Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:14]([CH2:23][CH3:24])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:47]([O:51][CH2:52][CH3:53])(=[O:50])[CH:48]=[CH2:49]>CN(C)C=O.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:12][C:8]1[C:7]2[N:13]=[C:14]([CH2:23][CH3:24])[N:15]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:6]=2[C:5]2[CH:4]=[CH:3][C:2](/[CH:49]=[CH:48]/[C:47]([O:51][CH2:52][CH3:53])=[O:50])=[CH:11][C:10]=2[N:9]=1
Reactant: C=CC(=O)OCC
Reactant: CCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc2c(c1)nc(N)c1nc(CC)n(CC3CCOCC3)c12
Temperature: 120 °C
Yield: 72.4 %

Procedure:
A thick walled glass vessel, equipped with a stir bar, was charged with a warmed solution of 7-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.5 g, 6.42 mmol) in N,N-dimethylformamide (50 mL). To the solution was added in succession, a solution of palladium acetate (144 mg, 0.642 mmol) and tri-ortho-tolylphosphine (390 mg, 1.28 mmol) in N,N-dimethylformamide (5 mL), triethylamine (2.7 mL) and a solution of ethyl acrylate (0.77 g, 7.7 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was purged with nitrogen. The vessel was sealed and heated at 120° C. for 18 hours. The reaction was cooled to ambient temperature and then concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (150 mL) and washed with saturated aqueous potassium carbonate (100 mL). The fractions were separated and the organic fraction was concentrated to dryness under reduced pressure. The resulting off-white solid was purified by chromatography using a HORIZON HPFC system (silica cartridge, 0-15% CMA/chloroform). A final recrystallization from acetonitrile provided 1.9 g of ethyl (2E)-3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate as an off-white crystalline solid, mp 209-210° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][OH:10])=[C:5]([Cl:11])[C:4]([Cl:12])=[N:3]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][O:10][S:14]([CH3:13])(=[O:16])=[O:15])=[C:5]([Cl:11])[C:4]([Cl:12])=[N:3]1
Reactant: Cn1nc(Cl)c(Cl)c1SCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nc(Cl)c(Cl)c1SCCOS(C)(=O)=O
Yield: 76 %

Procedure:
A solution of 5 g (0.022 moles) 1-methyl-3,4-dichloro-5-(2-hydroxyethylthio)pyrazole and 2.52 g (0.022 moles) methane sulfonyl chloride in 100 ml methylene chloride was stirred at room temperature for two days. To that mixture, 2.4 g (3.3 ml) triethylamine was added. The reaction mixture was then stirred over the weekend. The mixture was filtered and the filtrate was washed with water, then dried over magnesium sulfate, and then cooled with dry ice. Stripping of the solvent, followed by chromatography on silica gel, eluting with 5% ethyl acetate/methylene chloride gave 5.1 g of the product as a viscous yellow oil.
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])([O-:3])=[O:2].[CH3:11][OH:12]>>[CH3:11][O:12][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:4][N+:1]([O-:3])=[O:2]
Reactant: O=C1CCCCC1[N+](=O)[O-]
Reactant: CO
Product: COC(=O)CCCCC[N+](=O)[O-]
Yield: 89 %

Procedure:
2-Nitrocyclohexanone (6.77 g; 47.3 mmol) was dissolved in dried MeOH (150 mL) and a two fold excess by weight of Amberlyst® A21 (13.5 g) was added. The mixture was refluxed under nitrogen for 1.5 h then filtered and evaporated to give 6-nitrohexanoic acid methyl ester (7.72 g; 42 mmol). Yield: 89%.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:12]=[CH:11][C:7](C([O-])=O)=[CH:6][CH:5]=1.ClC(OCC)=O.[NH2:20]C1C=CC=CC=1.C1C2CC3(N)CC(C2)CC1C3>>[C:3]([NH2:20])(=[O:2])[C:4]1[CH:12]=[CH:11][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: CCOC(=O)Cl
Agent: NC12CC3CC(CC(C3)C1)C2
Product: NC(=O)c1ccccc1

Procedure:
As shown in the reaction scheme 2, firstly, monomethylterephthalate may be converted to an anhydride by employing ethyl chloroformate. Then, the anhydride may be reacted with aniline or adamantamine, to produce a benzamide compound. The next reactions may be performed by the same procedure described in the reaction scheme 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH2:7][CH2:6][CH2:5]2.[Li]CCCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.CCOC(C)=O>C1COCC1>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][CH2:7]2)=[CH:3][C:2]=1[B:18]([OH:23])[OH:19]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc2c(cc1Br)CCC2
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(cc1B(O)O)CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A solution of 1.06 g (4.69 mmol) of 5-bromo-6-methoxyindane in 10 mL of THF was cooled to −78° C. and treated in a dropwise manner with 2.90 mL (4.64 mmol) of 1.6 M n-BuLi in hexanes. The mixture was stirred for 1 hr and was treated with 1.90 mL (8.2 mmol) of triisopropyl borate. The reaction was allowed to warm slowly to 0° C. and was stirred at this temperature for 0.5 hr. The reaction was quenched by the careful addition of 12 mL of aq 1N HCl. The layers were separated and the aqueous layer extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford 1.02 g. Flash chromatography (SiO2; 15% EtOAc in hexanes) gave 0.62 g (69%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.52 (s, 2H), 7.41 (s, 1H), 6.84 (s, 1H), 3.75 (s, 3H), 2.81 (t, J=7.3 Hz, 2H), 2.73 (t, J=7.3 Hz, 2H), 2.00-1.92 (m, 2H); IR (CHCl3) 3505 (br), 2945, 1612, 1570, 1487, 1465, 1417, 1297, 1252, 1161, 1129 cm−1; FDMS 192 (M+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.Cl[C:13]1[C:14](=[O:27])[NH:15][C:16]2[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=2>CN1C(=O)CCC1.O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:13]2[C:14](=[O:27])[NH:15][C:16]3[C:21]([N:22]=2)=[CH:20][C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1)NCCC2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4ccc(F)cc43)nc2c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
To a solution of 7-fluoro-1,2,3,4-tetrahydroquinoline (1 g, 6.61 mmol) in NMP (30 ml) was added methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (900 mg, 3.77 mmol) and then stirred for 2 h at 150° C. The resulting solution was diluted with water ((900 ml). The solids were collected by filtration to afford methyl 3-(7-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a brown solid (900 mg, 39%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[C:25](Cl)(=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:26][C:25](=[O:34])[NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:4]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(CNC(=O)OCc2ccccc2)c2ccccc2c1=O

Procedure:
The product of Example 42 and benzyl carbonochloridate were treated using a method similar to that described in Example 128 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.50-11.71 (m, 1H), 8.32 (dd, J=7.6, 1.5 Hz, 1H), 8.08-8.11 (m, 1H), 7.88-8.01 (m, 3H), 7.28-7.48 (m, 9H), 5.06-5.07 (bs, 2H), 4.54 (d, J=5.9 Hz, 2H), 3.68 (s, 2H); MS (ESI+) M/Z 494 (M+NH4)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[CH3:15])[CH:4]([CH3:6])[CH3:5].[CH3:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=O)[CH:25]=2)[NH:20][N:19]=1>C(O)C>[CH2:3]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])/[CH:15]=[CH:27]/[C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[C:18]2[CH3:17])[CH:4]([CH3:6])[CH3:5]
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Reactant: CC(=O)c1ccccc1OCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1n[nH]c2ccc(/C=C/C(=O)c3ccccc3OCC(C)C)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.8 %

Procedure:
To a solution of NaOH (0.2 g, 5 mmol) in 3 mL ethanol were added commercially available 1-(2-isobutoxyphenyl)ethanone (100 mg, 0.52 mmol) and commercially available 3-methyl-1H-indazole-5-carbaldehyde (200 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 24 h, concentrated under reduced pressure and the product was purified by SiO2 flash chromatography (60:40 hexanes/ethyl acetate) to afford (E)-1-(2-isobutoxyphenyl)-3-(3-methyl-1H-indazol-5-yl)prop-2-en-1-one (50 mg, 28.6%). C21H22N2O2: 335 (MH+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.C(OCC)C.[Pt]=O>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCCc1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCOCC
Product: OCCCCCC1CCCCC1

Procedure:
To a solution of 5-phenylpentanol (2.21 g., 13.5 mmol) in ten ml glacial acetic acid was added amorphous platinum oxide (0.40 g., 1.76 mmol, oxygen activated). This mixture was subjected to three atm. of hydrogen with agitation (Parr hydrogenator) at room temperature for four hours. The reaction mixture was diluted with ethyl ether, filtered through celite, washed repeatedly with saturated sodium bicarbonate, followed by water and saturated sodium chloride solution. The organic portion was filtered, dried over magnesium sulfate, filtered and concentrated to give the desired alcohol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:18]([OH:22])(=[O:21])[CH2:19][SH:20]>N1C=CC=CC=1>[C:12]1([C:4]2[CH:3]=[C:2]([S:20][CH2:19][C:18]([OH:22])=[O:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Reactant: O=C(O)CS
Solvent: c1ccncc1
Product: O=C(O)CSc1cc(-c2ccccc2)nc2ccccc12
Yield: 86.6 %

Procedure:
4-Chloro-2-phenylquinoline (3 g) and thioglycolic acid (1.38 g) in pyridine (40 cc) are heated under reflux for 4 hours. After evaporation of the pyridine under reduced pressure, the residue is taken up with water (125 cc) and normal aqueous sodium hydroxide solution (40 cc). The aqueous phase is washed with ethyl ether (2×50 cc), acidified to pH 5 with glacial acetic acid and extracted with ethyl ether (3×50 cc). The ether phase is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. [(2-Phenyl-4-quinolyl)thio]acetic acid (3.2 g), m.p. 138° C., is thereby obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]4)=[C:20]([CH:23]=3)[CH:21]=O)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[NH2:34][OH:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH2:32]4)=[C:20]([CH:23]=3)[CH:21]=[N:34][OH:35])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC1CCN(CCOc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2C=O)CC1
Reactant: NO
Product: CC1CCN(CCOc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2C=NO)CC1

Procedure:
The product was obtained analogously to Example 14.1d starting from 5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-methylpiperidin-1-yl)ethoxy]benzaldehyde (Example 14.1c) and hydroxylamine. Yield: 40 mg (46% of theoretical); C28H28ClN3O2 (M=473.994); calc.: molpeak (M+H)+: 474/476 (Cl); found: molpeak (M+H)+: 474/476 (Cl); HPLC-MS: 5.68 minutes (method A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][Si](C)(C)C)=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][Cl:16]>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:14][CH2:15][Cl:16])=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: C[Si](C)(C)Sc1ccc(Cl)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: ClCCSc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
A mixture consisting of 12.21 g (56.5 mmoles) of 4-chlorophenylthio(trimethyl)silane, 20 ml of hexamethylphosphoric triamide and 18.7 ml (226 mmoles) of 1-bromo-2-chloroethane was heated at 60° C. and it was established that the conversion was complete after 10 minutes. After treating the reaction mixture as described in Example 3, there were obtained 10.03 g (85.7% yield) of 2-chloroethyl 4-chlorophenyl sulfide boiling at 105°-109° C./1.0 mm Hg and melting at 28°-29° C. The residue of the distillation contained 1,2-bis(4-chlorophenylthio)ethane as a by-product which after crystallization from methanol melted at 87°-88° C.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([NH:16][C:17](=[O:20])[CH2:18][Cl:19])[S:14][CH:15]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[K+]>C(O)C.O>[CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([NH:16][C:17](=[O:20])[CH2:18][Cl:19])[S:14][CH:15]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)OCC)c1csc(NC(=O)CCl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Temperature: 25 °C
Yield: 91 %

Procedure:
1.06 g of ethyl α-ethoxyimino-2-(chloroacetylamino)thiazol-4-ylacetate is suspended in a solution of 0.94 g of potassium hydroxide in a mixture of 40 ml of ethanol and 2 ml of water and the suspension is stirred at room temperature to make it to be a solution, followed by further stirring for 45 minutes at room temperature. The reaction solution is subjected to the distillation of ethanol under reduced pressure and the residue is adjusted to pH 2.0 with 1 N hydrochloric acid under ice-cooling, to precipitate crystals. The crystals are filtered, washed with water and dried. The procedure yields 0.88 g of α-ethoxyimino-2-(chloroacetylamino)thiazol-4-ylacetic acid. Yield 91%.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[CH2:39][C:40]([NH:42][CH3:43])=[O:41]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[C:17]4[CH:20]=[CH:21][C:22]([CH:24]5[CH2:29][CH2:28][N:27]([CH2:39][C:40]([NH:42][CH3:43])=[O:41])[CH2:26][CH2:25]5)=[CH:23][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Reactant: CNC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Product: CNC(=O)CN1CCC(c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Reaction time: 24 h
Yield: 14.3 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (150 mg, 0.35 mmol) was added triethylamine (107 μL, 0.77 mmol) followed by 2-chloro-N-methyl-acetamide (41 mg, 0.38 mmol). The resultant mixture was stirred overnight before the addition of tetrabutylammonium iodide (13 mg, 0.04 mmol) and the reaction stirred for 24 hours. The mixture was washed with water then extracted with 10% MeOH in DCM (×5). The combined organic layers were dried (MgSO4), concentrated in vacuo and purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM) twice to afford 275 (23 mg, 0.05 mmol, 14%). LCMS: RT=2.63 min, [M+H]+=464. 1H NMR δ (ppm) (CDCl3): 8.42 (1H, d, J=8.30 Hz), 7.59 (1H, s), 7.00 (1H, dd, J=8.35, 1.83 Hz), 6.88 (1H, d, J=1.79 Hz), 5.91-5.81 (1H, m), 4.48-4.44 (2H, m), 4.42-4.36 (2H, m), 3.13-2.91 (4H, m), 2.85 (3H, d, J=4.98 Hz), 2.56-2.48 (1H, m), 2.39 (3H, s), 2.33 (2H, s), 1.87 (2H, s), 1.78 (2H, s), 1.54 (6H, d, J=6.65 Hz). NH not observed.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>ClCCl>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:6]2[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][O:1][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][O:31]3)[O:4][CH:5]=2)=[CH:17][CH:16]=1
Reactant: C1=COCCC1
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COc1ccc(COc2coc(COC3CCCCO3)cc2=O)cc1
Temperature: 25 °C

