Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[OH-].[K+].[N+](=C)=[N-].CCOCC.[OH:25][C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][C:29]([C@H:35]2[S:39][C@H:38]([C:40]3[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH3:49])=[C:42]([O:50][CH3:51])[CH:41]=3)[CH2:37][S:36]2)=[CH:28][C:27]=1[O:52][CH3:53]>C(OCC)C.C(Cl)(Cl)Cl.CO>[CH3:53][O:52][C:27]1[CH:28]=[C:29]([C@H:35]2[S:39][C@H:38]([C:40]3[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([O:46][CH3:47])[CH:45]=3)[CH2:37][S:36]2)[CH:30]=[C:31]([N+:32]([O-:34])=[O:33])[C:26]=1[O:25][CH3:1]
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc([N+](=O)[O-])c1O
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc([C@@H]2CS[C@@H](c3cc(OC)c(OC)c([N+](=O)[O-])c3)S2)cc(OC)c1OC
Reaction time: 5 h

Procedure:
Using the Aldrich diazald kit, diazald (13.0 g, 60.7 mmole) predissolved in 100 ml diethyl ether was added dropwise to an aqueous potassium hydroxide solution (ethanol, 27 ml; H2O, 21 ml; and potassium hydroxide, 13.3 g) at 65° C. The diazomethane/ether distillate was added at 0° C. to a solution of trans-2-(4-hydroxy-3-methoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane (1) (FIG. 20) predissolved in 25 ml chloroform and 50 ml methanol. The reaction was stirred to completely homogenize the solution and was then allowed to stand at room temperature under an argon atmosphere for 5 hours. The solvent was removed in vacuo and the remaining oil was dissolved in 10 ml diethyl ether. The product crystallized out of the ether solution to yield 3.285 g (98%) of light yellow crystals.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:15]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][O:33][CH3:34])[CH:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.O.[C:45](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:35][CH:36]2[CH2:41][CH2:40][N:39]([CH3:45])[CH2:38][CH2:37]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:15]([C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][O:33][CH3:34])[CH:30]=2)[CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(CCOC)c2)c1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2cnn(CCOC)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 125 %

Procedure:
To a mixture of 3-butyl-4-{4-cyclohexyloxy-3-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-phenyl}-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.0776 mmol, 49.9 mg) in DCM (1 mL) was added formaldehyde solution in water (37%, 0.23 mmol, 0.017 mL), and 1 drop of acetic acid. Sodium triacetoxyborohydride (0.31 mmol, 69.2 mg, 95%) was added. The reaction mixture was stirred at room temperature for 1 h and partitioned between ethyl acetate (10 mL) and saturated aq. sodium bicarbonate solution (10 mL). The ethyl acetate layer was separated and dried over sodium sulfate. The crude product was purified by column chromatography on basic alumina using 0-3% MeOH in DCM, dissolved in MeOH and treated with 4 N HCl in dioxane. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether. The yellow solid was dried overnight under high vacuum to provide the title compound (30.1 mg). LCMS: m/z 549 [M+1] 1H NMR (400 MHz, CD3OD) δ 8.24-8.27 (1H, m), 8.04-8.07 (1H, m), 7.90-7.98 (1H, m), 7.78-7.83 (1H, m), 7.37-7.43 (1H, m), 7.27-7.31 (1H, m), 5.37-5.46 (1H, m), 4.59-4.62 (1H, m), 4.38 (2H, t), 3.77 (2H, t), 3.16-3.66 (9H, m), 2.95 (3H, s), 1.25-2.59 (18H, m), 0.82 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH:10]1[C:15]([C:16]([CH2:18]Br)=O)=[CH:14][CH:13]=[C:12]([Cl:20])[CH:11]=1.C(=O)(O)[O-].[Na+]>>[Cl:20][C:12]1[CH:13]=[CH:14][C:15]([C:16]2[N:9]=[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][N:7]3[CH:18]=2)=[CH:10][CH:11]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: COc1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc2nc(-c3ccc(Cl)cc3)cn2c1

