Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O-:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2]
Reactant: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc([O-])c(C#N)cc34)cc2)cc1
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCN5CCOCC5)c(C#N)cc34)cc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
The sodium 6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate (100 mg) synthesized in Example 87 was dissolved in dimethylformamide (2.5 ml), and then potassium carbonate (65 mg, 0.4690 mmol) and 1-chloro-3-(morpholin-4-yl)propane (38 mg, 0.2345 mmol, J. Am. Chem. Soc. 67, 736 (1945)) were added and the mixture was heated and stirred at 80° C. for 2 hours. After allowing the mixture to stand and adding saturated saline, it was extracted with ethyl acetate, the extract was washed with saturated saline and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system). The obtained crystals were suspended in ethyl acetate, the suspension was diluted with diethyl ether, and the crystals were filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (120 mg) as light yellow crystals.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[CH:8]2[CH2:9][CH:10]=[CH:11][CH2:12][CH:7]2[C:5]1=[O:6])[CH:2]=[CH2:3].NCP(=O)(O)[OH:18].O.OO>S([O-])(O)(=O)=O.C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[O:18]1[CH:11]2[CH:10]1[CH2:9][CH:8]1[C:13](=[O:14])[N:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:6])[CH:7]1[CH2:12]2
Reactant: NCP(=O)(O)O
Reactant: C=CCN1C(=O)C2CC=CCC2C1=O
Agent: O=[W](=O)([O-])[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=S(=O)([O-])O
Solvent: O
Product: C=CCN1C(=O)C2CC3OC3CC2C1=O
Reaction time: 4 h
Yield: 1000.2 %

Procedure:
In a 50 mL three-necked flask equipped with stirrer, dropping funnel and Dimroth condenser tube there were charged 5.15 g of N-allyl-4-cyclohexene-1,2-dicarboximide, 0.23 g of methyltrioctylammonium hydrogensulfate, 0.22 g of sodium tungstate dihydrate and 0.03 g of aminomethylphosphonic acid. The mixture was heated using an oil bath kept at 90° C., and after adding 4 ml of 30% hydrogen peroxide water dropwise over a period of 30 minutes through a dropping funnel, the mixture was aged for 4 hours. It was then cooled in an ice bath, and after removing the excess hydrogen peroxide with 15 mL of saturated aqueous sodium thiosulfate, extraction was performed 5 times with 10 mL of ethyl acetate. The obtained ethyl acetate solution was dried overnight over anhydrous sodium sulfate, a rotary evaporator was used to remove the ethyl acetate solvent to obtain 3.21 g of a crude product of 4,5-epoxy-N-allylcyclohexane-1,2-dicarboximide, and then purification was performed by chromatography with a column packed with 25% hydrated silica gel. Structural isomers of 4,5-epoxy-N-allylcyclohexane-1,2-dicarboximide exist due to the epoxy group, and of these there were obtained 0.72 g of 4,5-epoxy-N-allylcyclohexane-1,2-dicarboximide 1 and 0.56 g of 4,5-epoxy-N-allylcyclohexane-1,2-dicarboximide 2. An AL-400 nuclear magnetic resonance apparatus by JEOL Corp. was used to measure the 1H-NMR and 13C-NMR spectra of the 4,5-epoxy-N-allylcyclohexane-1,2-dicarboximide 1 in a heavy chloroform solvent, thus allowing confirmation of the structure. The 1H-NMR and 13C-NMR spectra of the 4,5-epoxy-N-allylcyclohexane-1,2-dicarboximide 1 are shown in FIGS. 1 and 2, respectively, and the 1H-NMR integral values of the 4,5-epoxy-N-allylcyclohexane-1,2-dicarboximide 1 are shown in Table 1 below.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: Cc1ccc(C)c(N=C=S)c1
Reactant: CCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2cc(C)ccc2C)C1=S
Yield: 42.7 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 16.3 g of 2,5-dimethylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 250 mL of chloroform. Crystallization from ethyl acetate afforded the title compound (10.6 g) as an off-white solid, m.p. 176°-178° C. Anal. Calcd. for. C13H16N2O S: C,62.87; H, 6.49; N, 11.28. Found: C, 62.70; H, 6.46; N, 11.27. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [Cl:1]C(OCC)=O.[CH3:7][O:8][C:9](=[O:31])[CH:10]=[N:11][O:12][CH2:13][C:14]1[CH2:19][C:18]([CH3:20])=[C:17]([CH3:21])[CH2:16][C:15]=1[CH2:22]N1CC(C)OC(C)C1>C1COCC1>[CH3:7][O:8][C:9](=[O:31])[CH:10]=[N:11][O:12][CH2:13][C:14]1[CH2:19][C:18]([CH3:20])=[C:17]([CH3:21])[CH2:16][C:15]=1[CH2:22][Cl:1]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)C=NOCC1=C(CN2CC(C)OC(C)C2)CC(C)=C(C)C1
Solvent: C1CCOC1
Product: COC(=O)C=NOCC1=C(CCl)CC(C)=C(C)C1