Procedure:
2-Hydroxymethyl-5-(4-methoxybenzyloxy)-4-pyrone (2.62 g) was dissolved in dichloromethane (48 ml). To the solution was added, while stirring at room temperature, p-toluenesulfonic acid (100 mg). To the mixture was added dropwise 3,4-dihydro-2H-pyrane (2.28 ml). The mixture was stirred for 3 hours at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate and an aqueous saline solution, which was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The concentrate was crystallized from ether, and the crystals were collected by filtration to give 1.85 g of 5-(4-methoxybenzyloxy)-2-(tetrahydropyran-2-yl)oxymethyl-4-pyrone as colorless crystals, m.p.95°-96° C. IR(KBr): 3070, 2940, 1650, 1620, 1510, 1450, 1210, 1020 cm-1. 1H-NMR(DMSO-d6) ε: 1.4-1.8(6H,m), 3.4-3.55(1H,m), 3.65-3.85(4H,m), 4.40(2H,ABq,J=14 Hz), 4.07(1H,br.), 4.86(2H,s), 6.38(1H,s), 6.93(2H,d,J=8 Hz), 7.33(2H,d,J=8 Hz), 8.16(1H,s)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH3:22])[C:17]([OH:23])=[C:16]([CH2:24][CH2:25][CH3:26])[CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:27])[CH:3]=1.Br[CH:29]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[C:30]([CH:29]([CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[O:23][C:17]1[C:16]([CH2:24][CH2:25][CH3:26])=[CH:15][C:14]([CH2:13][N:8]2[C:6]3=[N:7][C:2]([CH3:1])=[CH:3][C:4]([CH3:27])=[C:5]3[N:10]=[C:9]2[CH2:11][CH3:12])=[CH:19][C:18]=1[CH2:20][CH2:21][CH3:22])([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1O
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C)nc32)cc(CCC)c1OC(CCc1ccccc1)C(=O)OCC
Temperature: 60 °C
Yield: 63.6 %

Procedure:
To a stirred solution of 0.150 g (0.41 mmol) of 5,7-dimethyl-2-ethyl -3-[4-hydroxy-3,5-dipropylphenyl]methyl-3H-imidazol[4,5-β]pyridine (Step G of Example 13) and 0.127 g (0.49 mmol) of ethyl α-bromo-4-phenylbutanoate in 2 mL anhydrous DMF was added 0.290 g (0.82 mmol) cesium carbonate and the reaction mixture was stirred and heated at 60° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with methylene chloride, filtered, and evaporated in vacuo. The residue was then purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. The purified fractions were combined, evaporated and dried in vacuo to afford 0.145 g (64%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:24])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].[NH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:40][CH2:39][CH:36]1[CH2:37][CH2:38][N:33]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=4[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:24])=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:31][CH3:32])[CH2:34][CH2:35]1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCN1CCC(CO)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
(2-{[7-(2-Chloroethoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (50 mg), 4-piperidine methanol (38 mg), and potassium carbonate (76 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (31 mg, yield 54%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C(C1CCC(N)CC1)C>C(O)(=O)C>[CH2:24]([CH:4]1[CH2:5][CH2:6][CH:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH2:2][CH2:3]1)[CH3:25]
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: CCC1CCC(N)CC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CCC1CCC(n2cnc3c(-c4ccccc4)csc3c2=O)CC1
Yield: 4.7 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 4-ethylcyclohexanamine (0.133 ml, 0.90 mmol), and acetic acid (0.1 ml) were used to give 6.8 mg (0.02 mmol, 4.7% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH:12](OC)(OC)OC>CO>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[CH3:11]
Reactant: Cc1c(Cl)cccc1C(=O)O
Reactant: COC(OC)OC
Solvent: CO
Product: COC(=O)c1cccc(Cl)c1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 96.1 %

Procedure:
Alternatively, to a suspension of 3-chloro-2-methylbenzoic acid (6.8 g, 40 mmol) in methanol (40 mL) was added trimethyl orthoformate (4.4 mL, 40 mmol). HCl gas was then bubbled through the suspension for 20 minutes. The resulting solution was then heated in a 60° C. oil bath. After stirring at 60° C. for 16 hours, the solution was allowed to cool to ambient temperature and concentrated under reduced pressure to afford a thick yellow paste. The semi-solid was melted under reduced pressure using a heat gun, and then cooled to afford 3-chloro-2-methylbenzoic acid methyl ester (7.1 g, 95% yield) as a yellow crystalline solid: 1H-NMR (400 MHz, CDCl3): δ 7.70 (1H, d, J=7.8 Hz), 7.51 (1H, d, J=7.8 Hz), 7.17 (1H, t, J=7.8 Hz), 3.91 (s, 3H), 2.60 (s, 3H) ppm.