Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([S:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:14]([C:22]1([C:28](O)=[O:29])[S:27][CH2:26][CH2:25][CH2:24][S:23]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].S1CCCSC1C(O)=O.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C(Br)CCCCCCC>>[CH3:13][S:12][C:11]1[C:2]([NH:1][C:28]([C:22]2([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[S:23][CH2:24][CH2:25][CH2:26][S:27]2)=[O:29])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: CSc1ccc2ncccc2c1N
Reactant: CCCCCCCCC1(C(=O)O)SCCCS1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)C1SCCCS1
Agent: [Na+]
Solvent: CCCCCCCCBr
Product: CCCCCCCCC1(C(=O)Nc2c(SC)ccc3ncccc23)SCCCS1

Procedure:
5-Amino-6-methylthioquinoline, prepared as described in Example 34, was coupled with 2-octanyl-1,3-dithiane-2-carboxylic acid, prepared by treatment of 1,3-dithiane-2-carboxylic acid with sodiumhexamethyldisilazide and octanyl bromide, according to Example 25 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=O)[O:6][C:5]2=[CH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.O.[NH2:20][NH2:21].O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:6])[NH:21][N:20]=[C:5]2[CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1OC(=Cc2cccnc2)c2cc(Cl)ccc21
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(Cc2cccnc2)c2cc(Cl)ccc12

Procedure:
5-Chloro-3-(pyrid-3-yl)methylenephthalide (2.68 g) was dissolved in 100 ml of ethanol, followed by the addition of 2.0 ml of hydrazine monohydrate. The obtained mixture was heated under reflux for 4 hours, followed by the addition of 200 ml of water. The resulting mixture was neutralized with dilute hydrochloric acid to precipitate crystals, which were recovered by filtration to give 1.87 g of the title compound as a yellow powder.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:26])=O.Cl>CN(C)C=O.ClCCl>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([Cl:26])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A stirred mixture of triphenylacetic acid (21.7 g; 0.075 mol) and dry dimethylformamide (2 drops) in dry dichloromethane (100 cm3) was treated with oxalyl chloride (14 g; 0.11 mol) which was added in 4 approximately equal portions over ˜25 minutes. The mixture was stirred at 35° until evolution of hydrogen chloride had ceased (˜4 hrs). The resulting colourless solution was evaporated in vacuo at 40° to constant weight to give the title compound as a colourless crystalline solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([OH:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[CH:40][CH:41]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
A mixture of ethyl (1-benzyl-3-hydroxy-1H-pyrazol-4-yl)acetate (521 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (628 mg), potassium carbonate (553 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl [1-benzyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetate (731 mg, yield 68%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: C([Mg]Br)C.[O:5]([C:13]1[CH:26]=[CH:25][C:24]2[C:15](=[C:16]3[C:21](=[CH:22][N:23]=2)[C@@H:20]([CH3:27])[CH2:19][C:18]([O:30][CH3:31])([O:28][CH3:29])[C@@H:17]3[OH:32])[CH:14]=1)[Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:33]([Si:37]([C:40]#[C:41]/[CH:42]=[CH:43]\[C:44]#[CH:45])([CH3:39])[CH3:38])([CH3:36])([CH3:35])[CH3:34].Cl[C:47]([O:49][CH2:50][CH:51]=[CH2:52])=[O:48]>O1CCCC1>[O:5]([C:13]1[CH:26]=[CH:25][C:24]2[N:23]([C:47]([O:49][CH2:50][CH:51]=[CH2:52])=[O:48])[C@@H:22]([C:45]#[C:44]/[CH:43]=[CH:42]\[C:41]#[C:40][Si:37]([C:33]([CH3:35])([CH3:36])[CH3:34])([CH3:39])[CH3:38])[C:21]3[C@@H:20]([CH3:27])[CH2:19][C:18]([O:28][CH3:29])([O:30][CH3:31])[C@H:17]([OH:32])[C:16]=3[C:15]=2[CH:14]=1)[Si:6]([C:9]([CH3:11])([CH3:12])[CH3:10])([CH3:8])[CH3:7]
