Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.O>CN1CCCC1=O>[ClH:11].[Cl:11][C:8]1[CH:9]=[CH:10][C:3]2[C:2]([NH:1][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[CH:6][S:5][C:4]=2[CH:7]=1
Reactant: Nc1csc2cc(Cl)ccc12
Reactant: Clc1ccncc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1ccc2c(Nc3ccncc3)csc2c1
Yield: 174.5 %

Procedure:
A solution of 3-amino-6-chlorobenzo[b]thiophene (5 g, 27 mmol) and 4-chloropyridine hydrochloride (6 g, 40 mmol) in 75 mL of 1-methyl-2-pyrrolidinone was stirred at 80° for 1.5 h, and then was cooled, stirred with water and extracted with ether. The aqueous layer was basified with sodium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution and then was dried (anhydrous magnesium sulfate), filtered and concentrated to a dark oil. Elution through silica with ethyl acetate via flash column chromatography yielded 7 g of an amber oil. Conversion to the hydrochloride salt in 20% methanol in ether yielded 4.2 g of yellow crystals, mp 264-266° (dec.).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1>>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)=[O:13])=[CH:18][C:17]=1[N:23]1[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)c1ccnc2ccccc12
Product: COc1ccc(NC(=O)c2ccnc3ccccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from quinoline-4-carboxylic acid and 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP0533268A1) using a similar procedure to Example 1.
Reaction SMILES: [CH2:1]([C:5]1([N:28]([CH3:30])[CH3:29])[CH2:10][CH2:9][CH:8]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:27])[CH3:26])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Si]([Cl:35])(C)(C)C>C(OCC)(=O)C>[ClH:35].[C:25]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]=1[CH:8]1[CH2:9][CH2:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])([N:28]([CH3:30])[CH3:29])[CH2:6][CH2:7]1)(=[O:27])[CH3:26]
Reactant: C[Si](C)(C)Cl
Agent: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2CCCCOC(C)=O)CC1
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
Acetic acid 4-[2-(4-butyl-4-dimethylaminocyclohexyl)-1H-indol-3-yl]butyl ester (non-polar diastereomer) (206 mg, 0.5 mmol) was dissolved in ethyl acetate (50 ml). Me3SiCl (126 μl, 1 mmol) was then added dropwise at RT and the mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl acetate (2×5 ml) and then dried. Example 177 (150 mg, m.p. 128-131° C., 67%) was obtained as a white solid
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Reactant: CC(C)(C)OC(=O)Nc1cnccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(-c2ccncc2NC(=O)OC(C)(C)C)c(C)c1
Yield: 115.1 %

Procedure:
A solution of tert-butyl N-(4-iodo-3-pyridyl)carbamate (20.0 g, 62 mmol), mesitylboric acid (10.2 g, 62 mmol), Pd(PPh3)4 (3.6 g, 3.12 mmol), barium hydroxide octahydrate (49.3 g, 47.3 mmol) in 1,2-dimethoxyethane (400 mL) and water (67 mL) was heated under reflux for six hours. The mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated, to give the title compound (containing 22.3 g of impurities) as pale brown crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([Cl:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:35]([OH:37])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:71][NH:72][CH2:73][CH2:74][CH2:75][CH2:76][CH:77]=[CH2:78].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:26][C:19]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[C:23]2[C:18]=1[N:17]=[C:16]([C:27]1[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=1)[CH:15]=[C:14]2[O:13][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C@H:9]([C:35](=[O:37])[N:72]([CH2:73][CH2:74][CH2:75][CH2:76][CH:77]=[CH2:78])[CH3:71])[CH2:10]1
Reactant: C=CCCCCNC
Reactant: COc1ccc2c(O[C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Compound 133 (20.5 g) was dissolved in anhydrous DMF (48 mL) at room temperature. O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.25 eq.) was added at room temperature and the reaction mixture was stirred for 10 min. Compound 32a (1.1 eq.) was added and the reaction mixture was stirred for additional 10-15 min. After cooling to 5° C., diisopropylethylamine (3 eq.) was added. After warming to room temperature for 1 hr, the reaction mixture was diluted with ethyl acetate, washed with brine and ammonium chloride, dried over Na2SO4, and concentrated under vacuum to give crude 134 (22.09 g) as an orange foam. The crude product was crystallized from ethyl acetate and heptane to give compound 134 (20.55 g) as a white powder in 92% yield and 98% purity.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:32])[C:16](=[O:31])[C:17]([C:29]#[N:30])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>CC(=O)OCC>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH3:32])[C:16](=[O:31])[C:17]([C:29]#[N:30])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1
Reactant: Cn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)c(C#N)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1c(N2CCC(N)CC2)nc(-c2ccc(C#N)c(F)c2)c(C#N)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
To a solution of {1-[5-cyano-4-(4-cyano-3-fluoro-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (150 mg, 0.33 mmol) in EA (5 mL) was added a 5N HCl solution in EA (5 mL). The reaction mixture was stirred at RT for 2 h, and the solvent was concentrated in vacuo to give 120 mg of the title product as HCl salt (94%). 1H NMR (400 MHz, CD3OD): δ 1.67-1.72 (m, 2H), 2.02-2.06 (m, 2H), 3.13-3.16 (m, 2H), 3.34-3.38 (m, 1H), 3.42 (s, 3H), 3.98-4.02 (m, 2H), 7.82-7.90 (m, 3H). [M+H] Calc'd for C18H17FN6O, 353. Found, 353.
Reaction SMILES: C(=O)CCC.C=O.[CH2:8]([C:10]([CH2:15][OH:16])([CH2:13][CH3:14])[CH:11]=[O:12])[OH:9]>C(O)=O>[CH2:8]([C:10]([CH2:15][OH:16])([CH2:11][OH:12])[CH2:13][CH3:14])[OH:9]
Reactant: CCC(C=O)(CO)CO
Agent: C=O
Solvent: O=CO
Solvent: CCCC=O
Product: CCC(CO)(CO)CO

Procedure:
In the Cannizzaro process, butyraldehyde is reacted with formaldehyde in the presence of a stoichiometric amount of base. This initially forms 2,2-dimethylolbutanal which then reacts with a further molecule of formaldehyde in a cross-Cannizzaro reaction to form formic acid and trimethylolpropane. The disadvantage of this method is that one molar equivalent of formate is formed as coproduct. This has to be worked up and increases the consumption of formaldehyde.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH2:34][CH3:35])[CH:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH2:34]([N:32]1[CH:33]=[C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:36])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:22][CH2:21]3)=[CH:24][CH:25]=2)[CH:30]=[N:31]1)[CH3:35]
Reactant: CCn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Agent: Cl
Solvent: CO
Product: CCn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)cn1
Yield: 96 %

Procedure:
A solution of the compound (297 mg, 0.57 mmol) obtained in Example 73-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (10 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate (10 mL) was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=20:80) to obtain the title compound (224 mg, 96%) as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]([C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1[O:16][CH3:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:18][C:19]([F:30])([F:29])[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH3:17][O:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=1[CH:2]([NH:1][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][C:19]([F:18])([F:29])[F:30])=[CH:22][CH:23]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)C(NCc1ccc(OC(F)(F)F)cc1)c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the chlorhydrate salt of ethyl 2-amino-2-(2,6-dimethoxyphenyl)acetate (8.43 mmol), 4-(trifluoromethoxy)benzaldehyde (1.603 g; 8.43 mmol), DIPEA (2.179 g; 16.86 mmol), NaBH(OAc)3 (2.633 g; 11.80 mmol), and acetic acid (506 mg; 8.43 mmol) in anh. DCE (9 ml) was stirred at rt, under nitrogen, for 16 h. 1 M aq. NaOH (17 ml) was added, and the separated aq. layer was further extracted with DCM (3×50 ml). The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded ethyl 2-(2,6-dimethoxyphenyl)-2-((4-(trifluoromethoxy)benzyl)amino)acetate. LC-MS (conditions D): tR=0.92 min.; [M+H]+: 414.05 g/mol.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][CH2:23][C:24]#[CH:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([NH:18][CH2:19][CH2:20][OH:21])[CH:17]=2)[C:12](O)=[O:13])=[N:6][CH:7]=1.C(N(CC)CC)C.[BH4-].[Na+].CO>O1CCCC1>[Br:1][C:2]1[C:3]([O:22][CH2:23][C:24]#[CH:25])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][OH:21])[CH:15]=[C:11]([CH2:12][OH:13])[CH:10]=2)=[N:6][CH:7]=1
Reactant: C#CCOc1nc(Nc2cc(NCCO)cc(C(=O)O)c2)ncc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: C#CCOc1nc(Nc2cc(CO)cc(NCCO)c2)ncc1Br

Procedure:
To a mixture of 3-[[5-bromo-4-(prop-2-ynyloxy)pyrimidin-2-yl]amino]-5-[(2-hydroxyethyl)amino]benzoic acid and triethylamine (57 μl) in tetrahydrofuran (4 ml) was added ethyl chloroformiate (37 μl) at −10° C. After stirring for 15 minutes at 0° C. sodium borohydride (44 mg) and methanol (3.6 ml) were added and stirring continued over night at room temperature. After dilution with water the reaction mixture was extracted with ethyl acetate and the organic layer subsequently washed with saturated NaHCO3-solution and brine After drying (Na2SO4) and evaporation the residue was subjected to chromatography on-silica gel (hexanes/ethyl acetate) to yield the title compound (59 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([C:15]([CH3:21])([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:16])[N:3]=1.O.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(COC)OC.C(O)C>[CH3:16][C:15]([C:4]1[CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[N:7]=[C:2]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[N:3]=1)([S:17]([CH3:20])(=[O:19])=[O:18])[CH3:21]
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2ccc(N)cc2)n1
Temperature: 90 °C
Yield: 139.9 %

Procedure:
(3S)-4-{2-Chloro-6-[1-methyl-1-(methylsulfonyl)ethyl]pyrimidin-4-yl}-3-methylmorpholine (2.2 g, 6.59 mmol) was dissolved in a solution of 18% DMF in a mixture of 7:3:2 dimethoxyethane:water:ethanol (18 mL). [4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (2.17 g, 9.89 mmol), 2M sodium carbonate solution (8 mL) and dichlorobis(triphenylphosphine) palladium catalyst (232 mg, 0.33 mmol) were then added and the reaction refluxed at 90° C. for 2 hours under a nitrogen atmosphere. The reaction was allowed to cool to room temp then partitioned between ethyl acetate (20 mL) and water (20 mL). The organics were dried over magnesium sulphate, filtered and concentrated in vacuo. The crude solid was chromatographed on silica, eluting with 0-10% methanol in DCM to give the desired material as a brown oil (3.6 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]([F:14])([F:13])[C:8](OCC)=[O:9]>>[Br:6][C:7]([F:14])([F:13])[C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: C1CCNC1
Reactant: CCOC(=O)C(F)(F)Br
Product: O=C(N1CCCC1)C(F)(F)Br
Reaction time: 1 h

Procedure:
Pyrrolidine (7.7 g, 108 mmol) was added to ethyl bromodifluoroacetate (20.2 g, 100 mmol) at 30° C. The mixture was stirred for 60 min; then all volatiles were removed under reduced pressure and the residue (24.0 g, >90% purity by NMR) was used in subsequent steps without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.CS[C:17]1[NH:18][CH:19]=[CH:20][C:21](=[O:23])[N:22]=1>>[O:23]=[C:21]1[CH:20]=[CH:19][NH:18][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)=[N:22]1
Reactant: COC(=O)C/C=C/c1ccc(N)cc1
Reactant: CSc1nc(=O)cc[nH]1
Product: COC(=O)C/C=C/c1ccc(Nc2nc(=O)cc[nH]2)cc1
Reaction time: 0.33 h
Yield: 35.3 %

Procedure:
A mixture comprising 3.00 g of methyl (E)-4-(4-aminophenyl)-3-butenoate and 2.34 g of 2-methylthio-1,4-dihydro-4-oxopyrimidine was stirred at 150° to 160° C. for 20 minutes. The reaction mixture was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1)] to obtain 1.58 g of the title compound as a light brown powder (yield: 35%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8]C(=O)C)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH:14]([OH:35])[CH2:15][S:16]([CH2:19][CH:20]([OH:34])[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([NH:29]C(=O)C)=[CH:23][C:22]=1[CH3:33])(=[O:18])=[O:17].S(=O)(=O)(O)O>>[CH3:33][C:22]1[CH:23]=[C:24]([NH2:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=1[CH:20]([OH:34])[CH2:19][S:16]([CH2:15][CH:14]([OH:35])[C:3]1[CH:4]=[C:5]([O:12][CH3:13])[C:6]([NH2:8])=[CH:7][C:2]=1[CH3:1])(=[O:18])=[O:17]
Reactant: COc1cc(C(O)CS(=O)(=O)CC(O)c2cc(OC)c(NC(C)=O)cc2C)c(C)cc1NC(C)=O
Agent: O=S(=O)(O)O
Product: COc1cc(C(O)CS(=O)(=O)CC(O)c2cc(OC)c(N)cc2C)c(C)cc1N
Yield: 94 %