Procedure:
A mixture of 1.3 g (10.5 mmol) of 5-methoxy-2-pyridinamine, 2.44 g (1eq) of α-bromo-4-chloroacetophenone and 1.76 g (2eq) of sodium bicarbonate in 20 ml of 95% strength alcohol is heated under reflux for 4 h 30 min. under argon. The mixture is evaporated to dryness and the residue taken up between CH2Cl2 and H2O, followed by washing, drying and evaporation. The product is purified by chromatography and then crystallized in ether. M.p. 148°-9° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].[Br:9][CH2:10][CH2:11][CH3:12].[CH3:13][CH:14](O)[CH3:15]>COCCOC>[Br-:9].[CH2:10]([N+:3]1[CH:4]=[CH:5][N:6]([CH2:13][CH2:14][CH3:15])[C:2]=1[CH3:1])[CH2:11][CH3:12]
Reactant: CCCBr
Reactant: CC(C)O
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCn1cc[n+](CCC)c1C
Product: [Br-]
Temperature: 60 °C
Reaction time: 48 h

Procedure:
2-Methylimidazole was allowed to react with one equivalent of sodium hydride at room temperature in 1,2-dimethoxyethane as a solvent, and then three equivalents of 1-bromopropane was slowly added thereto, followed by stirring at 60° C. for two days. About one day after the start of stirring, an adequate amount of 2-propanol was added thereto as a co-solvent. After the completion of stirring, the solvent and unreacted 1-bromopropane were distilled off. The residual solid was recrystallized twice from acetone to give 1,3-di-n-propyl-2-methylimidazolium bromide as transparent and colorless crystals (ionic liquid No. 3 in Table 1). Then, 1,3-di-n-propyl-2-methylimidazolium bromide was dissolved in water, and one equivalent of silver sulfate was added thereto, followed by stirring for about 1 hour at room temperature. The resultant precipitate of silver bromide was removed by filtration, and then water was distilled off. The residual solid was recrystallized from acetonitrile to give 1,3-di-n-propyl-2-methylimidazolium sulfate as white fine crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([C:21]4([C:24]5[CH:25]=[C:26]6[C:31](=[CH:32][CH:33]=5)[N:30]=[CH:29][CH:28]=[CH:27]6)[CH2:23][CH2:22]4)=[N:19][N:20]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].Cl>O1CCCC1.CO.O>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:18]([C:21]4([C:24]5[CH:25]=[C:26]6[C:31](=[CH:32][CH:33]=5)[N:30]=[CH:29][CH:28]=[CH:27]6)[CH2:22][CH2:23]4)=[N:19][N:20]=3)[N:17]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1F
Yield: 82.8 %

Procedure:
Methyl 2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl) [1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoate (0.15 g, 0.34 mmol) was dissolved in a solution of tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL) under N2 atmosphere. To the solution was added lithium hydroxide aqueous solution (2.0 M, 0.30 mL) with stirring. The mixture was stirred at RT for 1 h, and acidified with 1.0 M of hydrogen chloride in water (0.68 mL). The organic solvents were removed. The formed precipitate was collected by filtration, and dried in-vacuo to afford the desired product (120 mg). Analytical LCMS: (M+H)+=427.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[OH:19]O.CSC>C(O)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][S:10]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:19]
Reactant: O=C(CSc1ccc(O)cc1)c1ccccc1O
Reactant: OO
Solvent: CC(=O)O
Solvent: CSC
Product: O=C(CS(=O)c1ccc(O)cc1)c1ccccc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
6.0 g (23.1 mmol) of 2′-hydroxy-2-(4-hydroxyphenylthio) acetophenone and 50 mL of acetic acid were added under a room temperature into a 100 mL flask with four inlets and attached with a stirrer and a thermometer. To the resultant solution, 2.8 g (24.7 mmol) of 30% aqueous solution of hydrogen peroxide was added, and the solution was stirred for 12 hours at a room temperature. Following to the completion of the reaction, 0.5 g of dimethyl sulfide was added into the solution, and then, the solution was extracted with MIBK. The MIBK layer was washed several times with water, and followed by washing with sodium hydrogencarbonate. The MIBK in the solution was distilled out under reduced pressure, and the resultant residue was subjected to recrystallization with ethyl acetate to obtain 4.5 g of 2′-hydroxy-2-(4-hydroxyphenylsulfinyl) acetophenone. The yield was 71% and the melting point of the compound was in a range of 166 to 167° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][NH:4][N:3]=1.[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH:19]=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>CO>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:19][NH:1][C:2]2[C:6]([C:7]([OH:9])=[O:8])=[CH:5][NH:4][N:3]=2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: Nc1n[nH]cc1C(=O)O
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2n[nH]cc2C(=O)O)cc1OC1CCCC1
Yield: 48.5 %