Reactant: C#C/C=C\C#C[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)Cl
Reactant: COC1(OC)C[C@H](C)c2cnc3ccc(O[Si](C)(C)C(C)(C)C)cc3c2[C@H]1O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCOC(=O)N1c2ccc(O[Si](C)(C)C(C)(C)C)cc2C2=C([C@@H](C)CC(OC)(OC)[C@@H]2O)[C@@H]1C#C/C=C\C#C[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
A solution of ethylmagnesium bromide in tetrahydrofuran (1.0M, 13.6 mL, 13.6 mmol, 0.90 equiv) was added to a solution of (7S,10R)-2-(tert-butyldimethylsiloxy)-7,8,9,10-tetrahydro-9,9-dimethoxy-7-methyl-10-phenanthridinol (17, 6.10 g, 15.1 mmol, 1 equiv) in tetrahydrofuran (30 mL) at -78° C. The mixture was stirred in an ice bath for 10 min, then was cooled to -78° C. In a separate flask, a solution of ethylmagnesium bromide in tetrahydrofuran (1.0M, 22.7 mL, 22.7 mmol, 1.50 equiv) was added to a solution of tert-butyl[(Z)-3-hexene-1,5-diynyl]dimethylsilane (18, 5.75 g, 30.2 mmol, 2.00 equiv) in tetrahydrofuran (20 mL) at 0° C. The resulting solution was warmed to 23° C., then was heated briefly to reflux with a heat gun. After the mixture had cooled to 23° C., it was transferred via cannula over 3 min to the cold solution of magnesium alkoxide derived from the TBS quinoline. Allyl chloroformate (1.20 mL, 14.4 mmol, 2.00 equiv) was added, and the solution was stirred in an ice bath for 2 h. The reaction mixture was partitioned between aqueous phosphate buffer solution (pH 7, 0.05M in sodium hydrogen phosphate and 0.05M in potassium dihydrogen phosphate, 150 mL) and ethyl acetate (150 mL). The aqueous layer was separated and extracted further with ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated. The residue was purified by flash column chromatography (10% ethyl acetate-hexanes initially, grading to 20% ethyl acetate-hexanes) to afford allyl(6S,7S,10R)-2-(tert-butyldimethylsiloxy)-6-[(Z)-6-(tert-butyldimethylsilyl)-3-hexene-1,5-diynyl]-7,8,9,10-tetrahydro-10-hydroxy-9,9-dimethoxy-7-methyl-5(6H)-phenanthridinecarboxylate (19) as a light yellow foam (9.16 g, 89%). The other product, structure 20, was not used. ##STR31##
Reaction SMILES: [CH:1]1([OH:9])[CH:8]2[N:4]([CH2:5][CH2:6][CH2:7]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].[Cl-].[NH4+].[Na]>ClCCl>[CH3:17][S:18]([O:9][CH:1]1[CH:8]2[N:4]([CH2:5][CH2:6][CH2:7]2)[CH2:3][CH2:2]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCN2CCCC12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN2CCCC12
Temperature: 0 °C
Yield: 66.8 %

Procedure:
A mixture of perhydro-1-pyrrolizinol (0.5 g, 3.94 mmol) and triethylamine (0.60 g, 5.91 mmol) in dichloromethane (10 ml) was stirred at 0° C. under an atmosphere of nitrogen. Methanesulfonyl chloride (0.68 g, 5.91 mmol) was added, then the mixture was allowed to warm to ambient temperature and stirred for 8 hours. Saturated aqueous ammonium chloride (10 ml), dichloromethane (25 ml) and saturated aqueous sodium bicarboante (10 ml) were added. The organic layer was dried over magnesium sulfate filtered and the filtrate evaporated under reduced pressure to give a residue. Purification of the material by flash chromatography on silica gel using heptane/ethyl acetate (1:3) as an eluent yielded perhydro-l-pyrrolizinyl methanesulfonate (0.54 g): 1H NMR (DMSO-d6, 400 MHz) δ 4.96 (m, 1H), 3.61 (m, 1H), 2.9-3.3 (m, 6H), 2.35 (m, 1H), 1.55-2.25 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18]>C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Nc1ccc(F)cc1C(F)(F)F