Procedure:
292.9 Parts of 2-methyl-4-acetylamino-5-methoxyphenyl-β-hydroxyethylsulfone (purity: 98%) and 500 parts of diatomaceous earth were fed into a dispersion kneader (manufactured by Inoue Seisakusho) operated at 70 r.p.m. and then 210 parts of 70% sulfuric acid (molar ratio: 1.5) were added thereto. The mixture was maintained at 95° to 100° C. under reduced pressure (300 mmHg) for 7 hours while distilling off the produced water and acetic acid. The reaction product was analyzed by liquid chromatography, obtaining 2-methyl-4-amino-5-methoxyphenyl-β-hydroxyethylsulfone in a 94% yield.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=[O:6])[CH:2]=[CH2:3].[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:29]([S:31][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])[CH2:9]1)(=[O:32])[CH3:30]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
A solution of (2S,4R)-1-allyloxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (12.4 g: 30.46 mmole) and 90% potassium thioacetate (5.22 g: 45.69 mmole) in dimethylformamide (130 ml) is heated with stirring at 60° C. for 4 hours. The reaction mixture is diluted with ethyl acetate (200 ml) and ice water (200 ml). The organic layer is taken, successively washed with water (3 times) and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give crude (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-phthalimidomethylpyrrolidine (9.33 g). Yield: 81%. NMR δ(CDCl3) ppm: 1.7 to 1.9(m, 1H), 2.33(s, 3H), 2.4 to 2.7(m, 1H), 3.25 (dd, J=6.8 Hz, J=11.4 Hz, 1H), 3.7 to 4.0(m, 2H), 4.0 to 4.2(m, 2H), 4.3 to 4.6(m, 3H), 5.0 to 5.3(m, 2H), 5.7 to 5.9(m, 1H), 7.7(m, 2H), 7.85(m, 2H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:9]=1[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Cl:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:9]=1[CH:10]=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1c(F)cccc1Cl
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1c(F)cccc1Cl

Procedure:
Under an argon atmosphere, to a suspension (1.1 L) of methyltriphenylphosphonium bromide (90 g) in dry tetrahydrofuran was added a solution (264 mL) of 1 mol/L-potassium tert-butoxide in tetrahydrofuran with stirring under ice-cooling, and the mixture was stirred at the same temperature for 30 min. Then, a solution (165 mL) of 2-chloro-6-fluorobenzaldehyde (34.5 g) in tetrahydrofuran was added to the mixture, and the mixture was stirred for 30 min. The insoluble material was removed with celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue and, after triturating, the crystals were collected by filtration and concentrated. The residue was purified by silica gel column chromatography (developing solvent: hexane) using NH-silica gel (manufactured by Fuji Silysia Chemical Ltd.) to give the title compound as a colorless oil (yield: 20.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20](/[CH:23]=[CH:24]/[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[O:21][CH:22]=1>>[CH:25]1(/[CH:24]=[CH:23]/[C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(/C=C/C2CCCCC2)n1
Product: C(=C/C1CCCCC1)\c1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 67 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-[(E)-2-cyclohexylethenyl]oxazole to give 2-[(E)-2-cyclohexylethenyl]-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 67%. Recrystallization from isopropylether gave colorless prisms, mp 62-63° C.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(COc2ccnc(NC(=O)OC(C)(C)C)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1csc(COc2ccnc(N)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
tert-Butyl N-{4-[(4-isopropyl-1,3-thiazol-2-yl)methoxy]-2-pyridyl}carbamate (706 mg, 2.202 mmol) dissolved in dichloromethane (20 ml) was added dropwise with trifluoroacetic acid (20 ml) under ice cooling, then warmed to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with chloroform, then neutralized with saturated aqueous sodium hydrogencarbonate and extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=50:1→30:1→20:1) to obtain 331 mg (66%) of the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH3:44])=[C:38]([O:45][CH2:46][CH3:47])[CH:37]=3)[S:34][CH:35]=2)=[CH:27][CH:26]=1)(=O)C.C[O-].[Na+]>CO.ClCCl>[C@@H:6]1([O:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[N:32]=[C:33]([C:36]4[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH3:44])=[C:38]([O:45][CH2:46][CH3:47])[CH:37]=4)[S:34][CH:35]=3)=[CH:29][CH:30]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CCOc1ccc(-c2nc(-c3ccc(O[C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)cc3)cs2)cc1OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOc1ccc(-c2nc(-c3ccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)cc3)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
In 6 ml of a methanol-dichloromethane (2:1) mixed solvent was suspended 0.15 g of 4-[4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)phenyl]-2-(3,4-diethoxyphenyl)thiazole. Thereto was added a catalytic amount of sodium methylate. The mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation. The residue was recrystallized from methanol to obtain 71 mg of 4-[4-(β-D-glucopyranosyloxy)phenyl]-2-(3,4-diethoxyphenyl)thiazole.