Procedure:
1.4 ml of ethyl chloroformate are added to a solution of 2.1 g of methyl[2-(2,6-dimethylmorpholin-4-ylmethyl)-4,5-dimethylcyclohexa-1,4-dienyl]methoxyiminoacetate in 25 ml of THF. The mixture is now heated for 20 hours at 70°. After the mixture has been evaporated, the residue is chromatographed on silica gel (ether/hexane 1:2). This gives 1.2 g of crystals of the title compound of melting point 65-68°.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19](O)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH:19]([N:4]2[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]2)[CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nn(C2CCN(C(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.5 %

Procedure:
To a solution of 3-methyl-4-nitro-1H-pyrazole (3.0 g, 23.6 mmol, 1.00 eq), tert-butyl-3-hydroxypyrrolidine-1-carboxylate (4.42 g, 23.6 mmol, 1.00 eq), and triphenylphosphine (6.19 g, 23.6 mmol, 1.00 eq) in THF (60 mL) was added a solution of diethyl azodicarboxylate (4.34 mL, 23.6 mmol, 1.00 eq) in THF (10 mL) in a drop-wise manner over 30 min. The reaction mixture was allowed to stir at ambient temperature for 20 hr and then concentrated. The crude reaction mixture was purified via repeated flash chromatography on silica gel eluting with a gradient of 0-35% EtOAc in heptane to give the title compound (2.48 g, 35% yield) as a colorless oil that was the early eluting of two structural isomers. 1H NMR (400 MHz, CDCl3) δ ppm 8.15 (s, 1 H) 4.80 (quin, J=5.7 Hz, 1 H) 3.83 (dd, J=6.0, 12.0 Hz, 1 H) 3.79-3.45 (m, 3 H) 2.52 (s, 3 H) 2.38 (q, J=7.0 Hz, 2 H) 1.46 (s, 9 H). m/z (APCI+) for C13H21N4O4 197.2 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH2:52][CH3:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].[C:57]([O:60][CH2:61][C:62](Cl)=[O:63])(=[O:59])[CH3:58]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][C:62](=[O:63])[CH2:61][O:60][C:57](=[O:59])[CH3:58])[CH:46]([O:51][CH2:52][CH3:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1N
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Product: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1NC(=O)COC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (40 mg) in dry methylene chloride (0.4 ml) is cooled to 0° C. To this solution is added a solution of acetoxyacetyl chloride (9 mg) in methylene chloride (0.5 ml). The reaction mixture is stirred at 0° C. for 30 minutes, and quenched with a drop of methanol. Purification by preparative tlc on silica gel gives the title compound.
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[OH:9][N:10]=[CH:11][C:12]1[CH:27]=[CH:26][C:15]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=1.[C:28]([C:30]1[CH:35]=[N:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][C:39]([S:42]([CH:45]([CH3:47])[CH3:46])(=[O:44])=[O:43])=[CH:38][CH:37]=2)[N:31]=1)#[CH:29].CCN(CC)CC>CN(C=O)C.CCOC(C)=O.O>[CH:45]([S:42]([C:39]1[CH:38]=[CH:37][C:36]([C:32]2[N:31]=[C:30]([C:28]3[O:9][N:10]=[C:11]([C:12]4[CH:13]=[CH:14][C:15]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:26][CH:27]=4)[CH:29]=3)[CH:35]=[N:34][CH:33]=2)=[CH:41][CH:40]=1)(=[O:43])=[O:44])([CH3:47])[CH3:46]
Reactant: CN(Cc1ccc(C=NO)cc1)C(=O)OC(C)(C)C
Reactant: C#Cc1cncc(-c2ccc(S(=O)(=O)C(C)C)cc2)n1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)S(=O)(=O)c1ccc(-c2cncc(-c3cc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)no3)n2)cc1
Temperature: 65 °C
Reaction time: 0.75 h

