Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:25]1([OH:28])[CH:26]=[CH:27][N:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:23]=[CH:24]1
Reactant: c1ccc2occc2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cc3ccccc3o2)C=CN(Cc2ccccc2)C=C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of benzofuran (4 g, 33.9 mmol) in tetrahydrofuran (90 ml) at -10° C. was slowly added a solution of n-butyllithium (2.5M in hexanes, 13.6 ml, 34 mmol), keeping the temperature at -10° C. The reaction was stirred and allowed to warm to room temperature over 1 hr, after which a solution of 1-benzyl-4-piperidone (6.3 ml, 34 mmol) in tetrahydrofuran (30 ml) was added dropwise. Stirring was continued for 2 hr at room temperature. The solvent was evaporated and the residue partitioned between saturated aqueous sodium carbonate (75 ml) and ethyl acetate (3×100 ml). The combined organics were dried (MgSO4) and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate, to give 4-(benzofuran-2-yl)-1-benzyl-4-hydroxypyridine (7.5 g, 75%); δH (CDCl3) 1.96-2.00 (2H, m, piperidinyl CH2), 2.21-2.29 (2H, m, piperidinyl CH2), 2.44 (1H, t, J 6.2 Hz, piperidinyl CH), 2.56 (2H, dt, J 11.1, 2.7 Hz, piperidinyl CH2), 2.64-2.68 (3H, m, piperidinyl CH2, OH), 2.73 (1H, t, J 6.2 Hz, piperidinyl CH), 3.55 (2H, s, PhCH2N), 6.58 (1H, s, 3'-H), 7.19-7.34 (7H, m, ArH), 7.44 (1H, d, J 7.3 Hz, ArH), and 7.52 (1H, d, J 6.6 Hz, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=[O:6].[O-:14][Mn](=O)(=O)=O.[K+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[C:5]([OH:14])=[O:6]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCOc1ccc(C=O)cc1Br
Agent: [K+]
Product: CCCOc1ccc(C(=O)O)cc1Br

Procedure:
3-Bromo-4-propoxybenzaldehyde was oxidized by KMnO4, according to the procedure as described in Example 47, Step A, to give the title compound in 96%, as white solid. 1H-NMR (DMSO-d6) 0.98 (t, 3H, J=7.32 Hz); 1.68-1.79 (m, 2H); 4.06 (t, 2H, J=6.39 Hz); 7.14 (d, 1H, J=8.7 Hz); 7.87 (dd, 1H, J=2.07, 8.61 Hz); 8.01 (d, 1H, J=2.04 Hz); 11.2 (broad s, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28](O)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[N:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][CH2:35][NH:34][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([CH2:24][C@@H:19]2[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]2[C:9]2[O:10][C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH:26]=1
Reactant: NCCc1ccccn1
Reactant: O=C(O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccn1)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a mixture of (S)-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (120 mg, 0.276 mmol) and 2-(2-aminoethyl)pyridine (0.040 ml, 0.331 mmol) in DMF (5 ml) was added 1-hydroxybenzotriazole (56 mg, 0.414 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (106 mg, 0.552 mmol). After stirring the resulting mixture at room temperature for 2 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with water, saturated sodium hydrogencarbonate solution, water and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (methylene chloride:MeOH, 20:1 elution) to give (S)-N-[2-(2-pyridyl)ethyl]-3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzamide (138.8 mg, 93%).
Reaction SMILES: [CH3:1]N(C)C=O.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1.CI>O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[N:16]=[CH:15][N:14]=[C:13]2[O:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]([CH3:1])[C:30](=[O:38])[O:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:27][CH:28]=1
Reactant: CN(C)C=O
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCC4)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(N(C)C(=O)OC4CCCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (7 mg), and cyclohexyl N-{4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (35 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of methyl iodide (47 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (30 mg, yield 83%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([O:8]C)=[N:6][CH:7]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(Br)cc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]cc(Br)cc1N1CCOCC1
Temperature: 100 °C
Yield: 93 %

Procedure:
To a solution of 4-(5-bromo-2-methoxypyridin-3-yl)morpholine (1.0 equiv.) in 1,4-dioxane (0.3 M) was added concentrated HCl (5 equiv.) and the solution was heated to 100° C. for 1 h. Upon cooling to room temperature, the solution was concentrated to dryness under vacuo, then dissolved in water and neutralized with solid sodium bicarbonate. The precipitate was filtered, washed with water and dried under vacuo to give 5-bromo-3-morpholinopyridin-2(1H)-one as a beige solid in 93% yield. LCMS m/z (M+H)=258.9/260.9, Rt=0.48 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1)[CH3:2].Cl.Cl.[CH:20]1([NH:23][C:24](=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[C:27]([CH3:37])[CH:26]=2)[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:24](=[O:38])[C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][N:34]([CH2:16][C:6]4[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]5[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=5[CH:7]=4)[CH2:35][CH2:36]3)=[C:27]([CH3:37])[CH:26]=2)[CH2:22][CH2:21]1
Reactant: CCOc1cc(C=O)cc2c1OC(C)C(=O)N2
Reactant: Cc1cc(C(=O)NC2CC2)ccc1N1CCNCC1
Agent: Cl
Product: CCOc1cc(CN2CCN(c3ccc(C(=O)NC4CC4)cc3C)CC2)cc2c1OC(C)C(=O)N2

Procedure:
Using 398B and N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide-2HCl in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.51-0.57 (m, 2H) 0.63-0.70 (m, 2H) 1.33 (t, J=7.07 Hz, 3H) 1.41 (d, J=6.82 Hz, 3H) 2.25 (s, 3 H) 2.52-2.60 (m, 4H) 2.81 (td, J=7.26, 3.92 Hz, 1H) 2.89 (br. s., 4H) 3.42 (s, 2H) 3.98-4.10 (m, 2H) 4.54-4.66 (m, 1H) 6.51 (d, J=1.52 Hz, 1H) 6.63 (d, J=1.77 Hz, 1H) 7.01 (d, J=8.08 Hz, 1H) 7.55-7.66 (m, 2H) 8.23 (d, J=4.04 Hz, 1H) 10.57 (s, 1H). ESI-MS: m/z 479.5 (M+H)+. mp 223.4-223.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](SC)=[CH:22][N+:23]([O-:25])=[O:24])[CH2:17][CH2:16]1.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:22][N+:23]([O-:25])=[O:24])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCN(C(=C[N+](=O)[O-])SC)CC3)c2cc1OC
Reactant: NCc1ccncc1
Solvent: c1ccncc1
Product: COc1cc2ncnc(N3CCN(C(=C[N+](=O)[O-])NCc4ccncc4)CC3)c2cc1OC
Temperature: 80 °C
Yield: 15.5 %

Procedure:
To a pyridine solution (10 mL) of Compound 58 produced in Example 58 (730 mg, 1.87 mmol), 4-aminomethylpyridine (0.57 mL, 5.61 mmol) was added, followed by stirring in argon atmosphere under heating at 80° C. for 5 hours. After the reaction solution was allowed to stand for cooling, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography to give the target compound (130 mg, 0.29 mmol).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1>N.[Ni].CO.C(Cl)(Cl)Cl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][NH2:11])=[CH:7][CH:8]=1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: [Ni]
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NCCc1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
(4-Trifluoromethyl-phenyl)-acetonitrile (2 g, 10.81 mmol) in methanolic ammonia (50 mL) was added to Raney nickel (400 mg) in methanol taken in a parr hydrogenator. The flask was stirred at 50 PSI overnight. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mixture was filtered through celite bed and the filtrate was dried under reduced pressure to afford 2 g of the product (97.89% yield).
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][C:10]2[C:11]([C:21]3[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=3[F:29])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=CC=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>CC#N.O>[F:29][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=1[C:11]1[C:10]([CH2:9][NH2:8])=[CH:19][C:18]2[C:13](=[C:14]([CH3:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COc1ccc(CNCc2cc3cccc(C)c3nc2-c2c(F)cccc2OC)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(F)c1-c1nc2c(C)cccc2cc1CN

Procedure:
Prepared according to Procedure G using N-(4-methoxybenzyl)(2-(2-fluoro-6-methoxyphenyl)-8-methylquinolin-3-yl)methanamine (1.1795 g, 2.8320 mmol, 1 eq) and ammonium cerium(iv) nitrate (5.434 g, 9.912 mmol, 3.5 eq) in CH3CN—H2O (2:1, 13 mL). After purification, (2-(2-fluoro-6-methoxyphenyl)-8-methylquinolin-3-yl)methanamine was obtained as yellow sticky solid. 1H NMR (DMSO-d6) δ ppm 8.41 (1 H, s), 7.82 (1 H, d, J=7.4 Hz), 7.55-7.60 (1 H, m), 7.45-7.54 (2 H, m), 7.03 (1 H, d, J=8.2 Hz), 6.92-7.00 (1 H, m), 3.71 (3 H, s), 3.59 (2 H, q, J=16.6 Hz), 2.64 (3 H, s), 1.88 (2 H, br. s.). Mass Spectrum (ESI) m/e=297.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:10]2[S:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20].O>CN(C=O)C>[CH2:20]([O:1][C:2]1[C:10]2[S:9][C:8]([CH3:11])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: Cc1nc2cccc(O)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cccc2nc(C)sc12
Temperature: 50 °C
Yield: 71.4 %

Procedure:
To 7-hydroxy-2-methylbenzothiazole (500 mg, 3.0 mmol) in DMF (3 mL) was added K2CO3 (459 mg, 3.32 mmol) followed by allyl bromide (287 uL, 3.32 mmol). The reaction was heated at about 50° C. for about 4 hours and then poured into water. The aqueous mixture was extracted with EtOAc, the combined organic layers were dried over Na2SO4, and the solvent then removed by rotary evaporation. The resulting oil crystallized on standing to give 7-allyloxy-2-methyl-benzothiazole as yellow crystals (440 mg, 71%); LSIMS m/z 206, m.p. 38-39° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[CH2:3][NH:4]C(=O)OCC1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:4][CH2:3][C@@H:2]([OH:1])[CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1
Reactant: [H][H]
Reactant: CN1CCN(C[C@H](O)CNC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C[C@H](O)CN)CC1
Reaction time: 12 h
Yield: 106.9 %

Procedure:
Benzyl N-[(2R)-2-hydroxy-3-(4-methylpiperazin-1-yl)propyl]carbamate 20d (830 mg, 2.70 mmol) was dissolved in 40 mL of methanol followed by the addition of palladium/carbon (85 mg, 10%), filled with hydrogen three times. The reaction solution was stirred for 12 hours and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (2R)-1-amino-3-(4-methylpiperazin-1-yl)propan-2-ol 20e (500 mg) as a light yellow oil, which was used in the next step without further furification.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>ClCCl>[CH3:16][O:15][C:14]1[C:13]([O:17][CH3:18])=[CH:12][CH:11]=[C:10]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:9]=1[O:8][CH2:7][C:3]1([CH2:2][O:1][C:39](=[O:40])[NH:38][CH2:36][CH3:37])[CH2:4][O:5][CH2:6]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)COC2)c1OC
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)OCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)COC1
Temperature: 50 °C

Procedure:
To a stirring solution of 4-[2-(3-Hydroxymethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 104)(100 mg, 0.2604 mmol) in dichloromethane (15 mL), were added triethylamine (0.1 mL, 0.772 mmol) and ethyl isocyanate (55 mg, 0.78 mmol) and the resultant reaction mixture was heated to 50° C. for 16 h. The reaction mixture was quenched with sodium bi carbonate solution and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-25% ethyl acetate in pet ether) to afforded the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[C:36]([O:41][CH3:42])[C:35]([O:43][CH3:44])=[N:34]2>O1CCOCC1.O>[CH3:42][O:41][C:36]1[C:35]([O:43][CH3:44])=[N:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([CH2:30][NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=3[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=3)=[O:13])[CH:32]=2)[N:37]=1
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: COc1nc2ccc(CBr)cc2nc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C#CCOc1ccc(NCc2ccc3nc(OC)c(OC)nc3c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 82 mg (0.280 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone in 3 ml dioxane is added 193 mg (1.40 mmol) potassium carbonate and 119 mg (0.419 mmol) 6-Bromomethyl-2,3-dimethoxy-quinoxaline. The mixture is stirred at 80° C. for two days, diluted with water and extracted with CH2Cl2. Purification of the crude product by chromatography (ethyl acetate/hexanes 1:1) affords a yellow oil.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([OH:5])=O.[C:22]([NH:26][CH2:27][CH3:28])([CH3:25])([CH3:24])[CH3:23]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:21])=[CH:10][CH2:11][CH2:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18])[C:3]([N:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:27][CH3:28])=[O:5]
Reactant: CCNC(C)(C)C
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CCN(C(=O)C(C)=CCCC(C)=CCCC(C)=CCCC(C)=O)C(C)(C)C

Procedure:
Starting material: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid and tert-butylethylamine.
Reaction SMILES: [CH2:1]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:14][C:15]1[C:20]([F:21])=[C:19]([C:22]#[N:23])[CH:18]=[CH:17][C:16]=1[OH:24].[O-]CC.[Na+]>C(O)C>[CH2:1]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][O:24][C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[C:20]([F:21])[C:15]=2[F:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(CCl)cc1
Reactant: N#Cc1ccc(O)c(F)c1F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCc1ccc(COc2ccc(C#N)c(F)c2F)cc1

Procedure:
A mixture of 0.12 mole of p-pentylbenzyl chloride and 20 ml of ethanol is added to a mixture of 0.1 mole of 2,3-difluoro-4-cyanophenol (prepared as in Example 1) and 0.1 mole of sodium ethoxide in 60 ml of ethanol, and the mixture is heated at the boil for 5 hours. After the ethanol has been distilled off, the reaction mixture is allowed to cool and is poured onto 15 ml of 5% aqueous sodium hydroxide solution. Working up in the customary manner gives 4-(4-pentylbenzyloxy)-2,3-difluorobenzonitrile.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[Na].[H][H]>O.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: O=C(O)C1CCC=CO1
Agent: [Pd]
Agent: [Na]
Solvent: O
Product: O=C(O)C1CCCCO1

Procedure:
3,4-Dihydro-2 H-pyran-2-carboxylic acid, sodium salt (5.0 g) in water (30 ml) was treated with 10% Palladium on carbon catalyst (0.2 g) and the mixture hydrogenated until there was no further uptake of hydrogen. The mixture was filtered through Kieselguhr, the filtrate passed through a column of 'Amberlite IR120(H+), evaporated in vacuo and the residue dissolved in dichloromethane, dried and evaporated to give the title compound as colourless oil. (3.3 g, 76%); (Found: M+, 130.0631. C6H10O3 requires M, 130.0630; νmax (CH2Cl) 3500-2750 (v.br), 1772, 1725 cm-1 ; δH (CDCl3), 1.5-1.7 (4 H, m), 1.8-2.1 (2 H, m), 3.50-3.59 (1 H, m), 3.99-4.14 (2 H, m) and 7.28 (1 H, br.s).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[CH:14]=[C:15]([CH3:20])[C:16]([CH3:19])=[N:17][CH:18]=1>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]([CH3:20])[C:16]([CH3:19])=[N+:17]([O-:9])[CH:18]=1
Reactant: Cc1cc(Br)cnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Br)c[n+]([O-])c1C

Procedure:
m-Chloroperbenzoic acid (71.42 g) in dichloromethane (11) was added dropwise to a stirred solution of 5-bromo-2,3-lutidine (70.0 g) over I hour. After 23 hours the solution was cooled to 15° and ammonia gas bubbled through to give a white precipitate, which was filtered off. The filtrate was washed with 5% aqueous sodium sulphite, dried, and stripped to give 5-bromo-2,3-lutidine-N-oxide, 61.78 g, m.p. 80°-2°, from ethyl acetate.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6](I)[C:5]([CH2:10][CH3:11])=[N:4]1)[CH3:2].[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.CC(C)([O-])C.[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[C:5]([CH2:10][CH3:11])=[N:4]1)[CH3:2]
Reactant: CCc1nn(CC)c(C)c1I
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nn(CC)c(C)c1-c1ccncc1
Temperature: 100 °C

Procedure:
A mixture of 17.05 g (64.6 mmol) of 1,3-diethyl-4-iodo-5-methylpyrazole (from Step D) and 11.9 g (105.4 mmol) of pyridine 4-boronic acid in 300 mL of dioxane was treated with a solution of 44 g (392 mmol) of potassium tert-butoxide in 100 mL of water. The resulting mixture was treated with 3.75 g (3.2 mmol) of tetrakis(triphenylphosphine)palladium(0), put under an argon atmosphere and heated at 100° C. for 18 h. The mixture was cooled and partitioned between 1 L of ether and 500 mL of water. The organic layer was separated, dried over MgSO4 and concentrated. Flash chromtography on a Biotage 75S afforded of the title compound. 1H-NMR (500 MHz) δ 1.19 (t, J=7.5, 3H), 1.48 (t, J=7.5, 3H), 2.27 (s, 3H), 2.67 (q, J=7.5, 2H), 4.09 (q, J=7.5, 2H), 7.18 (dd, J=2.0, 4.5, 2H), 8.60 (dd, J=2.0, 4.5, 2H).
Reaction SMILES: [C:1]([C:6]1[S:10][C:9]([CH2:11][CH3:12])=[C:8]([CH:13]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].O1CCCC1.[OH-].[Na+]>C(O)C>[C:1]([C:6]1[S:10][C:9]([CH2:11][CH3:12])=[C:8]([CH:13]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cc(C(Nc2ccc(C(=O)OC)cc2)C2CCCCC2)c(CC)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(=O)c1cc(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)c(CC)s1
Yield: 94.9 %

Procedure:
To a mixture of methyl 4-{[(5-butanoyl-2-ethylthiophen-3-yl)(cyclohexyl)methyl]amino}benzoate (316 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (5 and the mixture was stirred with heating under reflux for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (5 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (290 mg, 95%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:28](OC)=[O:29])[C:15](=[O:27])[N:16]3[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:28]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:29])[C:15](=[O:27])[N:16]3[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(OC)cc2)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(OC)cc2)c1=O
Yield: 89 %

Procedure:
In a similar manner to that described in example 196, from methyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[4-(methyloxy)phenyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (50 mg, 0.115 mmol) and [2-(methyloxy)ethyl]amine was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(methyloxy)ethyl]-1-[4-(methyloxy)phenyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (47 mg, 89% yield) as a white solid. 1H NMR (CDCl3) δ 10.14 (s, 1 H), 8.47 (s, 1 H), 7.12-7.04 (m, 4 H), 7.00-6.96 (m, 2 H), 6.93-6.89 (m, 2 H), 6.74 (s, 1 H), 3.91 (s, 2 H), 3.86 (s, 3 H), 3.59 (m, 2 H), 3.51 (m, 2 H), 3.31 (s, 3 H); HRMS m/z calcd for C26H25FN3O5: 478.1773. Found: 478.1773.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][C:21]#[N:22]>>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:20]([CH2:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH3:11])[C:21]([NH2:22])=[N:1]2)=[CH:6][CH:7]=1
Reactant: Nc1cc(Cl)ccc1C=O
Reactant: COc1ccccc1CCC#N
Product: COc1ccccc1Cc1cc2ccc(Cl)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4-chlorobenzaldehyde and 3-(2-methoxyphenyl)propionitrile.