Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.Cl[CH2:13][CH2:14]Cl>>[O:11]=[C:5]([CH:13]=[CH2:14])[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C1CCC(=O)O1
Reactant: ClCCCl
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)CCC(=O)O

Procedure:
[cf. J. Chem. Soc., 3922 (1958)]. A mixture of aluminum chloride (66.7 g., 0.5 M), succinic anhydride (25 g., 0.25 M) and 1,2-dichloroethane (1 liter) in a 2 liter 3 neck flask equipped with a gas inlet tube, a mechanical stirrer and a drying tube is stirred rapidly and ethylene is bubbled in for 4.5 hours. This is poured into 900 ml. 5% hydrochlorc acid and ice. The layers are separated and the organic layer is washed with water and taken to dryness in vacuo. The aqueous layer is extracted with ether (300 ml.). This extract is washed with water and combined with the material from the original organic layer. After removal of solvent, 150 ml. of 10% potassium carbonate solution is added and the mixture is heated on a steam cone for 15 minute. After cooling, the product 4-oxo-5-hexenoic acid is extracted into ether, dried and freed of solvent in vacuo leaving 10.9 g. (34%) of brownish liquid which solidifies on standing. This is distilled to give 7.1 g. (22%) of colorless liquid which solidifies on standing, b.p. ~120°-130°/0.5 mm.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][OH:23])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:21][CH2:22][OH:23]
Reactant: OCC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: OCC[C@H]1CNCCN1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
Dissolve (S)-2-(1,4-dibenzylpiperazin-2-yl)ethanol (11.7 g, 0.038 mol) in 380 mL of ethanol, add 10% palladium on carbon (3.7 g of wet reagent, 50% by weight) as a suspension in a few mL of ethanol. Add excess ammonium formate (16.8 g, 0.27 mol) all at once. Heat at reflux for 5 h, cool to room temperature and filter through a celite pad, washing well with ethanol. Concentrate filtrate in vacuo to provide the title compound (5 g, quantitative) as a cloudy residue. Use directly on the next step without further purification: mass spectrum (APCI): m/z=131.1 (M+1).
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][C:8]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])([CH2:12][OH:13])[CH:9]([F:11])[F:10])(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[Cl:29][CH:30](C)[C:31](Cl)=O>Cl.O1CCOCC1.ClCCl>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([F:21])=[C:14]([C:8]([NH:7][C:6](=[O:22])[CH:30]([Cl:29])[CH3:31])([CH2:12][OH:13])[CH:9]([F:10])[F:11])[CH:19]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)(c1cc(Br)ccc1F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(Cl)C(=O)NC(CO)(c1cc(Br)ccc1F)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[1-(5-Bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester [Example 42 step c)] (2.21 g, 5.75 mmol) was dissolved in 20 mL HCl solution 4 mol/L in dioxane and stirred at room temperature for 60 minutes. The reaction mixture was evaporated to give a white solid which was directly taken up in 15 mL dichloromethane. 20 mL aqueous Na2CO3 solution (10% w/w) was added and the emulsion was cooled to 0-5° C. Racemic 2-chloro-propionyl chloride (787 mg, 6.20 mmol) was added dropwise and the reaction mixture was slowly warmed to room temperature. After 30 minutes, the layers were separated and washed with dichloromethane. The organic layers were combined, dried over Na2SO4 and evaporated. The crude product was purified on a silica gel column by eluting with heptanes/EtOAc 3/1->2/1 to give 632 mg of the first eluting and 619 mg of the second eluting diastereomer.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([S:14][CH2:15][C@@H:16]([OH:21])[C:17]([O:19]C)=[O:18])[CH:8]=[CH:7]2.Cl>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([S:14][CH2:15][C@@H:16]([OH:21])[C:17]([OH:19])=[O:18])[CH:8]=[CH:7]2
Reactant: COC(=O)[C@H](O)CSc1ccc2cc(Cl)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@H](O)CSc1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
An aqueous 8N sodium hydroxide solution (6.8 mL) was added to a suspension of methyl (2S)-3-[(6-chloronaphthalen-2-yl)thio]-2-hydroxypropionate (5.4 g) obtained in Reference Example 1a) in ethanol (150 mL) and the mixture was stirred at room temperature for 3 hours. Ethanol was distilled off under reduced pressure and then the resulting precipitate was obtained by filtration. The solid was suspended in water (100 mL), pH of the suspension was adjusted to about 3 with 1N hydrochloric acid and then the precipitate was collected by filtration to obtain the title compound (5.0 g, 97%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:38].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N+:12]([O-:19])=[C:11]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH2:38])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCCCCCCCCCc1cc(OCc2ccccc2)c2ccccc2[n+]1[O-]
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NCCCCCCCCCCCc1cc(OCc2ccccc2)c2ccccc2[n+]1[O-]
Reaction time: 1.5 h
Yield: 21.5 %

Procedure:
In this example, 5 m moles of 4-benzyloxy-2-(10-formyldecyl) quinoline-N-oxide is dissolved in methanol, and 50 m moles of ammonium acetate and 15 m moles of sodium cyanoborohydride are added thereto with ice cooling. Then, the mixture is stirred for 1.5 hours. After the reaction, the solvent is removed therefrom by distillation, and then the mixture is extracted with chloroform. The chloroform layer is dried over anhydrous sodium sulfate, and the solvent is removed therefrom by distillation. The residue is purified by silica gel column procedure, whereby the captioned compound is obtained as colorless crystals (yield: 21.5%).
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16](=[O:29])[C:17]([CH:25]2[CH2:28][CH2:27][CH2:26]2)([OH:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[CH:25]1([C:17]([OH:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]([O:15][CH:12]2[CH2:13][CH2:14][N:9]([CH2:7][CH2:19][CH:18]=[C:17]([CH3:25])[CH3:16])[CH2:10][CH2:11]2)=[O:29])[CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)C(O)(c2ccccc2)C2CCC2)CC1
Agent: Cl
Solvent: CO
Product: CC(C)=CCCN1CCC(OC(=O)C(O)(c2ccccc2)C2CCC2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 175.3 %

Procedure:
A 10% methanolic solution of hydrochloric acid was added to a solution of 2.68 g of (1-t-butoxycarbonylpiperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetate in 50 ml of methanol, and this mixture was stirred at room temperature for 10 hours. The solvent was distilled off under reduced pressure to obtain 2.24 g of the title compound.
Reaction SMILES: [C:1]([Si:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][CH2:7][CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@@H:10]1[CH2:16][OH:17])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[O:39](S(C(F)(F)F)(=O)=O)[S:40]([C:43]([F:46])([F:45])[F:44])(=O)=[O:41].[Cl-].[NH4+]>ClCCl>[C:1]([Si:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][CH2:7][CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@@H:10]1[CH2:16][O:17][S:40]([C:43]([F:46])([F:45])[F:44])(=[O:41])=[O:39])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)O[C@@H](CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](CO)O1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)O[C@@H](CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](COS(=O)(=O)C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{(4R,5S)-5-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-yl}-methanol (159 mg, 0.38 mmol) was dissolved in dichloromethane (1.15 mL). Diisopropylethylamine (200 μL, 1.15 mmol) and Tf2O (77.4 μL, 0.46 mmol) were added at 0° C., and the mixture was stirred at room temperature for one hour in a nitrogen atmosphere. Saturated aqueous ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give trifluoro-methanesulfonic acid (4R,5S)-5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester as a crude product.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1)([O-])=O>CO>[NH2:1][C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Solvent: CO
Product: COC(=O)c1cc(N)[nH]n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 5-nitro-1H-pyrazole-3-carboxylate (compound 260.1, 2.5 g, 14.6 mmol) in methanol (10 mL). The system was purged with nitrogen, then palladium/carbon (10 wt % Pd, 0.8 g) was added. The system was charged with hydrogen (1 atm) and the mixture was stirred overnight at room temperature. The system was purged with nitrogen, then the solids were removed by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound as an off-white solid (1.5 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:18][NH2:19])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](OC(=O)CCl)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:24]([CH2:23][Cl:22])=[N:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: CN1Cc2c(C(=O)NN)ncn2-c2cccc(Cl)c2C1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Yield: 53.3 %

Procedure:
15.3 g (50 mmol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylic acid hydrazide were stirred at room temperature overnight in 160 ml of N,N-dimethylformamide with 9.41 g (55 mmol) of chloroacetic anhydride. After evaporating the solvent the residue was stirred at room temperature over the weekend with 100 ml of a 10% solution of phosphorus pentoxide in methanesulphonic acid. The reaction mixture was treated with ice, made alkaline with conc. sodium hydroxide solution and extracted four times with methylene chloride. By drying the organic phase over magnesium sulfate, evaporation of the solvent and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 9.7 g (53%) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 201°-203°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1>CCO.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Solvent: C1COCCO1
Solvent: CCO
Product: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
In analogy to example 20.1, Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl ester in EtOH/dioxane was converted to yield Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester as a dark brown oil, MS: 396 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[F:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]>CC(=O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[F:26]
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(O)c2C)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)-3-methyl-phenyl]methyl amino]-2-methyl-phenol (269 mg, 0.8 mmol, 1 eq), in 2-butanone (10 mL) was added Cs2CO3 (368 mg, 0.9 mmol, 1.5 eq) and isopropyl 2-bromoacetate (163.5 mg, 0.9 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 2 h, then filtered to remove the solids. The filtrate was evaporated in vacuo and the crude residue obtained purified by column chromatography (petroleum ether:EtOAc, 100:1 to 15:1) to give the title compound as a yellow oil (300 mg, 87%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][C@@H:19]3[CH2:23][CH2:22][N:21]([C@H:24]4[CH2:29][CH2:28][C@@H:27]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH2:26][CH2:25]4)[C:20]3=[O:41])=[C:13](Cl)[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].C1COCC1.[OH-].[Li+].[ClH:50]>O.CO>[Cl:50][C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][C@@H:19]3[CH2:23][CH2:22][N:21]([C@H:24]4[CH2:29][CH2:28][C@@H:27]([O:30][Si:31]([CH:38]([CH3:40])[CH3:39])([CH:32]([CH3:33])[CH3:34])[CH:35]([CH3:36])[CH3:37])[CH2:26][CH2:25]4)[C:20]3=[O:41])=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN([C@H]4CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)CC4)C3=O)c(Cl)c2)cc1
Reactant: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)[Si](O[C@H]1CC[C@@H](N2CC[C@@H](Cc3ccc(-c4ccc(C(=O)O)c(Cl)c4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 1 °C

Procedure:
Stir a mixture of 3′,5′-dichloro-4′-[(R)-2-oxo-cis-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid methyl ester (35.6 g, 56.26 mmol), 150 mL THF and 100 mL methanol under nitrogen in an ice/water bath. Add a solution of lithium hydroxide (4.04 g, 168.79 mmol) in 100 mL water. Stir the mixture 4 hr at RT. Cool the solution to about 1° C. in an ice/acetone bath, dilute with 500 mL water, then adjust the pH to about 2-3 with 0.5 M aqueous hydrochloric acid. Extract with ethyl acetate (3×150 mL), wash with 100 mL each, water and brine then dry over magnesium sulfate. Filter, and concentrate to 34.6 g (99%) of a foam.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[NH:12][C:11]3[C:6](=[CH:7][C:8]([N+:16]([O-])=O)=[CH:9][CH:10]=3)[C:5](=[O:19])[C:4]=2[CH:3]=1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(O)C.O>[NH2:16][C:8]1[CH:9]=[CH:10][C:11]2[NH:12][C:13]3[C:4](=[CH:3][C:2]([NH2:1])=[CH:15][CH:14]=3)[C:5](=[O:19])[C:6]=2[CH:7]=1
Reactant: Nc1ccc2[nH]c3ccc([N+](=O)[O-])cc3c(=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc2[nH]c3ccc(N)cc3c(=O)c2c1
Reaction time: 16 h
Yield: 94.1 %

Procedure:
See Bogert et al., 1930. To a stirred suspension of 2-amino-7-nitro-9(10H)-acridone 11 (22.5 g, 88.2 mmol) in ethanol was added, in one lot, a solution of sodium sulphide nonahydrate (94.5 g, 0.394 mol) and sodium hydroxide (37.5 g, 0.938 mol) in water (1.625 L). The mixture was refluxed with stirring for 16 hr. On cooling, saturated sodium bicarbonate solution (250 mL) was added and the total volume of the mixture reduced to 700 mL on a rotary evaporator. The flask was chilled in ice for 3 hr after which the product was collected on a glass sinter. The product was washed with water (4×200 mL) followed by ice-cold ethanol (2×100 mL), dry ether (2×100 mL) and finally hexane (2×100 mL). The product, 12, was dried over P2O5 under vacuum to yield an olive-green solid (18.70 g, 94%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][O:32]2)=[CH:27][C:26]=1[F:38]>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][O:32]2)=[CH:27][C:26]=1[F:38])=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: Fc1cc(OCC2CCCO2)ccc1Br
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCC2CCCO2)cc1F)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and rac-2-(4-bromo-3-fluoro-phenoxymethyl)-tetrahydro-furan (Intermediate 26) in analogy to Example 1a): colorless gum.
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=O)=[O:3].CC(OC1C=CC=CC=1C(O)=O)=O.[O:27]=[CH:28][C@@H:29]([C@H:31]([C@@H:33]([C@@H:35]([CH2:37][OH:38])[OH:36])[OH:34])[OH:32])[OH:30]>O>[C:2]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:11]([C@@:31]([C@@H:33]([C@@H:35]([CH2:37][OH:38])[OH:36])[OH:34])([OH:32])[C@@H:29]([OH:30])[CH:28]=[O:27])=[O:13])(=[O:3])[CH3:1]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(=O)Oc1ccccc1C(=O)O
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)[C@](O)([C@H](O)[C@H](O)CO)[C@@H](O)C=O

Procedure:
Elemental analysis: C15H18O9, Calculated: C, 52.63; H, 5.30 Found: C, 52.51; H, 5.42. Mass: M+1, m/z 343.0999 (M+H calculated formula: C15H19O9. Solubility of glucose-3-aspirin in water: 2.32 g/100 mL, Aspirin solubility: 0.33 g/100 mL (1 g in 300 mL water at 25° C.) (Merck Index, pp. 134, vol. 11, 1989). Thus, the aspirin-glucose conjugate was 700 times more soluble than aspirin.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)(=[O:14])=[O:13]>C(Cl)Cl.C1COCC1.O=[Mn]=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)(=[O:14])=[O:13])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C(C)O)ccc2Cl)cc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)Nc2cc(C(C)=O)ccc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of N-[2-chloro-5-(1-hydroxy-ethyl)-phenyl]-3,4-dimethoxy-benzenesulfonamide (1.85 g, 5 mmol) in DCM/THF (1:1, 10 mL) was treated with MnO2 (10.8 g, 25 eq). The mixture was stirred at RT for 7 h, filtered over Celite and concentrated. The residue was purified by chromatography on SiO2 (hex/EA 1:1). The product was recovered as a colourless foam (1.58 g, 86%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15].C(N(CC)CC)C>CO>[F:12][C:13]([F:20])([F:19])[C:14]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:15]
Reactant: COC(=O)CCCCCN
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 86.6 %

Procedure:
To a 2 liter round bottom flask, charged with 100.2 g (0.552 mol) of amine hydrochloride 2 and 1 liter of methanol was added 100 g (0.703 mol) of ethyl trifluoroacetate followed by 120 mL (0.861 mol) of triethylamine. The mixture was stirred at 20-30° C. for 19 h and then concentrated via rotary evaporation. The residue was diluted with 500 mL of diethyl ether and then filtered. The filtrate was washed with 3×300 mL aliquots of 1N aqueous HCl, 200 mL of de-ionized water, 2×200 mL aliquots of saturated aqueous sodium bicarbonate and finally with 200 mL of de-ionized water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was distilled under vacuum to afford 115.3 g of the product (3) as a colorless oil: b.p.=113-116° C. at 120 mm Hg: 1H NMR (d6-DMSO) d 3.57 (3H, s), 2.75 (2H, m), 2.29 (2H, t), 1.60-1.40 (4H, m) and 1.37-1.19 (2H, m) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14](OC)=[O:15])=[CH:10][C:9]=2[C:18]2[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][CH:19]=2)[CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=2[C:18]2[C:22]([CH3:23])([CH3:24])[CH2:21][CH2:20][CH:19]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(-c2cc(Cl)ccc2F)c(C2=CCCC2(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCC=C1c1cc(CO)ccc1-c1cc(Cl)ccc1F
Reaction time: 1.5 h
Yield: 63.1 %

Procedure:
To a stirred solution of 78.9A (0.082 g, 0.23 mmol) in THF (5.00 mL) at 0° C. was added LAH (0.46 mL, 0.46 mmol, 1.0M). The reaction was then stirred for 1.5 hours. 1N NaOH(aq) was then added to the quench the reaction. The reaction was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was purified on silica gel (0-20% EtOAc in hexanes) to yield 78.9B as a colorless oil (0.048 g, 63% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[CH:19]([NH:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=1)([CH3:21])[CH3:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:23]([NH:22][CH:19]([CH3:21])[CH3:20])=[O:32])=[CH:29][CH:28]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CC(C)NC(=O)c1ccc(CN)cc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)NC(=O)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, p-aminomethyl-benzoic acid isopropylamide hydrochloride and DBU in DME. ES-MS m/e (%): 377 (M+H+, 100).