Procedure:
NCS (34.97 mg, 0.2619 mmol) was added to a solution of tert-butyl 4-((hydroxyimino)methyl)benzyl(methyl)carbamate (62.93 mg, 0.2381 mmol) in DMF (1 mL) and the mixture heated at 65° C. for 15 minutes. The reaction mixture was cooled to ambient temperature and 2-ethynyl-6-(4-isopropylsulfonylphenyl)pyrazine (75 mg, 0.2619 mmol) and DMF (2 mL) were added followed by the dropwise addition of Et3N (28.91 mg, 39.82 μL, 0.2857 mmol). The mixture was stirred at ambient temperature for 45 minutes then heated to 65° C. for 1 hour. The mixture was cooled to ambient temperature and diluted with EtOAc and water and the layers separated. The aqueous layer was extracted with EtOAc (×2) and the combined organic extracts washed with water (×3), brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 0 to 40% EtOAc/Petroleum Ether) to give the sub-title product as a yellow solid. 1H NMR (400.0 MHz, DMSO) d H NMR (400.0 MHz, DMSO) d 9.53 (s, 1H), 9.32 (s, 1H), 8.58 (d, 2H), 8.09 (s, 1H), 8.06 (d, 2H), 8.01 (d, 2H), 7.42 (d, 2H), 4.47 (s, 2H), 3.55 (sept, 1H), 2.82 (s, 3H), 1.46-1.41 (2×s, 9H) and 1.21 (d, 6H) ppm; MS (ES+) 493.2
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:8][O:9][CH3:10])=[NH:7])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[O:19][C:20]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:22]=1)CCC>O1CCOCC1.[Pd].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.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>[CH3:10][O:9][NH:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([C:20]2[O:19][C:18]([C:2]3[CH:12]=[CH:11][C:5]([C:6](=[NH:7])[NH:8][O:9][CH3:10])=[CH:4][N:3]=3)=[CH:22][CH:21]=2)=[N:3][CH:4]=1)=[NH:7]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc([Sn](CCCC)(CCCC)CCCC)o1
Reactant: CONC(=N)c1ccc(Cl)nc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CONC(=N)c1ccc(-c2ccc(-c3ccc(C(=N)NOC)cn3)o2)nc1
Yield: 35 %