Procedure:
A suspension of 3-amino-4-pyrazole carboxylic acid (3.56 g, 28 mmol) in 400 ml of methanol and 3-cyclopentyloxy-4-methoxybenzaldehyde (5.06 g, 23 mmol) was stirred at room temperature for 16 hours with sodium cyanoborohydride, 1.85 g (95% pure, 28 mmol). The methanol was evaporated under reduced pressure and the residue was taken up in 100 ml of 15% sodium hydroxide and-extracted twice with 100 ml portions of ether. The aqueous layer was acidified to pH 5 with 5N hydrochloric acid and extracted twice with 100 ml portions of ethyl acetate. The ethyl acetate was dried over sodium sulfate and evaporated. The residue was triturated with ether to give 3.7 g of 3-(3-cyclopentyloxy-4-methoxybenzylamino)-4-pyrazolecarboxylic acid (48.7%). Pure 3-(3-cyclopentyloxy-4-methoxybenzylamino)pyrazole carboxylic acid shows mp. 134-136° C. after crystallization from methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH3:24]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCI
Reactant: OC1(c2ccc(F)c(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(O)(c2ccc(F)c(F)c2)C1

Procedure:
Preparation according to Example 24: Enantiomer E2 of 3-(3,4-difluorophenyl)-pyrrolidin-3-ol (0.27 g, 1.35 mmol), acetonitrile (3 mL), potassium carbonate (0.279 g, 2.02 mmol) and iodopropane (137 μl, 1.35 mmol). Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 45:55 to 60:40). Yield: 0.125 g. [α]D=−21.1° (methanol). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 128-129° C.; MS m/z (relative intensity, 70 eV) 241 (M+, 9), 212, (bp), 182 (32), 141 (17), 84 (62).
Reaction SMILES: C[O:2][CH2:3][CH2:4][C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:7])[CH3:6].Br.C(O)(=O)C.[OH-].[K+]>C(Cl)(Cl)Cl.O>[C:9]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]([OH:7])([CH3:6])[CH2:4][CH2:3][OH:2]
Reactant: COCCC(C)(O)c1ccccc1-c1ccccc1
Agent: Br
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(O)(CCO)c1ccccc1-c1ccccc1
Reaction time: 2 h

Procedure:
2.56 g. of 1-methoxy-3-p-biphenylyl-3-butanol (obtainable from 3-methoxy-1-p-biphenylyl-1-propanone and CH3MgI) is boiled for 2 hours with a mixture of 5 ml. of 48% aqueous HBr and 5 ml. of acetic acid, 10 ml. of 10% methanolic KOH are added and boiling is continued for a further 2 hours and the mixture is worked up using water and chloroform to give 3-p-biphenylyl-1,3-butanediol, m.p. 115°-117°.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:18][C:19]1[C:23](C#N)=[C:22]([C:26]#[N:27])[NH:21][N:20]=1.C(O)(=[O:30])C>>[C:19]([C:23]1[C:22]([C:26]([NH2:27])=[O:30])=[N:21][N:20]2[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=[N:2][C:17]=12)#[N:18]
Reactant: N#Cc1[nH]nc(N)c1C#N
Reactant: CC(=O)O
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Product: N#Cc1c(C(N)=O)nn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 4.86 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone, 50 ml. of glacial acetic acid and 2.66 g. of 3-aminopyrazole-4,5-dicarbonitrile is refluxed for 16 hours and then evaporated. The residue is treated as described in Example 1, giving the desired product, m.p. 236°-238° C.
Reaction SMILES: [CH:1]1([C:4](=[O:26])[C:5](=[CH:22]OCC)[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18]([CH3:21])(=[O:20])=[O:19])=[O:7])[CH2:3][CH2:2]1.Cl.[CH2:28]([O:30][NH2:31])[CH3:29].C([O-])(=O)C.[Na+].O>C(O)C>[CH:1]1([C:4](=[O:26])[CH:5]([CH:22]=[N:31][O:30][CH2:28][CH3:29])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:10][C:9]=2[S:18]([CH3:21])(=[O:19])=[O:20])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC=C(C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O)C(=O)C1CC1
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCON=CC(C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-cyclopropyl-2-ethoxymethylene-1-(2-methylsulphonyl-4-trifluoromethylphenyl)propan-1,3-dione (3.5 g), O-ethylhydroxylamine hydrochloride (0.97 g) and sodium acetate (0.83 g) in ethanol (15 ml) was stirred at 25° C. for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate solution was dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated and the residue purified by column chromatography on silica, using a mixture of ethyl acetate and hexane as eluent. The resulting solution was evaporated and 3-cyclopropyl-2-(ethoxyiminomethyl)-1-(2-methylsulphonyl-4-trifluoromethylphenyl)propan-1,3-dione (compound 1) was obtained as white crystals (2 g), m.p. 46° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:46])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:35]=2)[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:31][C:30]1[CH:29]=[CH:28][C:27]([NH:32][C:33](=[O:46])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)[CH:35]=2)=[CH:26][C:25]=1[NH:24][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(=O)O)c2)CC1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCCCC3)c2)cc1N
Product: Cc1ccc(NC(=O)c2cccc(N3CCCCC3)c2)cc1NC(=O)c1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 57 %

