Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1.C([CH2:20][C:21]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])=[O:22])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:20]/[C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:22])=[CH:11][CH:10]=1
Reactant: COc1ccc(C=O)cn1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cn1
Yield: 52.7 %

Procedure:
Piperidine (220 μL, 2.2 mmol) was added to a suspension of 6-methoxy-3-pyridine carboxaldehyde (0.30 g, 2.2 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.44 g, 2.1 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. The crude product was recrystallised from EtOH providing (E)-2-[[3-(6-methoxypyridin-3-yl)-1-oxo-2-propenyl]amino]benzoic acid (0.33 g, 56%) as a colourless crystalline solid; mp 209-211° C.; δH (400 MHz, DMSO-d6) 3.85 (s, 3H, OCH3), 6.82 (d, J=15.6 Hz, 1H, CH═CHCO), 6.85 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.13 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.57 (d, J=15.6 Hz, 1H, CH═CHCO), 7.58 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.98 (d, J3,4=8.0 Hz, 1H, H3), 8.14 (dd, J5′,6′=8.0, J2′6′=1.6 Hz, 1H, H6′), 8.43 (d, J2′,6′=1.6 Hz, 1H, H2′), 8.57 (d, J5,6=8.0 Hz, 1H, H6), 11.29 (s, 1H, NH), 13.58 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 53.5, 111.0, 116.7, 120.3, 121.4, 122.8, 124.2, 131.1, 134.0, 137.3, 138.0, 140.9, 148.4, 163.7, 164.4, 169.4; HRMS (ESI) calculated for C16H14N2O4 [M−H]− 297.0870. found 297.0877; vmax 749, 1249, 1591, 1683, 3246 cm−1.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.CN(C=O)C.[CH3:29][C:30]1[O:34][N:33]=[C:32]([C@:35]([OH:39])([C:37]#[CH:38])[CH3:36])[CH:31]=1.C(N(CC)CC)C>C(#N)C.[Cu]I>[F:23][C:3]1[C:2]([C:38]#[C:37][C@@:35]([OH:39])([C:32]2[CH:31]=[C:30]([CH3:29])[O:34][N:33]=2)[CH3:36])=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1nc2n(c1C(F)(F)F)CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc([C@](C)(O)C#Cc2cc3c(cc2F)OCCn2c-3nc(C(N)=O)c2C(F)(F)F)no1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
The title compound was prepared similarly according to Procedure E. To a solution of 10-bromo-9-fluoro-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (73 mg, 0.12 mmol) in a mixture of anhydrous DMF (0.5 mL) and acetonitrile (0.7 mL) were introduced (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol (168 mg, 1.10 mmol), copper(I) iodide (4 mg, 0.02 mmol) and triethylamine (700 mg, 6.92 mmol). The solution was de-oxygenated by bubbling with nitrogen for 5 min, then bis(triphenylphosphine)palladium(II) chloride was added and bubbling continued for a further 5 min. The reaction mixture was warmed to 90° C. for 48 hr under an atmosphere of nitrogen, then allowed to stand at room temperature for a further 24 hr. Following evaporation of the reaction mixture in vacuo, the residue was re-dissolved in ethyl acetate (20 mL) and washed with saturated aqueous sodium bicarbonate solution (15 mL). The organic extract was dried over sodium sulfate, filtered and evaporated in vacuo. Purification by silica gel flash column chromatography (heptane/ethyl acetate gradient) furnished a tan solid which was suspended in acetonitrile (0.3 mL), sonicated for 30 seconds, and the solid isolated by suction filtration. Drying on the filter gave the title compound as an off-white solid: 1H NMR (500 MHz, DMSO) δ 1.81 (3H, s), 2.41 (3H, s), 4.50-4.55 (2H, m), 4.58-4.63 (2H, m), 6.35 (1H, d, J=0.63 Hz), 6.60 (1H, s), 7.10 (1H, d, J=10.40 Hz), 7.53 (1H, br. s.), 7.99 (1H, s), 8.63 (1H, d, J=8.20 Hz); 19F NMR (235 MHz, DMSO) δ −54.3, −108.0; LC-MS: m/z 465.05 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)CCC>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]=O>[NH2:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]([C:9]#[N:10])=[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: Cl[Pd]Cl
Agent: O=[Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(-c2ccccn2)c1C#N
Temperature: 100 °C
Yield: 20.1 %

