Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[N:14]=3)=[C:11]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:10]=[CH:9]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.O.[CH3:36][S:37]([CH3:39])=O>C(OCC)(=O)C>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:11]2[N:10]=[CH:9][N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:36][S:37][CH3:39])[CH2:3][CH2:4]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH3:20])[N:14]=2)=[CH:26][CH:25]=1
Reactant: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2[C@H]2CC[C@H](O)CC2)n1
Reactant: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1nccc(-c2c(-c3ccc(F)cc3)ncn2[C@H]2CC[C@H](OCSC)CC2)n1
Temperature: 25 °C

Procedure:
The product of example 11 (7.76 g, 21 mmol) was dissolved with warming in DMSO (105 mL) while stirring under argon. Cooling to room temperature and addition of triethylamine (29 mL, 208 mmol) resulted in two phases. The mixture was cooled with stirring to 18° C. in a water bath. The sulfur trioxide pyridine complex (13.4 g, 84 mmol) in DMSO (42 mL) was added dropwise over 15 min. The mild exotherm was controlled by adding ice to the water bath. The maximum internal temperature was 20° C. After the addition was complete, the mixture was stirred for 15 min., diluted with ethyl acetate (800 mL) and extracted four times with water (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated on a rotary evaporator to give 7.9 g of a crude product which NMR indicated contained −5% of the title compound. The remainder of the crude material was mostly 5-[4-(2-methoxy)pyrimidinyl]-4-(4-fluorophenyl)-1-(4-oxocyclohexyl)imidazole. Careful chromatography on silica gel (700 g) eluted with 0.5-3% methanol in methylene chloride gave the title product as a white solid (0.368 g, 4%). MS(ES+) [M+H]+, 429.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:18]([C:25]([F:28])([F:27])[F:26])=[N:17]2)=[CH:12][CH:11]=1>CN(C=O)C>[N:3]1([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:24]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[C:18]([C:25]([F:28])([F:26])[F:27])=[N:17]3)=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1nn(-c2ccc(Cn3ccnc3)cc2)c2c1CCCC2
Reaction time: 1 h
Yield: 88 %

Procedure:
Sodium hydride (60% in mineral oil, 14.0 mg; 0.35 mmol) was added in one portion to a room temperature stirring solution of imidazole (11.5 mg; 0.17 mmol) in anhydrous DMF (1 mL). After stirring at this temperature for 1 hour, a solution of 1-[4-(chloromethyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (61.2 mg; 0.19 mmol) in anhydrous DMF (0.4 mL) was added in one portion and the resulting mixture stirred at room temperature for a further 16 hours. The reaction was quenched with aqueous hydrochloric acid (0.2 M; 0.2 mL), and purified by SCX column chromatography, giving the title compound as a yellow oil (51.8 mg; 89%).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]([C:12]1[C:13]([OH:21])=[C:14]2[S:20][CH:19]=[CH:18][C:15]2=[N:16][CH:17]=1)=[O:11])[CH3:8].Cl[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>ClCCl>[CH:26]([O:25][C:23]([N:16]1[CH:17]=[C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])[C:13](=[O:21])[C:14]2[S:20][CH:19]=[CH:18][C:15]1=2)=[O:24])([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1cnc2ccsc2c1O
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cn(C(=O)OC(C)C)c2ccsc2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Add pyridine (1.20 ml, 14.8 mmol) to a suspension of 7-hydroxy-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (1.10 g, 4.93 mmol) in dichloromethane (50 ml), and then add isopropyl chloroformate (1.0 N in toluene, 14.8 ml). Stir the reaction mixture at room temperature overnight. Wash the mixture with 1 N HCl (50 ml) followed by brine (3×50 ml). Separate the organic layer, dry over sodium sulfate, filter and concentrate. Purify using silica gel column chromatography (gradient eluent, 0-60% ethyl acetate in hexane) to provide 7-oxo-7H-thieno[3,2-b]pyridine-4,6-dicarboxylic acid 6-ethyl ester 4-isopropyl ester (1.37 g, 90%) as a white crystalline solid. MS (ES+): 310 (M+H).
Reaction SMILES: [OH:1][C@@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[OH:1][C@@:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([N:14]([CH3:13])[C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:5]
Reactant: C[C@](O)(C(=O)O)c1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)[C@](C)(O)c1ccccc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (2R)-2-hydroxy-2-phenylpropanoic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 407.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C([O:14][C:15](=[O:25])[CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:17]([CH2:16][C:15]([OH:25])=[O:14])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: CCOC(=O)CNCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Product: O=C(O)CN(Cc1ccccc1)c1cc(Br)ccc1[N+](=O)[O-]
Yield: 54.8 %

