Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14].C([BH3-])#N.[Na+]>CO>[CH2:10]([NH:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH2:9])=[O:8])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NC(=O)c1[nH]cnc1N
Reactant: CCCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1nc[nH]c1C(N)=O
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
4-Amino-1H-imidazole-5-carboxamide (13.0 g, 0.104 mol) and valeraldehyde (11 mL, 0.10 mol) were mixed in methanol (200 mL). After being stirred for 30 min, sodium cyanoborohydride (6.5 g, 0.10 mol) was added to the solution and stirring was continued overnight. The reaction mixture was concentrated under reduced pressure. The remaining residue was taken up in EtOAc and the resulting solution was washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. The residue was purified by flash chromatography (DCM to 5% MeOH/DCM) to give the desired product (12.9 g, 63.1%). LCMS calculated for C9H16N4O (M+H): 197.1. Found: 180.1 (M+H−NH3).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@H:4]1[OH:13].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH3:1][O:2][C@H:3]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@H:4]1[OH:13]
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 79 %

Procedure:
In the above Table I, it can be seen tht Sample A product composition gave a yield of 79.0% methyl-alpha-D-glucopyranoside and methyl-beta-D-glucopyranoside, and only 10.81% of polyglycosides and dextrose. Sample D produced 77.12% methyl-alpha-D-glucopyranoside and methyl-beta-D-glucopyranoside, while Sample G produced only 71.55% of the glucosides. At the same time, the percentages of polyglycosides and dextrose increased as the methanol:starch ratio decreased. The cost of removal of excess methanol must be balanced against the slightly increased yield of glucosides.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:5][CH:4]=[C:3]1[C:19]#[N:20].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:15]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[NH:7][C:2](=[O:1])[C:3]([C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[CH:4][N:5]=1)[CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)COc1ccccc1-c1ncc(C#N)c(=O)[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccccc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Yield: 54.9 %

Procedure:
A mixture of 1,6-dihydro-6-oxo-2-(2-isobutoxyphenyl)-pyrimidine-5-carbonitrile (3.78 g., 0.014 mole), sodium azide (1.0 g., 0.0154 mole), and ammonium chloride (0.824 g., 0.0154 mole) in N,N-dimethylformamide was heated at 125° for 19 hours stirring. The solvent was removed under reduced pressure. The residue was treated with water (40 ml.). The mixture was acidified with 6N hydrochloric acid with stirring. The mixture was filtered and the collected solid recrystallized from glacial acetic acid to give the title compound (2.4 g., 55% yield), m.p. 230°-231°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=O)[O:5][C:6]2=[O:12].C([O-])(=O)C.[Na+].C(O)(=O)C.[NH2:23][NH2:24]>O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=[O:5])[NH:23][NH:24][C:6]2=[O:12]
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c(F)ccc(F)c12
Temperature: 25 °C