Procedure:
To a stirred solution of 600 mg (2,45 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 12 ml dry DMF under argon at room temperature were added 1.08 g (2.94 mmol) 2-(tributylstannyl)pyridine, 86 mg (0.12 mmol) bis(triphenylphosphine) palladium(II) chloride and 195 mg (2,45 mmol) copper(II) oxide. The reaction mixture was heated at 100° C. for 16 h, then cooled to room temperature, 2 g of kieselgel added, and the mixture concentrated in vacuo. Flash chromatography (hexane then 1/8 ethyl acetate/hexane) followed by trituration in ether/hexane afforded 120 mg (20%) 2-amino-4-methylsulfanyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile as an off-white crystalline solid. EI-MS m/e (%): 243 (M+, 95), 242 ([M—H]+, 100).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Mg].II.[Si:15](Cl)([Cl:18])([Cl:17])[Cl:16]>C1COCC1>[C:2]1([Si:15]([Cl:18])([Cl:17])[Cl:16])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccccc12
Reactant: Cl[Si](Cl)(Cl)Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cl[Si](Cl)(Cl)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Under a dry nitrogen atmosphere, a solution of 1-bromonaphthalene (27.7 g, 0.134 mol) in THF (175 mL) was added slowly to a suspension of magnesium turnings (3.9 g, 0.16 mol) in THF (15 mL) that had previously been activated with an iodine crystal. After cooling to room temperature, this Grignard reagent was added via canula to a THF (70 mL) solution of SiCl4 (25.1 g, 0.148 mol) and stirred overnight. The mixture was evaporated to dryness, extracted with hexane and filtered to remove Mg halide. The product was distilled at 120° C. under dynamic vacuum to give a 67% yield (23.6 g, 0.0902 mol) of product. 1H NMR (CDCl3, ppm) 8.46 (dd, 1H), 8.21 (dd, J=6.8 Hz, J=1.2 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.69 (t, 1H), 7.62 (t, 1H), 7.57 (t, 1H). 13C{1H}NMR (CDCl3, ppm) 135.51 (CH), 134.42 (C), 134.07 (CH), 133.58 (C), 129.37 (CH), 127.91 (C), 127.45 (CH), 127.16 (CH), 126.56 (CH), and 124.65 (CH). 29Si{1H} (CDCl3, ppm) −0.17 (s).
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[C:8]([C:10]2[C:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:18]=3[C:17]([Br:27])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:7]=[C:6]([OH:28])[C:5]=1[OH:29].[C:30](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:3][C:4]1[C:5]([O:29][CH3:30])=[C:6]([OH:28])[CH:7]=[C:8]([C:10]2[C:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:18]=3[C:17]([Br:27])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:9]=1
Reactant: Oc1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(O)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Yield: 27.5 %

Procedure:
Iodomethane (0.074 mL, 1.2 mmol) was added dropwise to a rt, stirred light suspension of 3-bromo-5-(6-bromo-benzo [b]naphtho [2,3 -d]thiophen-11 -yl)-benzene-1, 2-diol (0.30 g, 0.60 mmol), potassium carbonate (0.083 g, 0.6 mmol) in DMF (1.5 mL) over a period of five minutes. After the mixture was stirred at ambient temperature for 1.5 h., the reaction mixture was quenched with aqueous hydrochloric acid to pH 1 and further diluted with water (80 mL) and aqueous mixture was extracted with methylene chloride (120 mL). The organic extract was washed with water and dried with brine. Silica gel (5 mL) was added. Solvent was removed and the adsorbate was flash chromatographed (eluents:petroleum ether:methylene chloride 7:3 to 1:1 and then petroleum ether: ethyl acetate 7:3) to provide the title compound as a white solid (85 mg, 29%): mp 233-234° C.: NMR (CDCl3); δ8.35 (ddd, J=8, 1, 1 Hz, 1 H), 7.82 (ddd, J=8, 1, 1 Hz, 1 H), 7.66 (ddd, J=8, 7, 1 Hz, 1H), 7.65 (dd, J=8, 1, Hz, 1 H), 7.48 (ddd, J=8, 7, 1 Hz, 1 H), 7.43 (ddd, J=8, 7, 1 Hz, 1 H), 7.17 (ddd, J=8, 7, 1 Hz, 1 H), 7.15 (d, J=2 Hz, 1 H), 7.00 (d, J=2 Hz, 1 H), 6.87 (ddd, J=8, 1, 1 Hz, 1 H), 5.93 (s, 1 H), 4.14 (s, 3); MS (EI): [M+], 2 bromine isotope pattern, 512; Anal. Calc. for C23H14Br2O2S: C, 53.72, H, 2.74, N, 0.00. Found: C, 53.85, H, 2.98, N, 0.02.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][OH:16])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[N:26]=[C:27]=S.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.O>[Cl:12][C:11]1[C:2]2[N:1]=[C:27]([NH:26][C:19]3[C:20]([CH3:25])=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=3[Cl:17])[N:13]([CH2:14][CH2:15][OH:16])[C:3]=2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=1
Reactant: Cc1cc(Cl)cc(Cl)c1N=C=S
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)cc(Cl)cc3Cl)n(CCO)c12
Temperature: 60 °C
Reaction time: 24 h
Yield: 30.3 %

Procedure:
A solution of methyl 3-amino-4-chloro-2-[(2-hydroxyethyl)amino]benzoate (290 mg, 1.19 mmol) and 2,4-dichloro-6-methylphenylisothiocyanate (284.4 mg, 1.3 mmol) in tetrahydrofuran (12 mL) was stirred at 45° C. for 62 hr. The mixture was warmed to 60° C. and stirred at, 60° C. for 24 hr. 2,4-Dichloro-6-methylphenylisothiocyanate (104 mg, 0.48 mmol) was added to the reaction mixture and the mixture was stirred at 60° C. for 26 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on NH-silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture give a red amorphous (261.4 mg). To a mixture of the amorphous (261.4 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (119 mg, 0.62 mmol) in tetrahydrofuran (11.2 mL) was added triethylamine (0.0866 mL, 0.62 mmol) at room temperature. The mixture was stirred at 50° C. for 16 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (156.3 mg, 0.36 mmol, 30%) as a pale yellow solid.
Reaction SMILES: C([Cu])#N.[C:4]([Mg]Cl)([CH3:7])([CH3:6])[CH3:5].Br[C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][CH:16]=1>C1COCC1>[C:4]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:15][CH:16]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Mg]Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Agent: N#C[Cu]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 21 %

Procedure:
To a mixture of anhydrous CuCN (2.7 g, 30.4 mmol) in 100 mL of THF was added a solution of tert-butylmagnesium chloride (30.4 mL, 60.2 mmol, 2M solution in THF) under N2 at −78° C. After 20 minutes, tert-butyl 5-bromopyridin-2-ylcarbamate (2.1 g, 7.6 mmol, Aldrich) was added. The reaction mixture was stirred for 2 hours at −78° C. and then at room temperature for 12 hours. The mixture was quenched with saturated aqueous NH4OH and basified to pH 7 with 20% aqueous NaOH. The solid was filtered through a pad of Celite. The filtrate was extracted with ether and washed with water. The organic extract was dried over MgSO4 and concentrated. Purification by column chromatography (SiO2,: 0-15% hexanes/ethyl acetate gradient) afforded 0.4 g of the title compound. MS (ESI+) m/z 251 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Br:8][CH2:9][C:10](Br)=[O:11]>O1CCCC1>[Br:8][CH2:9][C:10]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:11]
Reactant: CS(N)(=O)=O
Reactant: O=C(Br)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.68 g×60%) was added to a stirred solution of methanesulfonamide (2.0 g) in dry tetrahydrofuran (20 ml) at room temperature. The resulting solution was stirred at room temperature for 1 h, at which time it was treated with a solution of bromoacetyl bromide (4.2 g) in dry tetrahydrofuran (10 ml). After 1 h the solvent was removed under reduced pressure and the residue taken up in water and acidified to pH3. The acidic solution was extracted into ethyl acetate, dried (MgSO4), filtered and the solvent removed under reduced pressure. Recrystallisation from isopropanol afforded the product as white needles: mp 112°-114° C.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11](O)[CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20]>>[C:13]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH:9]([N:24]3[CH2:25][CH2:26][N:21]([CH:19]=[O:20])[CH2:22][CH2:23]3)[CH:10]=[CH:11]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=CN1CCNCC1
Reactant: OC1C=CCC1(c1ccccc1)c1ccccc1
Product: O=CN1CCN(C2C=CC(c3ccccc3)(c3ccccc3)C2)CC1

Procedure:
1-(4,4-Diphenyl-2-cyclopentenyl)piperazine dihydrochloride was obtained by reacting 5,5-diphenyl-2-cyclopenten-1-ol and 1-formylpiperazine according to a similar manner to that of Example 11 to give 1-(4,4-diphenyl-2-cyclopentenyl)-4-formylpiperazine, then eliminating formyl group thereof in a conventional manner.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:9])[CH:6]([CH3:8])[CH3:7].[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.BrBr>ClCCl>[CH3:7][CH:6]([CH3:8])[C:5]([C:12]1[S:11][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: c1ccsc1
Reactant: CC(C)C(=O)Cl
Agent: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)C(=O)c1cccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 125.3 %

Procedure:
Aluminum chloride (4.75 g, 35.7 mmol, 3 eq) was diluted in ice cold dichloromethane (30 mL). Isobutyryl chloride (4 mL, 38 mmol, 3.2 eq) in dichloromethane (30 mL) was added to the aluminum chloride suspension at 0° C., and the mixture was stirred at 0° C. for 30 minutes. Thiophene (1 g, 11.9 mmol) was added as a solution in dichloromethane (30 mL) over 10 minutes. The reaction was stirred at 0° C. for 30 minutes, then at rt for 1 h. Bromine (0.65 mL, 12.6 mmol, 1.1 eq) was added dropwise at 0° C., and the reaction mixture was slowly warmed to rt overnight. The mixture was cooled to 0° C., and was carefully quenched by the dropwise addition of water. The reaction mixture was extracted with dichloromethane, and the combined organics washed with saturated aqueous sodium bicarbonate. The combined organics were then dried over sodium sulfate, filtered, and concentrated. The crude product was purified by isco combiflash, eluting with 0-10% ethyl acetate in hexanes to afford a slightly yellow oil (2.3 g, >100%).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8].[C:11](Cl)(=O)C(Cl)=O>CO>[CH3:1][S:2][CH2:3][CH2:4][O:5][CH:6]([CH3:10])[C:7]([O:9][CH3:11])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CSCCOC(C)C(=O)O
Solvent: CO
Product: COC(=O)C(C)OCCSC
Yield: 96 %

Procedure:
Reaction of intermediate 9, 2-(2-(methylthio)ethoxy)propanoic acid, (13.70 g, 0.083 mol) with oxalyl chloride followed by reaction with methanol gave 14.27 g (96% yield) of the title ester as a clear oil; bp 55-60° C./0.3 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CDCl3) δ ppm: 1.42 (3H, d, J=7.0 Hz, CH3), 2.15 (3H, s, SCH3), 2.71 (2H, t, J=6.8 Hz, CH2), 3.56 (1H, m, CH), 3.75 (3H, s, OCH3), 3.78 (1H, m, CH), 4.15 (1H, q, J=7.0 Hz, OCH).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][C:36]([CH3:38])=[CH:37][C:30]=3[CH3:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: Cc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c(C)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2,4-dimethyl-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 497.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[N:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[N:6][CH:5]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)c1ccc(O)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccc3ccccc3n2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of 6-hydroxynicotinic acid methyl ester (10.0g, 0.0652 mol), prepared as in step 1, in DMF (350 ml) at room temperature was added anhydrous K2CO3 (19.0 g, 0.137 mol) followed by 2-chloromethylquinoline hydrochloride (14.0 g, 0.0652 mol), and the mixture was allowed to stir at room temperature overnight. Once the starting material was consumed, water (700 ml) was added to the mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The resulting white precipitate was filtered and washed with hexanes to give 15.20 g of 6-(quinol-2-ylmethoxy)nicotinic acid methyl ester.
Reaction SMILES: O[CH:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].CC(O)=O.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17]>CCO>[C:6]1([C:3]2[CH:2]=[N:17][N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:4]=2[NH2:5])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CC(=CO)c1ccccc1
Reactant: NNc1ccccn1
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1c(-c2ccccc2)cnn1-c1ccccn1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 3-hydroxy-2-phenylacrylonitrile (3.4 mmol) in EtOH (6.8 mL) is added AcOH (0.66 mL) and 2-hydrazinopyridine (6.8 mmol) at room temperature. After stirred at 80° C. for 5 h, the reaction mixture is cooling and concentrated in vacuo. The residue is diluted with H2O and extracted with AcOEt. The organic extracts are washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue is triturated with ether to give the title compound; 1H NMR (CDCl3) δ 6.27 (br, 2H), 7.11-7.14 (m, 1H), 7.21-7.25 (m, 1H), 7.40-7.48 (m, 4H), 7.65 (s, 1H), 7.79-7.84 (m, 1H), 8.02 (d, 1H), 8.35-8.37 (m, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH3:26])[C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[CH2:17][C:11]3=[CH:10][N:9]=2)[CH2:3][CH2:2]1.Br[CH2:28][CH2:29][OH:30].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN1C(=O)N(C)CCC1>[OH:30][CH2:29][CH2:28][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:13]=[C:12]3[N:14]([CH3:26])[C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH3:24])[CH2:17][C:11]3=[CH:10][N:9]=2)[CH2:3][CH2:2]1
Reactant: OCCBr
Reactant: Cc1ccccc1N1Cc2cnc(NC3CCNCC3)nc2N(C)C1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN1CCCN(C)C1=O
Product: Cc1ccccc1N1Cc2cnc(NC3CCN(CCO)CC3)nc2N(C)C1=O
Temperature: 100 °C
Yield: 62.2 %

Procedure:
A mixture of 7-(piperidin-4-ylamino)-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (0.1 g, 0.284 mmol) (prepared as described in Example 25), 2-bromoethanol (0.024 mL, 0.34 mmol), and triethylamine (0.047 mL, 0.34 mmol) in 10 mL of toluene and 1.5 mL of DMPU was heated at 100° C. for 17 hours. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel using 40:10:2 ethyl acetate/methanol/isopropylamine as eluant to give 70 mg (52%) of 7-[1-(2-hydroxyethyl)piperidin-4-ylamino]-1-methyl-3-ortho-tolyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([Br:13])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1ccc(O)c(Br)c1
Temperature: -15 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
This procedure is modified from the work of Oberhauser (J. Org. Chem, 1997, 62,4504). To a solution of 4-hydroxybenzoic acid ethyl ester (57.8 g, 348 mmol) in 480 mL of dry acetonitrile was added HBF4 EtO (54% in Et2O, 32.9 mL). The solution was cooled to −15° C. with an ice/methanol bath. N-bromosuccmimide (67.2 g, 378 mmol) was added portionwise at a rate where the temperature would not rise above −10° C. After addition was complete, the cooling bath was removed and the reaction mixture wag allowed to stir overnight at room temperature. Worked up by pouring the reaction mixture into aqueous sodium bisulfite (38%, 200 mL) and extracting four times with ethyl acetate. The organic layers were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, decanted, and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate/hexane gave 3-bromo-4-hydroxybenzoic acid ethyl ester (70.7 g, 83%) as a white solid. 1H NMR (300 MHz, CDCl3) δ1.39 (t, J=6.7 Hz, 3H, —CO2CH2CH3), 4.34 (t, J=6.7 Hz, 2H, —CO2CH2CH3), 7.02 (d, 1H, arom), 7.91 (dd, 1H, arom), 8.19 (d, 1H, arom).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[Br:41][C:42]1[CH:43]=[C:44]([NH2:54])[CH:45]=[N:46][C:47]=1[O:48][CH2:49][C:50]([F:53])([F:52])[F:51]>CN(C=O)C>[Br:41][C:42]1[CH:43]=[C:44]([NH:54][C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)[CH:45]=[N:46][C:47]=1[O:48][CH2:49][C:50]([F:51])([F:52])[F:53]
Reactant: O=C(O)c1cccnc1
Reactant: Nc1cnc(OCC(F)(F)F)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of nicotinic acid (454 mg, 3.69 mmol) in DMF (33 mL) were added successively TBTU (1.18 g, 3.69 mmol), N,N-diisopropylethylamine (3.16 mL, 18.4 mmol) and 5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-amine (1 g, 3.69 mmol). The brown mixture was stirred under argon for 3 h at room temperature. After evaporation of DMF, the brown oil was partitioned between ethyl acetate (50 mL) and 1M NaOH (30 mL). The aqueous layers were back-extracted with ethyl acetate (1×50 mL). The organic parts were washed with water (2×25 mL) and brine (25 mL), then dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 100% ethyl acetate in heptane) to deliver the desired product as a white solid (580 mg; 42%); MS (EI): 376.1; 378.0 (M+H).