Procedure:
In a manner as described above, 4-bromo-2-fluoro-1-nitro-benzene (11 g, 50 mmol), and N-benzyl-glycine ethyl ester (10 g, 50 mmol) were reacted to give crude [(5-bromo-nitro-phenyl)-benzyl-amino]-acetic acid (10 g, 55%). This product was reacted with iron powder to obtain crude 4-benzyl-6-bromo-3,4-dihydroquinoxalin-2(1H)-one (5 g, 58%). A sample was recrystallized from ethyl acetate/hexane: m.p. 174-176° C. 1H-NMR (DMSO-d6) δ3.75 (s, 2H), 4.43 (s, 2H), 6.71 (d, J=1.9 Hz, 1H), 6.81 (m, 2H), 7.32 (m, 5H), 10.57 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([O-:12])([OH:11])=[O:10]>>[N+:9]([O-:12])([OH:11])=[O:10].[N+:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: NCc1ccccc1
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])NCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 118 %

Procedure:
At a temperature of not higher than 0° C., 107 grams (1 mole) of benzylamine was dropped into 643 grams (10 moles) of 98% nitric acid over a period of 5 hours. After dropping was completed, the reaction was continued at 20°-25° C. for 3 hours with stirring. The resultant reaction mixture was poured into 750 grams of ice water to filter separated crystals, which were washed with an aqueous sodium chloride solution to obtain 254 grams of wet nitrobenzylamine nitrate crystals having a solid content of 61%.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].N([O-])=O.[Na+].[OH-].[NH4+].[ClH:24]>O>[Cl:24][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Cl
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1N
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccccn2)c1Cl
Reaction time: 0.5 h

Procedure:
The product from Example 4, 21.6 g, was dissolved in 100 mL of concentrated hydrochloric acid at 0° C. To this resulting clear solution was added a solution of sodium nitrite, 7.3 g, in 10 mL of water at 0° C. during 15 minutes. The resulting suspension was stirred an additional 30 minutes then added portionwise during 10 minutes to a solution of cuprous chloride, 9.3 g, in 100 mL concentrated hydrochloric acid. The reaction was very exothermic and accompanied by rapid nitrogen evolution. The suspension was then heated on the steambath until a test for diazonium salts was negative. The contents of the flask were cooled and the pH of the suspension adjusted to 8 with ammonium hydroxide and finally diluted with 100 mL of water. The solid were removed from the reaction by filtration through Celite® and the aqueous filtrate was washed with 200 mL of methylene chloride. After separating and drying the organic solution with anhydrous sodium sulfate, 17.4 g of a light brown oil was isolated after removal of the solvent by evaporation. The crude oil was flash chromatographed in Kieselgel 60, 230-400 mesh, using 1-1 hexanes/ethyl acetate as the eluent. 14.2 g of the title compound was obtained melting at 52°-53° C.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[C:13]3[CH:14]=[C:15]([CH3:17])[O:16][C:12]=3[CH:11]=[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:33])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:33][CH2:17][C:15]1[O:16][C:12]2[CH:11]=[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]=[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([CH:2]([F:1])[F:25])=[CH:24][CH:23]=3)[C:13]=2[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C)oc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(CBr)oc2c1
Yield: 50.5 %