Procedure:
To 4,7-difluoroisobenzofuran-1,3-dione (1.00 g, 5.43 mmol) and sodium acetate (0.535 g, 6.52 mmol) was added water (14 mL), acetic acid (7.15 ml, 125 mmol) and hydrazine (0.205 ml, 6.52 mmol) (slowly). A water condenser was attached and the mixture was heated to reflux for 20 hours. Cooled to RT and filtered the resulting solid. Washed with water and dried to yield 5,8-difluoro-2,3-dihydrophthalazine-1,4-dione as a white solid. MS m/z=199 [M+1]+. Calc'd for C8H4F2N2O2: 198.13.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]([CH:11]([F:13])[F:12])=[N:9][CH:10]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(Cl)Cl>[F:12][CH:11]([F:13])[C:8]1[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]([CH2:4][NH:3][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[CH:10][N:9]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)c1cc(CN)cnc1C(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(CNC(=O)C(C)C)cnc1C(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
Cool a mixture of ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate dihydrochloride (29.8 g, 111.8 mmol, 1.0 equiv), DCM (510 mL), and triethylamine (59.2 mL, 424.6 mmol, 3.8 equiv) to 0° C., then add a solution of isobutyryl chloride (15.3 mL, 145.3 mmol, 1.3 equiv) in DCM (23 mL) drop wise over 20 min. Stir overnight while allowing the mixture to warm to room temperature. Remove the solid precipitate by filtration, and rinse the filter with EtOAc (500 mL). Concentrate the filtrate under reduced pressure; filter the concentrate to remove the solids; and rinse the solids with EtOAc. Concentrate the filtrate under reduced pressure to give a yellow oil. Subject this crude material to silica gel chromatography eluting with a gradient of 40-90% EtOAc/hexanes gradient, to give the title compound as a light yellow crystalline solid (25.8 g, 77% yield). ES/MS (m/z) 301 (M+1).
Reaction SMILES: COC1C=C(OC)C=CC=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([S:22][C:23]#[N:24])[C:19]([N+:25]([O-:27])=[O:26])=[CH:18][N:17]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N+:25]([C:19]1[C:20]([S:22][C:23]#[N:24])=[N:21][C:16]([N:15]2[C:8]3[CH:9]=[C:10]([C:11]#[N:12])[CH:13]=[CH:14][C:7]=3[N:6]=[CH:5]2)=[N:17][CH:18]=1)([O-:27])=[O:26]
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(SC#N)n2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CSc1nc(-n2cnc3ccc(C#N)cc32)ncc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 0.58 g (1.25 mmol) 4-(2,4-dimethoxybenzylamino)-3-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)benzonitrile in 10 mL 30% (v/v) TFA in DCM was added 0.01 mL of triethylsilane. The mixture was stirred for 0.5 hr, LCMS indicated the completion of de-protection. A red residue was obtained after removing the volatiles on rotary evaporator, and was suspended (majority dissolved) in 10 mL 1:1 trimethyl orthoformate:MeOH. The resulting mixture was stirred for 2 hrs at room temperature. Yellow solids were precipitated. Desired product (0.38 g, ˜95% overall yield) was obtained after suction filtration and washing with cold MeOH twice. 1H-NMR (300 MHz, CDCl3+10% CD3OD) δ 9.5 (s, 1H), 9.2 (s, 1H), 9.1 (s, 1H), 7.9 (d, 1H), 7.7 (d, 1H) ppm; MS (ESI), m/z 324 ([M+H]+).
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[N:17]=[C:16]([NH2:21])[C:15]3[N:22]=[CH:23][N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:14]=3[C:13]=2[CH:12]=1>C(O)(=O)C>[CH3:27][CH:26]([CH3:28])[CH2:25][N:24]1[C:14]2[C:13]3[CH:12]=[C:11]([N:10]4[CH:3]=[CH:7][CH:6]=[CH:5]4)[CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:21])[C:15]=2[N:22]=[CH:23]1
Reactant: CC(C)Cn1cnc2c(N)nc3ccc(N)cc3c21
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CC(C)Cn1cnc2c(N)nc3ccc(-n4cccc4)cc3c21
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
2,5-Dimethoxytetrahydrofuran (1.6 mL of 95%, 12 mmol) was added to a suspension of 8-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.0 g, 12 mmol) in acetic acid (60 mL), and the reaction was heated at reflux for one hour. The resulting dark brown solution was concentrated under reduced pressure, and the residue was mixed with water. The resulting mixture was made basic with the addition of ammonium hydroxide and stirred for 30 minutes. The resulting precipitate was isolated by filtration, washed with water, dried, and recrystallized from ethanol (100 mL). The crystals were collected in three crops. The first crop was dried for a day in a vacuum oven at 100° C. to provide 2.1 g of 1-(2-methylpropyl)-8-(1-pyrrolyl)-1H-imidazo[4,5-c]quinolin-4-amine as a solid, mp 227.5–231.5° C.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:15])[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=1.[OH-:16].[Na+].Cl>O1CCOCC1>[OH:16][C:2]1[N:3]([CH3:15])[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1c(O)nc(-c2ccncn2)cc1=O
Temperature: 85 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (20 g, 90 mmol) in 1,4-dioxane (200 ml) was added 5N aqueous solution of sodium hydroxide (100 ml) at room temperature. The resulting mixture was heated to 85° C. and stirred for 18 hours. After cooling to room temperature, the reaction mixture was neutralized by the addition of 1N aqueous hydrochloric acid. The resulting solid was collected by filtration and washed by ethyl acetate. 2-Hydroxy-1-methyl-1H-[4,4′]bipyrimidinyl-6-one was then isolated as a white solid (14.5 g, 71 mmol, 79%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([Br:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH2:6][S:7]2.Cl.[CH3:15][O:16][NH2:17].C(O)C>N1C=CC=CC=1>[CH3:15][O:16][N:17]=[C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[C:11]([Br:12])[C:2]=2[CH3:1])[S:7][CH2:6][CH2:5]1
Reactant: Cc1c(Br)ccc2c1C(=O)CCS2
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CCSc2ccc(Br)c(C)c21
Yield: 93.2 %