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1ccc(F)cc1C(F)(F)F
Temperature: 100 °C
Yield: 50.6 %

Procedure:
A mixture of 4-fluoro-2-(trifluoromethyl)aniline (4.4 g, 24.6 mmol), 2,5-hexanedione (2.8 g, 24.5 mmol) and acetic acid (0.28 mL) was heated to 100° C. After 3 h the reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (SiO2), eluting with EtOAc/Hex (0:100 to 10:90) to afford 1-[4-fluoro-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole as a yellow oil (3.19 g, 50%); 1H NMR (CDCl3): δ 7.52 (dd, J=8, 3 Hz, 1H), 7.35 (dt, J=3, 8 Hz, 1H), 7.25 (dd, J=5, 8 Hz, 1H), 5.90 (s, 2H), 1.91 (s, 6H); MS (ESI) m/z 258 [M+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N+:10]([C:13]1[CH:14]=[C:15]2[C:20](=[O:21])[O:19][C:17](=O)[C:16]2=[CH:22][CH:23]=1)([O-:12])=[O:11].Cl.[CH2:25]([O:27][C:28](=[O:38])[C@H:29]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[NH2:30])[CH3:26]>C1(C)C=CC=CC=1.C(OCC)C>[N+:10]([C:13]1[CH:14]=[C:15]2[C:20](=[O:21])[N:30]([C@@H:29]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:27][CH2:25][CH3:26])=[O:38])[C:17](=[O:19])[C:16]2=[CH:22][CH:23]=1)([O-:12])=[O:11]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC[C@@H](C(=O)OCC)N1C(=O)c2ccc([N+](=O)[O-])cc2C1=O

Procedure:
Diisopropylethylamine (24 ml, 0.138 mole) (Aldrich) was added to a suspension of 4-nitrophthalic anhydride (25 g, 0.13 mole) (Tokyo Kasei) and L-glutamic acid diethyl ester hydrochloride (35 g, 0.146 mole) (Aldrich) in toluene (130 ml). The reaction mixture was stirred at reflux utilizing a Dean-Stark trap for 2.5 hours. After cooling, the solution was diluted with diethyl ether (300 ml), washed with water (75 ml), saturated NaHCO3 solution (50 ml), dried (MgSO4), and concentrated in vacuo at 70° C. to give diethyl (S)-2-(4-nitrophthalimido)glutarate as an oil that solidified to a white solid on standing (35.8 g). M.P.=65.5°-66.5° C. 1H NMR (DMSO-d6, 300 MHz) δ: 1.12 (t, J=7 Hz, 3H, ester CH3), 1.14 (t, J=7 Hz, 3H, ester CH3), 2.2-2.5 (m, 4H, glu CH2CH2), 3.96 (q, J=7 Hz, 2H, ester CH2), 4.08-4.19 (m, 2H, ester CH2), 4.97-5.04 (m, 1H, glu CH), 8.19 (dd, J=8,0.5 Hz, 1H, Ar), 8.56 (dd, J=2,0.5 Hz, 1H, Ar), 8.68 (dd, J=8,2 Hz, 1H, Ar). Mass spectrum (CI-CH4); 379 (M+1, 28.8%), 333 (71.6%), 305 (100%). Anal. Calculated for C17H18N2O8 : C, 53.97; H, 4.80; N, 7.40. Found: C, 53.89; H, 4.82; N, 7.42.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.ClCCl.Cl[C:22]1[O:23][C:24]2[C:25](=[C:27]([C:39]#[N:40])[C:28]([CH3:38])=[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:30]=2[F:31])[N:26]=1>C(OCC)(=O)C>[F:31][C:30]1[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:28]([CH3:38])[C:27]([C:39]#[N:40])=[C:25]2[C:24]=1[O:23][C:22]([N:11]([CH3:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:26]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CNc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)c3ccccn3)nc2c1C#N
Temperature: 50 °C
Yield: 57.7 %

Procedure:
Diisopropylethylamine (169 μl, 0.944 mmol) and 2-(methylamino)pyridine (102 μl, 0.994 mmol) were added to a dichloromethane (10 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (190 mg, 0.663 mmol), followed by heating under reflux in an oil bath at 50° C. for 3 hours. The reaction liquid was cooled to room, temperature, ethyl acetate (70 ml) was added, followed by washing with water (50 ml) and saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=4:1) to obtain the entitled compound (137 mg, 57.5%) as a colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]1([C@H:19]([N:21]2[N:25]=[CH:24][CH:23]=[N:22]2)[CH3:20])[CH2:18][O:17]1.O>CN(C)C=O.C(OCC)(=O)C>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:17])([C@H:19]([N:21]1[N:25]=[CH:24][CH:23]=[N:22]1)[CH3:20])[CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: C[C@@H](n1nccn1)[C@@]1(c2ccc(F)cc2F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1nccn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
1H-1,2,4-Triazole (41 mg) was added an ice-cooled dispersion of 60% sodium hydride in oil (23 mg) in dimethylformamide (1 ml) and the resulting mixture was stirred for 10 minutes at room temperature. To the mixture was added a solution of (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(2H-1,2,3-triazol-2-yl)ethyl]oxirane (76 mg) in dimethylformamide (0.8 ml), followed by heating for 5 hours at 50° C. and cooling. To the reaction mixture were added cold water (5 ml) and ethyl acetate (15 ml). The separated aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated saline, dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue was subjected to silica gel column chromatography (acetone/dichlormethane=1:2→1:1). The obtained oily substance was crystallized from isopropyl ether to give the title compound (Compound 8, 41 mg, 42%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][N:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1>>[O:36]1[C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][N:15]3[C:14](=[O:17])[N:11]4[N:12]=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)=[C:9]([C:18]5[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=5)[C:10]4=[N:16]3)=[CH:27][CH:28]=2)=[CH:33][CH:34]=[N:35]1
Reactant: BrCc1ccc(-c2ccno2)cc1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(F)cc3)cnn12
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(-c3ccncc3)c(-c3ccc(F)cc3)cnn12

Procedure:
The title compound was prepared by reacting 7-(4-fluorophenyl)-8-(pyridine-4-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3(2H)-one, prepared as described in Example 279F, 5-(4-(bromomethyl)phenyl)isoxazole, prepared as described in Example 250A by procedures analogous to those described in Example 2 as a yellow solid (68%). HPLC: 99% at 5.46 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 465 [M+H]+; 1H NMR (CDCl3, 400 MHz): δ 5.25 (s, 2H), 6.51 (d, J=0.96 Hz, 1H), 7.01-7.09 (m, 2H), 7.11-7.18 (m, 2H), 7.23 (dd, J1=4.40 Hz, J2=1.76 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H), 8.21 (s, 1H), 8.28 (d, J=1.76 Hz, 1H), 8.61-8.64 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([CH:19]([CH2:22][CH2:23][CH2:24][CH3:25])[CH:20]=O)[CH3:18].[CH3:26][OH:27]>>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:20]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)[CH:19]([CH2:17][CH3:18])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:26]=1[OH:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(C=O)CC
Reactant: CO
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Product: CCCCC(CC)C(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The procedure of Example 1 is repeated using 23.84 grams of 2,6-di-tert-butyl-4-mercaptophenol, 6.41 grams of 2-ethylhexanal, and 150 ml of methyl alcohol. The product is purified by dry-column chromatography to give 10.29 grams of a clear syrup.