Procedure:
Continuing with Scheme 5, a mixture of 26 (6, mmol), 2,5-bis(tri-n-butylstannyl)furan (3 mmol) and tetrakis(triphenylphosphine)-palladium(0) (150 mg) in dry 1,4-dioxane (20 mL) was heated under nitrogen at reflux (100–110° C.) for 24 h. The solvent was evaporated under reduced pressure, dissolved in methylene chloride, and the solution was passed through celite to remove Pd. The solution was evaporated, the solid was filtered and washed with hexanes to afford 27 (SiO2, hexanes/EtOAc, 1:1), yield 35%, mp 228–230° C. 1H nmr (DMSO-d6); δ 3.80 (s, 6H), 6.31 (s, 4H), 7.34 (s, 2H), 7.98 (d, J=8.4 Hz, 2H), 8.13 (dd, J=8.4, 2.4 Hz, 2H). 8.88 (d, J=2.4 Hz, 2H). 13C nmr; δ 153.5, 148.9, 148.3, 147.0, 134.1, 126.8, 118.1, 112.0, 60.7. MS (m/z, rel.int.); 366 (M+, 100), 335 (25), 319 (30), 288 (40). High resolution mass calcd. for C18H18N6O3: 366.14404. Observed: 366.14012.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:25]([CH3:27])[CH3:26]>CN(C)C=O>[F:17][C:2]([F:1])([F:16])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH:25]([CH3:27])[CH3:26])[CH:6]=1)=[O:4]
Reactant: COc1ccc2c(C(=O)C(F)(F)F)c[nH]c2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)C(F)(F)F)cn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-methoxy-1H-indol-3-yl)-ethanone (1.0 g, 4.11 mmol) in N,N-dimethylformamide (10 mL) at 25° C. was treated with potassium carbonate (1.42 mg, 10.28 mmol). The resulting mixture was stirred at 25° C. for 30 min and then was treated with 2-iodopropane (0.62 mL, 6.17 mmol). The reaction was heated at 65° C. for 20 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (25 mL), shaken, and separated. The organic layer was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/1 hexanes/ethyl acetate) afforded 2,2,2-trifluoro-1-(1-isopropyl-6-methoxy-1H-indol-3-yl)-ethanone (99 mg, 85%) as a yellow solid: mp 58-60° C.; EI-HRMS m/e calcd for C14H14F3NO2 (M+) 285.0977, found 285.0974.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[OH:34][C:31]1[CH:32]=[CH:33][C:28]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[N:9]3)=[CH:4][CH:3]=2)=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: COC(=O)c1cc(C(=O)OC)c2ccc(Br)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(C(=O)OC)c2ccc(-c3ccc(O)cc3)cc2n1
Yield: 50.9 %

Procedure:
A mixture of 150 mg (0.46 mmol) of dimethyl 7-bromo-2,4-quinolinedicarboxylate synthesized according the procedure of Corey, E. J. and Tramontano, A., 1981 J. Am. Chem. Soc. 103:5599-5600 and Carrigan, C. N., et al, 1999 Bioorg. Med. Chem. Lett. 9:2607-2612, 153 mg (0.69 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, 5 mg (0.02 mmol) of palladium acetate, 12 mg (0.05 mmol) of triphenylphosphine, 345 mg (1.62 mmol) of K3PO4, and 40 μL (2.31 mmol) of H2O in 3 mL of dioxane were stirred at 60° C. for 1.5 hr. EtOAc was then added and the solution washed with H2O. The aqueous layer was extracted with EtOAc and then the combined organics were washed with brine and concentrated. A small amount of cold EtOAc was added to the residue and the solids were collected by suction filtration, washed with cold EtOAc then dried to yield 79 mg (51%) of dimethyl 7-(4-hydroxyphenyl)-2,4-quinolinedicarboxylate as a brown solid. 1H NMR (400 MHz, CDCl3): δ 9.79 (s, 1H), 8.72 (d, J=9 Hz, 1H), 8.41-8.38 (m, 2H), 8.17 (d, J=9 Hz, 1H), 7.77 (d, J=8 Hz, 2H), 6.91 (d, J=8 Hz, 2H), 4.00 (s, 3H), 3.97 (s, 3H). ESI-LCMS m/z 338 (M+H)+.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].N1CCOCC1.N1C=CC=CC=1.[CH2:20]([CH:22]([CH2:25][CH:26]=[CH2:27])C=O)[CH3:21].Cl>C1(C)C=CC=CC=1.C(O)(=O)CC(O)=O.O.C(#N)C>[CH2:26]([CH:25]([CH2:22][CH:20]=[CH2:21])/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])[CH3:27]
Reactant: O=C(O)CC(=O)O
Reactant: C=CCC(C=O)CC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: C1COCCN1
Product: C=CCC(/C=C/C(=O)O)CC
Temperature: 80 °C
Reaction time: 13.5 h
Yield: 125.2 %