Procedure:
3.0 Grams (12 mmol) of 5-methyl-6-bromothiochroman-4-one and 1.9 g (23 mmol) of O-methylhydroxylamine hydrochloride were refluxed in a solvent mixture of 10 ml of ethanol and 10 ml of pyridine under heat for 30 minutes. The solvents were distilled off under reduced pressure, 50 ml of 5% hydrochloric acid was added, and a formed solid was recovered by filtration, washed with water and then dried to give 3.2 g (yield 93%) of 4-methoxyimino-5-methyl-6-bromothiochroman.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:23][B:22](B2OC(C)(C)C(C)(C)O2)[O:21]1.C([O-])(=O)C.[K+]>O1CCOCC1.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][C:4]1[CH:3]=[C:2]([B:22]([OH:23])[OH:21])[CH:7]=[N:6][CH:5]=1)=[O:18]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: COc1cccc(C(=O)Nc2cncc(Br)c2)c1
Agent: [Fe+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)Nc2cncc(B(O)O)c2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
N-(5-Bromopyridin-3-yl)-3-methoxybenzamide (3.07 g, 7.71 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.88 g, 23.16 mmol), potassium acetate (3.79 g, 38.62 mmol), bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (950 mg, 1.16 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (640 mg, 1.16 mmol) were suspended in dioxane (60 ml) and stirred at 90° C. overnight. The mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude was purified by reverse phase using SP1® Purification System to give 1 g (44% yield) of the title compound. Purity 93%.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[N:11][NH:12][C:13]=2[NH:14]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([O:20][CH:21]=[CH2:22])[CH3:19].Cl>C(Cl)Cl.O1CCOCC1>[CH2:18]([O:20][CH:21]([N:12]1[C:13]([NH2:14])=[C:9]([C:8]#[C:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:10]=[N:11]1)[CH3:22])[CH3:19]
Reactant: CC(=O)Nc1[nH]ncc1C#Cc1ccccc1
Reactant: C=COCC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(C)n1ncc(C#Cc2ccccc2)c1N
Temperature: 75 °C
Yield: 80.3 %

Procedure:
A solution of N-(4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide (17.6 g, 78 mmol), ethoxyethene (11.2 mL, 117 mmol) and HCl in 1,4-dioxane (1 mL, 4 mmol) in CH2Cl2 (520 mL) was stirred at room temperature for 1 h and concentrated in vacuo. The residue was dissolved in ethanol (260 mL) and 25% aq. NaOH solution (260 mL) and the reaction mixture was heated to 75° C. for 4 h and cooled to room temperature. The ethanol was part concentrated in vacuo and the resulting solid collected by filtration, washed with water and minimum cold ethanol and dried in vacuo to provide the title compound as a solid (16 g).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[N:5]2[CH:4]=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+].[CH3:27][CH2:28]I>CN(C)C=O>[CH2:27]([N:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[N:6]2[C:2](=[O:1])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][N:5]2[C:10]1=[O:11])[CH3:28]
Reactant: CCI
Reactant: CCOC(=O)c1cn2c(=O)[nH]c3ccccc3n2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(=O)n(CC)c3ccccc3n2c1=O
Reaction time: 20 h

Procedure:
5.22 g of 5,6-dihydro-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester made as in Example 1. 2.76 K2CO3 and 50 mM CH3CH2I are dissolved in 100 ml dimethylformamide and stirred for 20 hours. The crystalline 6-ethyl-5,6-dihydro-1,5-dioxo-1H-pyrazolo[1,2-a][1,2,4]benzotriazine-2-carboxylic acid, ethyl ester is isolated after filtration and recrystallized from dimethylformamide/ethanol. The yield is 4.7 g of white crystals having a melting point of 235°-237° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.C(N(CC)CC)C.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ccc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)C#CNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a stirred solution of 4-chloro-2-iodo-phenylamine (5 g, 19.73 mmol) in THF (40 ml) was added triethyl amine (6.836 ml, 49.32 mmol), and ethynyl-trimethyl-silane (5.576 ml, 39.45 mmol) at 25° C. The mixture was purged with argon for 10 min, followed by the addition of PdCl2(PPh3)2 (0.692 g, 0.99 mmol) and CuI (113 mg, 0.59 mmol) at 25° C. The reaction mixture was stirred at room temperature for 2 h and was subsequently diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude residue which was purified by flash column chromatography (2-5% ethyl acetate in hexane) to afford 4-chloro-2-trimethylsilanylethynyl-phenylamine (3.6 g, 82%) as a brown solid. GC-MS: 223 (M).
Reaction SMILES: C[O:2][C:3](=[O:42])[CH:4]=[C:5]([C:7]1[N:8]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[C:9]2[C:14]([CH:15]=1)=[C:13]([C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[C:18]([CH:25]([CH3:27])[CH3:26])[C:17]=1[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]=[CH:11][CH:10]=2)[CH3:6].[OH-].[Na+]>CO.O1CCOCC1.Cl.O>[C:36]1([S:33]([N:8]2[C:9]3[C:14](=[C:13]([C:16]4[CH:21]=[C:20]([CH:22]([CH3:23])[CH3:24])[CH:19]=[C:18]([CH:25]([CH3:26])[CH3:27])[C:17]=4[O:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:7]2[C:5]([CH3:6])=[CH:4][C:3]([OH:42])=[O:2])(=[O:34])=[O:35])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCCCOc1c(-c2cccc3c2cc(C(C)=CC(=O)OC)n3S(=O)(=O)c2ccccc2)cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CCCCOc1c(-c2cccc3c2cc(C(C)=CC(=O)O)n3S(=O)(=O)c2ccccc2)cc(C(C)C)cc1C(C)C
Yield: 107.9 %