Procedure:
To a solution of ethyl 4-[4-(difluoromethyl)phenoxy]-2-methyl-1-benzofuran-6-carboxylate (710 mg, 2.05 mmol) and NBS (438 mg, 2.46 mmol) in CHCl3 (25 mL) was added benzoyl peroxide (49.7 mg, 0.205 mmol). The mixture was refluxed for 14 hours. The solvent was evaporated, and the product was purified via gradient silica gel chromatography using hexanes/EtOAc (100/0 to 70/30) to give the title compound (440 mg, 51%) as a light-yellow solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.38 (t, J=7.16 Hz, 3 H) 4.38 (q, J=7.16 Hz, 2 H) 4.53 (s, 2 H) 6.39-6.89 (m, 2 H) 7.07 (d, J=8.48 Hz, 2 H) 7.49 (d, J=8.48 Hz, 2 H) 7.54 (d, J=0.94 Hz, 1 H) 8.01 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@@H:9]([C@H:10]([C:12](=C(C)C)[OH:13])[OH:11])[O:8][C:6](=[O:7])[C:5]=1[OH:17])[CH3:2]>O.C(O)C>[CH2:1]([O:3][C:4]1[C@@H:9]([C@H:10]([CH2:12][OH:13])[OH:11])[O:8][C:6](=[O:7])[C:5]=1[OH:17])[CH3:2]
Reactant: CCOC1=C(O)C(=O)O[C@@H]1[C@@H](O)C(O)=C(C)C
Solvent: CCO
Solvent: O
Product: CCOC1=C(O)C(=O)O[C@@H]1[C@@H](O)CO
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
12.4 g of the 3-O-ethyl-isopropylidene ascorbic acid prepared in Example 1 was dissolved in the mixed solvent of distilled water (10 ml)/ethanol (90 ml) together with 1.1 g of Nafion H, followed by stirring at 60° C. for 2 hours. Nafion H was eliminated by filtering and the mixture was concentrated into crude crystalline 3-ethyl-ascorbic acid. The crude crystalline 3-ethyl-ascorbic acid was re-crystallized in ethylacetate/ethanol (8:2) to give 7.6 g of white crystalline 3-O-ethyl-ascorbic acid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)([CH3:14])[C:9](OCC)=[O:10].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:14][C:8]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)([CH3:7])[CH2:9][OH:10]
Reactant: CCOC(=O)C(C)(C)c1cccnc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)c1cccnc1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
Tetrahydrofuran (10 mL) was added to lithium aluminum hydride (75 mg, 2.0 mmol). To this, a solution prepared by dissolving, in tetrahydrofuran (5 mL), ethyl 2-methyl-2-(pyridin-3-yl)propanoate (200 mg, 1.0 mmol) obtained in Step 1 of Reference Example 8-63 was slowly added with cooling in an ice bath, and the mixture was stirred at the same temperature for 1 hour. To this, sodium sulfate decahydrate was added and the mixture was stirred at room temperature for 1 hour. After Celite-filtration, the solvent in the filtrate was evaporated off under reduced pressure. Thus, 2-methyl-2-(pyridin-3-yl)propan-1-ol (Compound EK) (154 mg, yield: 99%) was obtained.
Reaction SMILES: C([NH:4][C:5]1[N:9]([CH2:10][C:11](OCC)=[O:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=O)C.[BH4-].[Na+]>C(O)C>[NH2:4][C:5]1[N:9]([CH2:10][CH2:11][OH:12])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2)c(C#Cc2ccccc2)c1NC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Nc1c(C#Cc2ccccc2)c(-c2ccccc2)nn1CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
To a suspension of ethyl 2-[5-acetamido-3-phenyl-4-(2-phenylethynyl)pyrazol-1-yl]acetate (22.4 g, 58 mmol) in ethanol (290 mL) was added sodium borohydride (11 g, 289 mmol) and the reaction stirred at room temperature for 16 h. The reaction mixture was partially concentrated to a final volume of 250 mL. 25% NaOH (250 mL) was added and the reaction mixture was stirred at 80° C. for 4 h. The reaction mixture was cooled down to room temperature and the two phases were separated. The aqueous phase was extracted with ethyl acetate three times and the organic phases combined, dried over MgSO4, filtered and evaporated. The residue was triturated from diethyl ether (20 mL) and the product was filtered and dried in vacuo to provide the title compound as an off-white solid (9.96 g). The mother liquor was concentrated in vacuo and purified by column chromatography (silica gel, gradient 0 to 100% ethyl acetate/isohexane) yielding a further 1.79 g of the title compound.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[OH:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2>>[OH:6][C:7]12[CH2:8][CH:9]3[CH2:15][CH:13]([CH2:12][C:11]([OH:2])([CH2:10]3)[CH2:16]1)[CH2:14]2
Reactant: O=S(=O)(O)O
Reactant: OC12CC3CC(CC(C3)C1)C2
Product: OC12CC3CC(C1)CC(O)(C3)C2
Temperature: 0 °C

Procedure:
To 324 ml of 70% sulfuric acid was added 0.33 mole of the 1-hydroxyadamantane obtained in Comparative Example 5, and the resultant mixture was stirred at the temperature of 95° C. for 4 hours. The reaction product was poured into ice water extracted with ethanol. The water phase was neutralized by sodium hydroxide and extracted with n-butanol, then the solvent was distilled off from the extract under reduced pressure. The crude product was recrystallized from n-hexane to obtain a powderly 1,3-dihydroxyadamantane.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH:13][CH:14]([C:16]1[CH:17]=[C:18]2[CH:24]=[CH:23][O:22][C:19]2=[CH:20][N:21]=1)[CH3:15]>>[C:14]([C:16]1[CH:17]=[C:18]2[CH:24]=[CH:23][O:22][C:19]2=[CH:20][N:21]=1)(=[O:13])[CH3:15]
Reactant: CC(O)c1cc2ccoc2cn1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(=O)c1cc2ccoc2cn1
Reaction time: 0.33 h

Procedure:
A liquid broth (pH 7) comprising 40 g of glucose, 3 g of yeast extract, 6.5 g of diammonium hydrogen phosphate, 1 g of potassium dihydrogen-phosphate, 0.8 g of magnesium sulfate heptahydrate, 60 mg of zinc sulfate heptahydrate, 90 mg of iron sulfate heptahydrate, 5 mg of copper sulfate pentahydrate, 10 mg of manganese sulfate tetrahydrate and 100 mg of sodium chloride, per liter, was distributed in 5-ml portions into large size test tubes and steam-sterilized at 120° C. for 20 minutes. These liquid broth portions were each aseptically inoculated with one loopful of one of the microorganisms listed in Table 4, and shake culture was carried out at 30° C. for 24 to 72 hours. After cultivation, 2 ml of each culture was centrifuged and the cells collected were suspended in 0.5 ml of 100 mM phosphate buffer (pH 6.5) containing 8% of glucose. This cell suspension was added to a test tube containing 2.5 mg of 5-acetylfuro[2,3-c]pyridine placed therein in advance, and the reaction was allowed to proceed at 30° C. for 26 hours. After reaction, the reaction mixture was analyzed in the same manner as in Example 1. The yield, optical purity and absolute configuration of the product 5-(1-hydroxyethyl)furo[2,3-c]pyridine per reaction mixture are shown in Table 4.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[C:20]([C:23]1[C:24]([OH:36])=[C:25]([O:34][CH3:35])[C:26]2[O:30][CH:29]=[CH:28][C:27]=2[C:31]=1[O:32][CH3:33])(=[O:22])[CH3:21]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:36][C:24]1[C:23]([C:20](=[O:22])[CH3:21])=[C:31]([O:32][CH3:33])[C:27]2[CH:28]=[CH:29][O:30][C:26]=2[C:25]=1[O:34][CH3:35])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Reactant: COc1c(C(C)=O)c(O)c(OC)c2occc12
Product: COc1c(C(C)=O)c(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c(OC)c2occc12

Procedure:
By carrying out the process in a manner similar to example 7, starting from 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 5-acetyl-4,7-dimethoxy-6-hydroxybenzofuran, the desired product is obtained and is directly used in the following deprotection step without prior purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]#[N:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:11][CH2:10][C:3]1[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(C)c(C#N)c(=O)[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(CN)c(=O)[nH]1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (500 mg, 3.4 mmol) in tetrahydrofuran (20 mL) was added lithium aluminum hydride (258 mg, 6.8 mmol) at 0° C. The mixture was stirred at 20° C. for 2 hours. Then water (1 mL) was added and the product 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one was obtained as a white solid (300 mg, 60%). 1H NMR (300 MHz, d6-DMSO): δ 11.84 (s, 1H), 7.95 (s, 2H), 5.97 (s, 1H), 3.77 (s, 2H), 2.19 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:30])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][CH:25]([CH2:28][F:29])[CH2:26][F:27])[CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.O>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:30])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][CH:25]([CH2:26][F:27])[CH2:28][F:29])[CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(OC(CF)CF)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(OC(CF)CF)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 81.1 %