Reaction SMILES: C([Cl:4])(=O)C.C(OC([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[N:19]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)[N:22]=2)[CH2:14][CH2:13]1)=O)(C)(C)C>C(O)C>[ClH:4].[ClH:4].[ClH:4].[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[N:22]=[C:18]([CH:15]3[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]3)[N:19]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:20]=2)=[CH:24][C:25]=1[C:30]([F:31])([F:32])[F:33]
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
In a 1 L 3 neck round bottom flask with a mechanical stirrer, thermocouple and nitrogen inlet charge ethanol (339.2 mL) and cool to −5 to 5° C. Add drop-wise neat acetyl chloride (78.5 g, 1 mol, 5 eq) at a rate to maintain temperature at 0-15° C. Cool the resulting solution to 0-5° C. and stir for 30 minutes. Add 4-(1-(2-(dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (96.9 g, 0.2 mol, 1 eq) over 5-10 minutes. Warm the reaction solution to RT (crystallization takes place) and stir the resulting suspension for 20-28 hours at RT. Once the reaction is deemed complete, filter the reaction mixture and wash the solids with ethanol (3×58 mL) then with heptane (2×96.9 mL). Dry solids under vacuum at 35-40° C. to afford the target compound (105.13 g, >100% yield) as a light tan solid. m/z (M+H): 385.2
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([OH:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42].C(O)(=O)[CH2:46][C:47](CC(O)=O)(C(O)=O)[OH:48]>CN(C)C(=O)C>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][C:12]([C:14]3[C:19]([O:20][C:41](=[O:43])[CH3:42])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[O:22][C@@H:23]3[O:31][C@H:30]([CH2:32][O:33][C:47](=[O:48])[CH3:46])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]3[OH:25])=[O:13])[CH:8]=[CH:9][C:2]1=2
Reactant: CC(=O)Cl
Reactant: Cc1cc(O)c(C(=O)CCc2ccc3occc3c2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cc(C)cc(OC(C)=O)c2C(=O)CCc2ccc3occc3c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
3-(5-Benzo[b]furanyl)-2'-(β-D-glucopyranosyloxy)-6'-hydroxy-4'-methylpropiophenone (500 mg) is dissolved in N,N-dimethylacetamide (3.5 ml), and thereto is added triethylamine (315 mg). To the mixture is added dropwise acetyl chloride (282 mg) under ice-cooling, and the mixture is stirred under ice-cooling for 30 minutes, and stirred at room temperature overnight. The reaction mixture is poured into chilled 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give 3-(5-benzo[b]-furanyl)-2'-(6-O-acetyl-β-D-glucopyranosyloxy)-6'-acetoxy-4'-methylpropiophenone (304 mg).
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:6])[CH2:4][CH3:5].Cl[C:8]1[CH:13]=[CH:12][N+:11]([O-:14])=[C:10]([CH3:15])[C:9]=1[CH3:16]>CS(C)=O.O>[CH2:3]([O:6][C:8]1[CH:13]=[CH:12][N+:11]([O-:14])=[C:10]([CH3:15])[C:9]=1[CH3:16])[CH2:4][CH3:5]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCOc1cc[n+]([O-])c(C)c1C
Temperature: 30 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
To a solution prepared by diluting 8.6 g (2.0 eq.) of 60% sodium hydroxide with 200 mL of dimethylsulfoxide, 13.0 g of 1-propanol (2.0 eq.) was added, and the mixture was allowed to react for one hour at 60° C. The reaction liquid was cooled to 30° C., and then a solution containing 17.0 g of 4-chlor-2,3-dimethylpyridine-1-oxide dissolved in dimethylsulfoxide (70 mL) was added dropwise. The mixture was allowed to react for 3 hours at 40 to 50° C., and then was left to stand overnight at room temperature. 15 mL of water was added to the reaction liquid, and the mixture was concentrated, to obtain a residue in the form of a black paste. Subsequently, the residue was dissolved in 500 mL of water, and then the aqueous solution was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, and the obtained residue was purified on a silica gel column, to obtain 20.3 g of 4-propoxy-2,3-dimethylpyridine-1-oxide.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][C:13](=[O:16])[C:14]=2[CH3:15])=[CH:5][CH:4]=1.B(Br)(Br)Br.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][C:13](=[O:16])[C:14]=2[CH3:15])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(C)c(=O)cc(-c3ccccc3)n2-c2ccccc2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(-c2ccc(O)cc2)n(-c2ccccc2)c(-c2ccccc2)cc1=O
Yield: 93.8 %

Procedure:
To 300 ml of a solution of 18.7 g (0.051 mole) of 2-(4-methoxyphenyl)-3-methyl-1,6-diphenyl-4(1H)-pyridinone in methylene chloride, 25.0 g (0.010 mole) of boron tribromide was added dropwise. After stirring the resultant mixture at room temperature for 15 hours, the reaction mixture was poured into water, followed by neutralization with sodium hydrogen carbonate. Deposited crystals were collected by filtration and washed with aceton, thereby affording 16.9 g of 2-(4-hydroxyphenyl)-3-methyl-1,6-diphenyl-4(1H)-pyridinone having a melting point of not lower than 300° C.