Procedure:
3-[1-Benzenesulfonyl-4-(2-butoxy-3,5-diisopropyl-phenyl)-1H-indol-2-yl]-but-2-enoic acid methyl ester (74 mg, 0.126 mmol) was dissolved in methanol (1 mL)/dioxane (1 mL) and treated with 1N NaOH (1 mL, 1 mmol) at 60° C. for 2 h. The reaction was diluted with 1N HCl (3 mL)/water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic portions were washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and evaporated in vacuo to provide 78 mg of a yellow oil. The material was purified using radial chromotagraphy with a gradient of hexane/ethyl acetate to provide 42 mg (58%) of a yellow amorphous foam. 1H NMR (250 MHz, CDCl3): δ 8.08 (d, 1H, 8.2),7.58 (m, 2H), 7.42-7.21 (m, 5H), 7.03 (d, 1H, J=2.2), 6.82 (d, 1H, J=2.2), 6.49 (s, 1H), 6.00 (bs, 1H), 3.28 (sep, 1H, J=6.9), 2.96 (t, 2H, J=6.0), 2.81 (sep, 1H, J=6.9), 1.18 (d 6H, J=6.9), 1.17 (d, 6H, J=6.9). MS [EI+] 574, (M+H)+, [EI−] 572 (M−H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[O:8][CH2:7][C@H:6]([CH:13]1[O:18][CH2:17][CH:16]([C:19]3[CH:28]=[C:27]4[C:22]([CH2:23][C@@H:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][O:26]4)=[CH:21][C:20]=3[F:34])[CH2:15][O:14]1)[CH2:5]2.C([Li])(CC)C.C1(C)C=CC(S([C:49]#[N:50])(=O)=O)=CC=1>C1COCC1.C1CCCCC1.CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[C:11]=1[C:49]#[N:50])[O:8][CH2:7][C@H:6]([CH:13]1[O:18][CH2:17][CH:16]([C:19]3[CH:28]=[C:27]4[C:22]([CH2:23][C@@H:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][O:26]4)=[CH:21][C:20]=3[F:34])[CH2:15][O:14]1)[CH2:5]2
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CCCCC[C@H]1COc2cc(C3COC([C@H]4COc5c(F)cc(F)cc5C4)OC3)c(F)cc2C1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCC[C@H]1COc2cc(C3COC([C@H]4COc5c(cc(F)c(C#N)c5F)C4)OC3)c(F)cc2C1
Temperature: -25 °C
Reaction time: 2 h

Procedure:
800 mg (1.68 mmol) of (R)-6,8-difluoro-3-[5-((R)-6-fluoro-3-pentylchroman-7-yl)-1,3-dioxan-2-yl]chroman are dissolved in 30 ml of THF, and 1.7 ml (2.38 mmol) of a 1.4 M solution of s-butyllithium in cyclohexane are added at −50° C. The batch is warmed at −25° C. for 5 min, left to stir at −70° C. for 2 h, and a solution of 400 mg (2.21 mmol) of p-toluenesulfonyl cyanide in 10 ml of THF is subsequently added at such a rate that the temperature does not exceed −65° C. After 1 h, the batch is allowed to thaw, diluted with ether and washed with dil. hydrochloric acid. The org. phase is dried over sodium sulfate and evaporated, and the crude product is chromatographed on silica gel with toluene, giving (R)-6,8-difluoro-3-[5-((R)-6-fluoro-3-pentylchroman-7-yl)-1,3-dioxan-2-yl]chroman-7-carbonitrile as colourless crystals of m.p. 111° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30]>[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:18][S:17][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:29](=[O:31])[CH3:30])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Product: CC(=O)Nc1ccc(O[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Yield: 51 %

Procedure:
30 mg of 10% palladium-on-charcoal are added to a solution of 150 mg (0.36.10-3 mol) of 4-nitrophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside in acetic anhydride, under a nitrogen atmosphere, and the reaction mixture obtained is then kept under hydrogen pressure (3.5.105Pa) at 50° C. for 15 hours. After filtration, the mixture is evaporated to dryness under reduced pressure and the residue obtained is purified by chromatography using a methylene chloride/methanol mixture (98/2 v/v) as the eluent to give 80 mg (yield: 51%) of the expected product.
Reaction SMILES: C1(C[O:8][C:9]2[C:10]([N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])[CH2:21][CH2:20]3)=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=2)C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[C:10]([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])[CH2:21][CH2:20]2)=[N:11][C:12]([C:15]([F:17])([F:16])[F:18])=[N:13][CH:14]=1
Reactant: O=C1CCCN1CC1CCN(c2nc(C(F)(F)F)ncc2OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: O=C1CCCN1CC1CCN(c2nc(C(F)(F)F)ncc2O)CC1
Yield: 55.3 %

Procedure:
A solution of XXVI (0.90 g, 2.1 mmol) in ethanol (75 mL) was hydrogenated with 10% Pd/C (0.20 g) at 60 psi for 2 hr. The mixture was filtered and concentrated in vacuo to give the product as a white powder (0.40 g, 54%, mp: 213°-215°).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C([O:23][C@@H:24]1[C@H:28]([O:29]C(=O)C2C=CC=CC=2)[C@@H:27]([CH2:38][O:39]C(=O)C2C=CC=CC=2)[O:26][C@H:25]1[N:48]1[CH:56]=[N:55][C:54]2[C:49]1=[N:50][C:51]([Cl:58])=[N:52][C:53]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:58][C:51]1[N:52]=[C:53]([NH:1][N:2]2[CH2:7][CH2:6][CH:5]([S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:4][CH2:3]2)[C:54]2[N:55]=[CH:56][N:48]([C:49]=2[N:50]=1)[C@@H:25]1[O:26][C@H:27]([CH2:38][OH:39])[C@@H:28]([OH:29])[C@H:24]1[OH:23]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NN1CCC(Sc2ccccc2)CC1
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCC(Sc5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 63.4 %

Procedure:
1-Amino-4-phenylthiopiperidine (1.10 g, 6.7 mmol) was reacted with 9-(2',3',5'tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.5 g, 4 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N-(4-phenylthio-1-piperidinyl)adenosine (1.25 g, 65%) as a foam, 1H NMR (DMSO-d6) δ3.51-3.60 (1H, m, H-5'a), 3.62-3.68 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.14 (1H, q, H-3'), 4.50 (1H, q, H-2'), 5.08 (1H, t, 5'-OH), 5.21, 5.50 (2H, 2d, 2'- and 3'-OH), 5.83 (1H, d, H-1'), 7.24-7.45 (5H, 2m, Ar-H), 8.41 (1H, s, H-8), 9.44 (1H, s, N-H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:18]([CH2:22][C:23]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:26]=3)=O)[C:19]([OH:21])=[O:20])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C1(=O)OC(=O)C=C1.FC1C=C2C(C=CN2CC2C=CC=CC=2)=CC=1.C(N1C2C(=CC=CC=2)C(C(CC(C2C3C(=CC=CC=3)N(CC)C=2C)=O)C(O)=O)=C1C)C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:18]3[CH:22]=[C:23]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=5)[N:27]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:26]=4)[O:20][C:19]3=[O:21])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(C(=O)O)c1cn(Cc2ccccc2)c2cc(F)ccc12)c1cn(Cc2ccccc2)c2cc(F)ccc12
Agent: CCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CC)c3ccccc23)c2ccccc21
Agent: Fc1ccc2ccn(Cc3ccccc3)c2c1
Agent: O=C1C=CC(=O)O1
Product: O=C1OC(c2cn(Cc3ccccc3)c3cc(F)ccc23)=CC1c1cn(Cc2ccccc2)c2cc(F)ccc12

Procedure:
Following a procedure similar to that described above in part A of this example except that 2,4-bis(6-fluoro-1-benzyl-3-indolyl)-4-oxobutanoic acid prepared by interaction of maleic anhydride and 6-fluoro-1-benzylindole by a procedure similar to that described in Example 3, part A is used in place of 2,4-bis(1-ethyl-2-methyl-3-indolyl)-4-oxobutanoic acid, there is obtained 3,5-bis(6-fluoro-1-benzyl-3-indolyl)-2(3H)-furanone (Formula II: R=C6H5CH2 ; R1 =H; Y=6-F).