Procedure:
Malonic acid (93.74 g, 0.90 mol), acetonitrile (306 mL), morpholine (26 mL, 0.30 mol), and pyridine (97 mL, 1.20 mol) were added in this order to the solution of 2-ethylpent-4-enal (58.44 g) in toluene obtained by the method described above under a nitrogen atmosphere, and the mixture was slowly warmed to approximately 80° C. over approximately 1 hour. After stirring at approximately 80° C. for 13.5 hours, malonic acid (6.24 g, 0.06 mol) was added thereto, and the mixture was further stirred at approximately 80° C. for 3 hours and cooled to room temperature. To the reaction mixture, water (408 mL) was added, and concentrated hydrochloric acid (130 mL) was added to separate an organic layer. The aqueous layer was subjected to extraction with toluene (153 mL), and the extract was combined with the organic layer, followed by two extractions of the compound of interest into aqueous layers using a 2 M aqueous NaOH solution (360 mL×1 and 90 mL×1). The aqueous layers were combined and then adjusted to be acidic by the addition of concentrated hydrochloric acid (80 mL), followed by two extractions with toluene (each with 204 mL). The organic layers were combined and then washed with water (102 mL). The organic layer was concentrated under reduced pressure to obtain the title compound (100.57 g, yellow oil substance).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH:22]=O)[N:6]=1)([CH3:4])[CH3:3].NCCC(O)=O.COC1C=CC(/C=[C:45]2/[C:46]([NH:48][C:49]([S:51]/2)=[NH:50])=[O:47])=CC=1OC1CCCC1>>[CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH:22]=[C:45]2[S:51][C:49](=[NH:50])[NH:48][C:46]2=[O:47])[N:6]=1)([CH3:3])[CH3:4]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C=O)nc1C(C)(C)C
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: NCCC(=O)O
Product: CC(C)(C)c1nc(C=C2SC(=N)NC2=O)nc(C(C)(C)C)c1O
Yield: 11.2 %

Procedure:
4,6-Bis-(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-pyrimidine carboxaldehyde (0.5 g, 1.5 mmoles) is treated with β-alanine (0.27 g, 3.1 mmoles) and pseudothiohydantoin (0.21 g, 1.8 mmoles) according to the procedure of Example 6 to give 0.056 g (11%) of 5-[[4,6-bis-(1,1-dimethylethyl]-5-hydroxy pyrimidinyl]methylene]-2-imino-4-thiazolidinone. MP=278°-281° C. dec.
Reaction SMILES: C(O[C:4](=[O:7])[C:5]#[CH:6])C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][NH:14][NH2:15])=[CH:11][CH:10]=1>C(O)CCC>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][N:14]2[C:4](=[O:7])[CH:5]=[CH:6][NH:15]2)=[CH:11][CH:10]=1
Reactant: NNCc1ccc(Cl)cc1
Reactant: C#CC(=O)OCC
Solvent: CCCCO
Product: O=c1cc[nH]n1Cc1ccc(Cl)cc1

Procedure:
9.8 g (0.1 mol) of propiolic acid ethyl ester and 15.6 g (0.1 mol) of p-chlorobenzylhydrazine in 100 ml of n-butanol were heated for 8 hours under reflux.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:47][C:48]4[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1cccnc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cccnc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-aminopyridine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H47Cl2N6O3 [(M+H)+] 741.3081, observed 741.3083.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[C:11](Cl)=[O:12].[CH:21]1([CH2:26][NH2:27])[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:21]1([CH2:26][NH:27][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]#[CH:20])=[C:8]([O:7][CH3:6])[CH:9]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCC1CCCC1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCOc1ccc(C(=O)NCC2CCCC2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To a mixture of 10 ml of THF and 0.3 g of 3-methoxy-4-(2-propynyloxy)benzoyl chloride were added dropwise 0.15 g of cyclopentylmethylamine and 0.16 g of triethylamine in order under ice cooling. The mixture obtained was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture and it was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.31 g of N-cyclopentylmethyl-4-(2-propynyloxy)-3-methoxybenzamide (hereinafter, described as the compound 11 of the present invention) represented by the formula: