isolated in the organic extraction and is finally separated from the aqueous solution with an SCX cartridge to afford 146 mg (78%) of [1-[3-(dimethylaminomethyl)-2-pyridyl]-3-methyl-pyrazol-4-yl]methanol that is used with no further purification. MS (m/z): 247 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]=[O:8].[Br:9]N1C(=O)CCC1=O.O.C(OCC)C>CN(C=O)C>[Br:9][C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH:7]=[O:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1sccc1C=O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: Cc1sc(Br)cc1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of 2-methylthiophene-3-carbaldehyde (0.204 g, 1.62 mmol, Comins, D. L.; Killpack, M. O. J. Org. Chem. 1987, 52(1), 104-109) in DMF (10 mL) was added N-bromosuccinimide (0.43 g, 2.43 mmol); the resulting mixture was stirred at rt for about 16 h and then water (75 mL) and diethyl ether (25 mL) were added. The layers were separated and the aqueous layer was extracted with diethyl ether (2×30 mL). The combined organic layers were washed with water (15 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/hexanes 1:9) to give 5-bromo-2-methylthiophene-3-carbaldehyde (0.272 g, 1.33 mmol, 82%) as a yellow oil which crystallized on standing: 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.72 (3 H, s), 7.33 (1 H, s), 9.9 (1 H, s).
Reaction SMILES: C[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.C1C(=O)N(Cl)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCOC(C)=O.[C:44]([Cl:48])(Cl)(Cl)[Cl:45]>>[Cl:45][CH:44]([Cl:48])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc2ncccc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Product: ClC(Cl)c1ccc2ncccc2n1

Procedure:
A mixture of 2-methyl-1,5-naphthyridine (CAS#7675-32-3, Synchem-OHG #CDP146FP1, 998 mg, 6.92 mmol), NCS (1109 mg, 8.31 mmol), and benzoyl peroxide (84 mg, 0.347 mmol) in CCl4 (34 mL) was stirred at reflux for 17 h. The reaction mixture was checked by TLC (100% EtOAc). Volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on an Analogix IF-280 (Agilent SF15-24 g, 7:3 to 3:7 hexane/EtOAc). Fractions #7-8 were combined and concentrated under reduced pressure to give the undesired byproduct, 2-(dichloromethyl)-1,5-naphthyridine, as an off-white solid (113 mg, 7.7% yield). Fractions #12-18 were combined and concentrated under reduced pressure to give the desired 2-(chloromethyl)-1,5-naphthyridine as an off-white solid (472 mg, 38.2%). 1H NMR (300 MHz, CDCl3) δ 8.99 (dd, J=4.2, 1.6, 1H), 8.45 (d, J=8.8, 1H), 8.38 (ddd, J=8.5, 1.5, 0.8, 1H), 7.85 (d, J=8.7, 1H), 7.66 (dd, J=8.6, 4.2, 1H), 4.86 (s, 2H). MS (DCI—NH3) m/z=179 (M+H)+, m/z=196 (M+NH4)+, m/z=213 (M+NH4+NH3)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:25]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([F:25])=[O:16])[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To a cooled (-15° C.) solution of t-butoxycarbonylisoleucine (0.482 g, 2 mmol) and pyridine (0.16 ml) in methylene chloride (5 ml) is dropped cyanuric fluoride (0.9 ml) and the mixture is stirred at -15° C. for 1 hour. The reaction mixture is diluted with methylene chloride and ice, and filtered on Celite. The filtrate is diluted with ice water and extracted with methylene chloride. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give t-butoxycarbonylisoleucine fluoride.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[C:23]([CH3:32])=[C:24]2[C:29](=[CH:30][CH:31]=1)[O:28][CH2:27][CH2:26][CH2:25]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCC1CCOCC1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2C)CCCO3)c2cc[nH]c2c(=O)n1C
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3CC2CCOCC2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 49 step D from methyl 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 4-(bromomethyl)tetrahydro-2H-pyran, and was isolated as beige solid after reverse phase chromatography (45%): 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29 (d, J=8.6 Hz, 0.5H), 7.02-6.96 (m, 0.5H), 6.96-6.90 (m, 1H), 6.80-6.66 (m, 1H), 5.81-5.67 (m, 1H), 5.46-5.10 (m, 1H), 4.54-4.28 (m, 2H), 4.28-4.12 (m, 2H), 4.03-3.91 (m, 2H), 3.75-3.64 (m, 3H), 3.46-3.30 (m, 2H), 2.81-2.55 (m, 2H), 2.22 (d, J=3.7 Hz, 1H), 2.17-2.05 (m, 2H), 2.05-1.88 (m, 3H), 1.65-1.46 (m, 2H), 1.46-1.28 (m, 2H), 1.15 (s, 6H), 1.02 (s, 3H); LCMS (m/z) ES+=523 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[O:12]C(=O)[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[CH:24][CH:23]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH:9]([NH:10][C:14](=[O:15])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[CH:26][CH:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2cccc(Cl)c2)C1Cc1ccc(CC(F)(F)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of tert-butyl (4RS,5SR)-5-(3-chlorophenyl)-2-oxo-4-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-1,3-oxazolidine-3-carboxylate (2.66 g, 5.12 mmol) in methanol-tetrahydrofuran (20 ml-20 ml) was added 1N sodium hydroxide (6.2 ml, 6.2 mmol), and the mixture was stirred overnight at room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give tert-butyl (1RS,2SR)-2-(3-chlorophenyl)-2-hydroxy-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]ethylcarbamate (2.11 g, 83%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:19]=3[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[C:27]([O:29]CC)=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[OH-].[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[S:21][C:20]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:19]=3[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[C:27]([OH:29])=[O:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In tetrahydrofuran (10 ml) was dissolved 1-(tert-butoxycarbonyl)-4-[(6-chlorobenzo[b]thien-2-yl)sulfonyl]-2-(ethoxycarbonyl)piperazine (2.25 g), followed by the addition of ethanol (20 ml) and a 3N aqueous solution (3 ml) of sodium hydroxide. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was adjusted to have pH of 1 to 2 by the addition of a 1N aqueous solution of hydrochloric acid. Ethyl acetate was then added and the organic layer was collected. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The solid thus precipitated was collected by filtration, whereby the title compound (2.17 g) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]=[C:19]=[S:20])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[C:26]([CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:32][CH2:31]1)([CH3:29])([CH3:28])[CH3:27]>C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:25])=[C:5]([C:21]([O:23][CH3:24])=[O:22])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([NH:39][CH2:38][CH2:37][CH2:36][N:33]3[CH2:32][CH2:31][CH:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:35][CH2:34]3)=[S:20])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(N=C=S)c1
Reactant: CC(C)(C)C1CCN(CCCN)CC1
Solvent: c1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)N1c1cccc(NC(=S)NCCCN2CCC(C(C)(C)C)CC2)c1
Yield: 64 %

Procedure:
1,4-Dihydro-2,6-dimethyl-4-(3-isothiocyanatophenyl)-3,5-pyrazinedicarboxylic acid, dimethyl ester (25 mg, 0.069 mmol) was refluxed with 4-tert-butyl-piperidine-1-propanamine (16 mg, 0.081 mmol) in 2 mL of benzene for 30 min. Chromatographic purification (silica gel, eluted with 10% (v/v) methanol in methylene chloride) of the resultant residue after concentration in vacuo gave the title compound as a yellow powder (64%); 1H-NMR (CDCl3) δ 8.20 (br, 1H), 7.98 (br, 1H), 7.05 (t, 1H, J=8.1 Hz), 6.79 (br, 1H), 6.66 (d, 1H, J=8.0 Hz), 6.50-6.60 (m, 2H), 3.70 (s, 6H), 3.55 (m, 2H), 3.28 (m, 2H), 2.72 (m, 2H), 2.30-2.55 (m, 2H), 2.37 (s, 6H), 1.86 (m, 2H), 1.50-1.80 (m, 2H), 0.95-1.25 (m, 1H), and 0.79 (s, 6H); 13C-NMR (CDCl3) δ 180.9, 166.3, 152.8, 150.1, 129.9, 116.3, 112.7, 109.9, 108.5, 53.9, 51.8, 44.9, 42.1, 32.1, 29.8, 27.2, 24.7, 24.5, and 17.8.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([N+:14]([O-])=O)[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:25][NH:26][CH2:27][CH2:28][CH3:29]>ClCCl>[CH3:18][O:17][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][C:11]=1[NH2:14])[N:5]([C:3](=[O:4])[CH2:2][N:26]([CH3:25])[CH2:27][CH2:28][CH3:29])[CH2:6][CH2:7]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Reactant: CCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCN(C)CC(=O)N1CCc2cc(OC)c(N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (4.0 g, 12.7 mmol) was dissolved in 50 mL of dichloromethane, then K2CO3 (4.4 g, 31.7 mmol) and N-methyl-1-propanamine (1.9 g, 25.4 mmol) in 10 mL dichloromethane were added, the reaction was stirred at RT for 3 hours. After filtration, the organic layers were washed with water (2×100 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting residue was dissolved in 10 mL of EA , 25 mL of MeOH and 15 mL of THF, then 0.8 g 10% Pd/C was added and the reaction was stirred at RT overnight under H2 pressure (65 psi). The catalyst was removed via filtration and the solvent was removed under reduced pressure to afford 5-(methyloxy)-1-{[methyl(propyl)amino]acetyl}-2,3-dihydro-1H-indol-6-amine as a yellow solid, 3.0 g (96%). 1HNMR (400 MHz, DMSO-d6) δ ppm: 0.81 (t, J=7.14 Hz, 3H), 1.40 (m, 2H), 2.21 (s, 3H), 2.35(m, 2H), 2.94 (t, J=8.24 Hz, 2 H), 3.17(s, 2H), 3.70 (s, 3H), 4.07 (t, J=8.33 Hz, 2 H), 4.60 (s, 2H), 6.67 (s, 1 H), 7.52 (s, 1 H).
Reaction SMILES: I[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1.[CH3:12][O-:13].[Na+].[Na]>CO.C1COCC1>[CH3:12][O:13][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10][CH3:11])=[O:9])[CH:4]=1
Reactant: COC(=O)c1cc(CI)on1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cc(C(=O)OC)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1.34 g (5 mmole) of methyl 5-(iodomethyl)-3-isoxazolecarboxylate in 20 ml of methanol and 5 ml of THF is added to a solution of methanol and 5 ml of THF is added to a solution of sodium methoxide prepared from 0.15 g (6.5 mmole) sodium and 10 ml of methanol. The reaction mixture is stirred at room temperature for four hours, heated to reflux for 30 minutes, and then worked up as usual giving 0.65 g of product. The crude ester is recrystallized from ether-cyclohexane mixture to give 0.33 g of off-white solid, mp 47.5°-49° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH:20]([C:21]([O:23]C(C)(C)C)=[O:22])[CH2:19][CH2:18][NH:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:36]([O:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:1]1([CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH:20]([C:21]([OH:23])=[O:22])[CH2:19][CH2:18][N:17]2[C:44]([O:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C1CCNC1CCCCCCC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCCCC1C(C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 17 (0.1 mol.) is added to a mixture of dichloromethane (200 ml.), triethylamine (0.11 mol.) and benzyloxycarbonyl chloride. The mixture is stirred for 2 hours at room temperature, washed with 5% potassium bisulfate, water, dried, and concentrated to dryness. The residue, 3-(t-butoxycarbonyl)-1-[(phenylmethyloxy)carbonyl]-2-pyrrolidineheptanoic acid phenylmethyl ester is dissolved in trifluoroacetic acid and the solution stored at room temperature for 1 hour. The solution is concentrated to dryness in vacuo yielding 3-carboxy-1-[(phenylmethyloxy)carbonyl]-2-pyrrolidineheptanoic acid phenylmethyl ester.
Reaction SMILES: [Cl:1][C:2]1([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:6](SC2C=CC=CC=2)[CH2:5][C:4](=[O:14])[O:3]1.ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[Cl:1][C:2]1([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH:6]=[CH:5][C:4](=[O:14])[O:3]1
Reactant: O=C1CC(Sc2ccccc2)C(Cl)(C(=O)OC(c2ccccc2)c2ccccc2)O1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1C=CC(Cl)(C(=O)OC(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
In 10 ml of dichloromethane was dissolved 0.30 g of the Compound (48) obtained in Example 48. To the solution was added 150 mg of 3-chloroperbenzoic acid. The mixture was stirred at room temperature for 30 minutes. The reaction solution was washed with an aqueous solution of sodium hydrogen carbonate and water, successively. The resultant was dried (Na2SO4), and the solvent was evaporated off. The residue was dissoved in 6 ml of toluene, and the solution was heated at 60° C. for 30 minutes, then the solvent was evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (5:1) to give 0.15 g of the subject Compound (49) as colorless crystals. Recrystallization from ethyl acetatehexane to give colorless needless, m.p. 99°-101° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[O:22][CH2:23][CH2:24][NH2:25].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[F:19][C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[O:22][CH2:23][CH2:24][NH:25][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1ccccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3ccccc3F)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 25.6 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(2-fluorophenoxy)ethylamine hydrochloride (700 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(2-fluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile hydrochloride (126 mg).
Reaction SMILES: Cl[Si](C)(C)C.Br[C:7]([F:14])([F:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1([CH2:24][NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)C2C=CC=CC=2N=N1>O1CCCC1.[Zn]>[CH2:11]([O:10][C:8](=[O:9])[C:7]([F:14])([F:13])[CH2:24][NH:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: c1ccc2c(c1)nnn2CNC1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)CNC1CCCC1
Reaction time: 0.17 h
Yield: 39.1 %

Procedure:
To a suspension of 4.3 g (0.066 g-atom) of zinc powder in 40 mL of tetrahydrofuran was added 4.1 mL (0.032 mole) of chlorotrimethylsilane. After stirring for 10 minutes, 6.6 g (0.032 mole) of ethyl bromodifluoroacetate was added dropwise at room temperature. After 10 minutes, a solution of 7.0 g (0.032 mole) of benzotriazol-1-ylmethyl-cyclopentyl-amine in tetrahydrofuran was added dropwise. The reaction mixture was stirred at room temperature for 3 hours and then quenched by the addition of saturated aqueous sodium carbonate. The mixture was filtered through Celite. The filtrate was extracted twice with ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was distilled under vacuum to give 2.77 g of 3-cyclopentylamino-2,2-difluoro-propanoic acid ethyl ester as a colorless oil. bp 75-82 degrees at 10 mm Hg.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22]Br>>[F:19][C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(Cc4ccc(F)cc4F)CC3)cccc2n1
Yield: 88 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2,4-Difluorobenzyl bromide (76.6 mg; 0.37 mmol) to obtain 65 mg. (88% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.87 (s, 1H), 7.67 (m, 3H), 7.48 (m, 1H), 7.24 (m, 3H), 7.09 (m, 1H), 3.61 (s, 2H), 3.02 (br d, J=10.8 Hz, 2H), 2.89 (m, 4H), 2.33 (m, 2H). ESIMS+371.5 m/z
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[BH3-]C#N.[Na+].[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH:33]=O>CO>[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH2:33][N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(Cc2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.7 %

Procedure:
To a solution of COMPOUND 249 (0.1182 g, 0.38 mmol) in MeOH (8 mL) was added NaBH3CN (0.0477, 0.76 mmol) and 2-imidazole carboxaldehyde (0.0438 g, 0.46 mmol), and stirred at room temperature for 24 hours then concentrated. Saturated NaHCO3 (15 mL) was added and extracted with CH2Cl2 (2×40 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 0.0486 g (31%) of COMPOUND 336 as a white solid. 1H NMR (CDCl3) δ 1.67-1.87 (m, 4H), 1.99 (t, 2H, J=11.3 Hz), 2.08 (s, 6H), 2.47-2.55 (m, 1H), 2.87 (d, 2H, J=11.1 Hz), 3.58 (s, 2H), 3.82 (s, 4H), 6.98 (s, 2H), 7.02-7.09 (m, 2H), 7.35 (d, 2H, J=7.2 Hz), 8.33 (d, 2H, J=3.9 Hz). 13C NMR (CDCl3) δ 18.39, 27.23, 54.15, 55.31, 56.25, 57.94, 121.88, 122.77, 127.09, 133.81, 138.42, 146.20, 157.67. ES-MS m/z 377 (M+Na+). Anal. Calcd. for C23H30N6.0.6CH4O: C, 69.18; H, 7.97; N, 20.51. Found: C, 69.05; H, 7.78; N, 20.39.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[C:11]([O:19][CH3:20])[N:10]=1)C1C=CC=CC=1>CO.CC(O)=O.[OH-].[Pd+2].[OH-]>[CH3:20][O:19][C:11]1[N:10]=[C:9]([NH2:8])[CH:14]=[CH:13][C:12]=1[C:15]([F:18])([F:16])[F:17]
Reactant: COc1nc(N(Cc2ccccc2)Cc2ccccc2)ccc1C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1nc(N)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of N,N-dibenzyl-6-methoxy-5-(trifluoromethyl)pyridin-2-amine (3.0 g, 8.056 mmol) in a mixture of methanol (30 mL) and AcOH (3 mL) was added palladium hydroxide (0.3 g, 0.43 mmol) under a nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (55 psi, 25° C.) overnight. The catalyst was removed by filtration through a pad of celite and the filtrate was neutralized by saturated Na2CO3. The aqueous layer was extracted with CH2Cl2 (30 mL×3) and the combined organic layers were concentrated under vacuum to give 6-methoxy-5-(trifluoromethyl)pyridin-2-amine (1.4 g, 90%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J=8.4 Hz, 1H), 6.03 (d, J=8.0 Hz, 1H), 4.64 (brs, 2H), 3.93 (s, 3H). MS (ESI) m/e (M+H) 193. 13C NMR (100 MHz, CDCl3) 159.4, 138.0 (d, J=5.9 Hz), 125.9, 122.3, 101.9 (d, J=44.4 Hz), 98.3, 53.6. 19F NMR (282.4 MHz, CDCl3)-62.6.