Procedure:
A mixture of methyl 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}benzoate (3.6 g, 8.2 mmol) in THF (50 mL) and water (50 mL) was treated with 1M sodium hydroxide solution (8.2 mL, 8.2 mmol) and allowed to stir at RT for 210 minutes. The THF was removed in vacuo, the residue filtered and extracted with ethyl acetate (30 mL). The aqueous layer was acidified with 2N hydrochloric acid, extracted with ethyl acetate (3×50 mL) and the combined organic extracts washed with water (10 mL), brine (10 mL) and concentrated in vacuo to give the desired material as a pale yellow foam (2.84 g). 1H NMR δ (CDCl3): 2.36-2.44 (m, 2H), 4.26 (t, 2H), 4.37 (t, 2H), 4.62-4.79 (m, 5H), 7.08 (t, 1H), 7.56-7.57 (m, 1H), 7.58-7.59 (m, 1H), 8.17 (d, 1H), 8.27 (d, 1H); m/z 426 (M+H)+, 424 (M−H)−
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.Cl[CH2:21][N:22]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][C:28]([O:37][CH3:38])=[CH:29][C:30]=2[CH:34]([CH3:36])[CH3:35])[S:23]1(=[O:25])=[O:24]>O>[S:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:21][N:22]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][C:28]([O:37][CH3:38])=[CH:29][C:30]=3[CH:34]([CH3:36])[CH3:35])[S:23]2(=[O:24])=[O:25])=[O:7])=[CH:2]1
Reactant: O=C(O)c1ccsc1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)c1ccsc1)C2=O
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A mixture of 3-thiophene carboxylic acid (0.26 g, 2.0 mmol), K2CO3 (0.28 g, 2.0 mmol) and DMF (4 ml) was stirred for 1 hour. 2-Chloromethyl-4-isopropyl-6-methoxy-saccharin (0.61 g, 2.0 mmol) was then added and the mixture was stirred for 24 hours. Water (20 ml) was added to the reaction mixture and the solution was extracted with ether (2×40 ml). The organic layer was separated, washed with water, then brine and was dried over anhydrous Na2SO4. The solvent was removed in vacuo and the solid residue was recrystallized from toluene/hexane to afford 0.5 g (65%) of 4-isopropyl-6-methoxy-2-saccharinylmethyl thiophene-3-carboxylate as a white powder, m.p. 125°-127° C.
Reaction SMILES: Cl.[NH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[C:12]([OH:14])=[O:13].[C:15]([S:18][CH2:19][CH:20]([CH2:24][S:25][C:26](=[O:28])[CH3:27])[C:21](Cl)=[O:22])(=[O:17])[CH3:16].Cl>N1C=CC=CC=1>[C:15]([S:18][CH2:19][CH:20]([CH2:24][S:25][C:26](=[O:28])[CH3:27])[C:21]([N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[C:12]([OH:14])=[O:13])=[O:22])(=[O:17])[CH3:16]
Reactant: CC(=O)SCC(CSC(C)=O)C(=O)Cl
Reactant: O=C(O)C1CCc2ccccc2N1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)SCC(CSC(C)=O)C(=O)N1c2ccccc2CCC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (±)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid hydrochloride (14.52 g) in pyridine (150 ml) was treated dropwise with 3-acetylthio-2-(acetylthiomethyl)propanoyl chloride with vigorous stirring. After stirring overnight at room temperature, the mixture was added to ice (300 g) and the pH was adjusted to 2.5 with concentrated hydrochloric acid. The mixture was extracted with ether and the ether extract dried over sodium sulfate and evaporated to a syrup. This (±) 1-(3-acetylthio-2-acetylthiomethyl-1-oxopropyl)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid was further purified by column chromatography (silica gel, toluene:ethyl acetate:acetic acid, 6.5:3:0.5); yield 2.5 g, m.p. 149°-151°.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])=[CH:9][CH:10]=1
Reactant: COCCCOc1ccccc1CCl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCOc1ccccc1COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method D, 0.200 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.113 g of 1-chloromethyl-2-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a yellowish oil. Rf=0.44 (1:2 EtOAc-heptane); Rt=6.25.