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 25, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-piperidinobenzamide to give N-[2-methyl-5-(3-piperidinobenzamido)phenyl]-3-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzamide in 57% yield; NMR Spectrum: (DMSOd6) 1.39 (s, 9H), 1.54 (m, 4H), 1.62 (m, 4H), 1.91 (m, 2H), 2.19 (s, 3H), 3.2 (m, 4H), 3.65 (m, 2H), 4.64 (m, 4H), 7.09 (m, 1H), 7.19 (m, 2H), 7.27 (m, 2H), 7.41 (t, 2H), 7.58 (m, 2H), 7.79 (m, 1H), 9.83 (s, 1H), 10.09 (s, 1H); Mass Spectrum: M−C3H7+ 557.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH2:13][CH3:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.C(OCC)C>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH:12]=[CH:11][N:10]=[C:9]3[CH2:13][CH3:14])=[CH:6][CH:7]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: CCc1nccn1-c1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCc1nccn1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Reaction time: 7 h
Yield: 75.6 %

Procedure:
1.9 g of 1-(4-aminophenyl)-2-ethylimidazole was added to a solution of 2.6 g of p-chlorobenzoyl chloride in 50 ml of toluene, and the mixture was refluxed with stirring for 7 hours. The reaction mixture was naturally cooled and diethyl ether was then added thereto. The precipitated crystal was recovered by filtration, washed sufficiently with ethyl ether and recrystallized from ethanol and then from water to obtain 2.5 g of the intended compound in the form of a hydrochloride. The melting point was 265° to 267° C.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N1C=CC=CC=1.[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]([CH3:39])[CH2:34][S:35](Cl)(=[O:37])=[O:36])([O-:26])=[O:25]>C(Cl)Cl.O>[N+:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]([CH3:39])[CH2:34][S:35]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])(=[O:37])=[O:36])([O-:26])=[O:25]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(CS(=O)(=O)Cl)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)CC(C)c3ccccc3[N+](=O)[O-])O2)c(=O)[nH]c1=O
Temperature: -15 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
242 mg thymidine (1 mmol, co-evaporated 3× each with 5 ml abs. pyridine) are dissolved in 2.5 ml abs. pyridine and cooled to -60° C. 396 mg 2-(2-nitrophenyl)propylsulfonyl chloride (1.5 mmol) in 2.5 ml abs. CH2Cl2 are added drop-wise to this within 10 Min. After stirring 4 h at a temperature between -60 and -30° C., the temperature is allowed to increase to -15° C. After a total of 61/4 h, the reaction is mixed with 15 ml H2O and CH2Cl2 respectively and the aqueous phase is extracted 4× each with 15 ml CH2Cl2. The combined organic phases are dried over Na2SO4, filtered and rotary evaporated. This is co-evaporated 3× with toluene and 1× with methanol. The crude product (600 mg) is purified over flash chromatography (39 g silica gel, 3×11 cm, Sol.: CH2Cl2 /MeOH, cond.: CH2Cl2, gradient: 100 ml CH2Cl2, each 150 ml 100:1, 100:2, 100:3 and 100:4). 290 mg (0.62 mmol, 62%) 5'-O-[2-(2-nitrophenyl)propyl-sulfonyl]-thymidine are obtained as a colorless foam. The obtained mixed fractions are purified by a further column (4.5 g silica gel, 1×11 cm, Sol.: CH2Cl2 /MeOH, cond.: CH2Cl2, gradient: 100 ml CH2Cl2, each 50 ml 100:0.5, 100:1 and 100:2). 128 mg (0.18 mmol, 18%) 3',5'-Di-O-[2-(2-nitrophenyl)-propylsulfonyl]-thymidine are isolated as a colorless foam and 26 mg (0.06 mmol, 6%) 3 '-O-[2 -(2-nitrophenyl)-propylsulfonyl]-thymidine as a light red foam.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:18][C:17]2[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH2:22][CH2:23][C@H:24]([OH:26])[CH3:25])[C:14](=[O:27])[N:13]([CH3:28])[C:12]=2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:36]([O:26][C@H:24]([CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20][N:15]1[C:16](=[O:19])[C:17]2[NH:18][C:10]([CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:11][C:12]=2[N:13]([CH3:28])[C:14]1=[O:27])(=[O:38])[CH3:37]
Reactant: C[C@@H](O)CCCCn1c(=O)c2[nH]c(COCc3ccccc3)nc2n(C)c1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2[nH]c(COCc3ccccc3)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a stirred solution of (R)-8-benzyloxymethyl-1-(5-hydroxyhexyl)-3-methylxanthine (19.9 g, 51.5 mmol), triethylamine (10.4 g, 103 mmol) and 4-dimethylaminopyridine (1.33 g, 11 mmol) in chloroform (130 ml) was added acetic anhydride (6.57 g, 64.4 mmol). After stirring for 3 hours at room temperature, the reaction mixture was quenched by addition of methanol (5 ml). The mixture was washed with aqueous potassium hydrogen sulfate solution (0.1 N) to pH 6-7, with water (2×50 ml) and with saturated aqueous sodium chloride solution (50 ml). After drying over magnesium sulfate, the organic solution was evaporated under reduced pressure to provide (R)-1-(5-acetoxyhexyl)-8-benzoxymethyl-3-methylxanthine (19.6 g, 88% yield) as white colored solid.
Reaction SMILES: C([S:4][CH:5]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=1)[CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[SH:4][CH:5]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:19]=1)[CH2:6][C:7]#[C:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCCCCc1ccc(OCC(CC#CCCCC(=O)OC)SC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCc1ccc(OCC(S)CC#CCCCC(=O)O)cc1

Procedure:
A mixture of 0.73 g of methyl 8-(acetylthio)-9-(4-pentylphenoxy)-5-nonynoate, the product of Example 12a, 1.25 g of potassium carbonate, 0.6 ml of H2O and 32 ml of MeOH was stirred at RT for 12 hr. MeOH was removed and the residue was acidified with 3N HCL and extracted with Et2O to obtain the crude product. The crude product was purified by silical gel chromatography (CH2Cl2 -MeOH) and then recrystallized in petroleum ether-Et2O to obtain the title compound, mp 70.0-70.5.
Reaction SMILES: NC(N)=O.[CH2:5]([NH:7][S:8]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([NH2:18])[C:12]=1[OH:19])(=[O:10])=[O:9])[CH3:6].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]=[C:28]=[O:29]>>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:28]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])=[O:29])=[C:12]([OH:19])[C:11]=1[S:8]([NH:7][CH2:5][CH3:6])(=[O:9])=[O:10]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=O
Product: CCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Cl)c1O
Yield: 33.1 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-ethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (266 mg, 1.06 mmol) and 2-chlorophenylisocyanate (163 mg, 1.06 mmol) were coupled to form the desired urea (142 mg, 33%). LC-MS (m/z) 04.0 (M+).