Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]([CH3:19])=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.C(Cl)(Cl)=O.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1COCC1.CS(C)=O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]2[NH:8][CH:9]=[C:10]([CH3:19])[C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(=Cc1ccc(F)cc1)CNC(=O)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using the general procedure of N. Engel and W. Steglich, Angew. Chem. Int. Ed. Engl., 17, 676 (1978), to a slurry at room temperature of 28.7 g (0.1 mole) of 4-fluoro-N-[3-(4-fluorophenyl)-2-methyl-2-propenyl]benzamide in 100 ml toluene containing 1 ml DMF, stirred under nitrogen, with a dry ice condenser attached, was added dropwise a solution of 39.6 g (28.3 ml, 0.4 mole) of phosgene in 100 ml toluene. The mixture was warmed slightly with a heat gun, then stirred at room temperature overnight. The solution was concentrated by rotary evaporation to give a yellow oil. This was dissolved in 100 ml dry THF (small amount of insoluble solid removed by decanting the solution) and the solution was added dropwise to a cool (15°) solution of 33.5 g (0.3 mole) of potassium t-butoxide in 150 ml DMSO. The dark purple solution was stirred at ~20° C. for 1 hour, then was poured into 1 liter ice water. This was extracted with ether and the ether layers backwashed with water. The ether layer was dried and concentrated and the residue was chromatographed on 900 g of silica gel, eluting with hexane containing 10-40% toluene, to give, after recrystallization from methyl cyclohexane, 10.8 g (40%) of white product, m.p. 126°-7° C.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH:4]=[C:5]([CH3:8])[CH:6]=[CH2:7].[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I-].[PH4+]>C1C=CC=CC=1>[I-:1].[CH3:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH2:3][CH2:2][P+:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CC(C)=CCCI
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [PH4+]
Solvent: c1ccccc1
Product: C=CC(C)=CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 89.0 g. (0.40 mole) of iodo-4-methyl-3,5-hexadiene, 150 g. (0.40 mole) of triphenylphosphine and 350 ml. of benzene was stirred and refluxed for 8 hours. The solvent was removed in vacuo. After addition of about 1 l. of ether the oily mixture was left for one day at 0°. The crystallized salt was suction filtered, finely grinded and washed with ether, then dried for 4 hours at 80°/0.01 Torr. Obtained: 140 g. of phosphonium iodide, m.p. 124°-128°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:11]1[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:15][CH:16]=1.[Cl-]>O1CCCC1.CN1CCCC1=O.C(OCC)C>[CH2:9]([C:13]1[CH:12]=[C:11]([CH:10]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:16]=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CN1CCC(OC(c2cccc(OS(=O)(=O)C(F)(F)F)c2)c2nc3ccccc3s2)CC1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCCCc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3s2)c1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
80A To a mixture of trifluoromethanesulfonic acid 3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl ester (110 mg) and ferric acetylacetonate (4 mg) in a mixture of tetrahydrofurane (4.5 mL) and N-methylpyrrolidone (0.25 mL) cooled at 0° C. is added a 2M solution of butylamgnesium chloride in tetrahydrofurane (150 μL). The mixture is stirred at room temperature for 25 min, then warmed at 30° C. for 15 min. A second addition of butylamgnesium chloride in tetrahydrofurane (150 μL) is performed. The mixture is then diluted with diethyl ether and quenched with 0.5N hydrochloric solution. The aqueous phase is extracted with diethyl ether, then ethyl acetate. Organic phases are pooled, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradiant heptane/ethyl acetate from 99/1 to 90/10). The product is then refluxed in methanol and concentrated to give 2-[(3-butylphenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([CH3:27])([CH3:26])[CH2:6][C:7]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:14]2[C:9](=[N:10][C:11]([O:24][CH3:25])=[CH:12][CH:13]=2)[CH:8]=1)[CH3:2].[CH3:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32](Cl)=[O:33].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]([CH3:27])([CH3:26])[CH2:6][C:7]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:14]2[C:9](=[N:10][C:11]([O:24][CH3:25])=[CH:12][CH:13]=2)[C:8]=1[C:32](=[O:33])[CH2:31][C:30]([CH3:36])([CH3:35])[CH3:29])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1cc2nc(OC)ccc2n1Cc1ccc(Cl)cc1
Reactant: CC(C)(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)CC(C)(C)C)c2nc(OC)ccc2n1Cc1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
3-[5-Methoxy-1-(4-chloro-benzyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]-2,2-dimethyl-propionic acid ethyl ester (Example 5, Step 4; 0.133 g, 0.33 mmol) was dissolved in dichloroethane (5 mL). 3,3-Dimethyl-butyryl chloride (0.12 mL, 0.86 mmol) and aluminum chloride (0.137 g, 1.03 mmol) were added, and the reaction was heated to 80° C. under N2 for 1.5 hours. The reaction mixture was cooled to room temperature and quenched with saturated potassium sodium tartrate tetrahydrate solution. The mixture was extracted with EtOAc three times, the combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude material was purified on silica gel (0-50% EtOAc in hexanes) to give the desired product.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:19][NH:20][C:21]([NH2:23])=[O:22]>>[CH:1]([NH:4][CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)/[C:10](=[N:19]\[NH:20][C:21]([NH2:23])=[O:22])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: NNC(N)=O
Reactant: CC(C)NCCN1C(=O)C(=O)c2ccccc21
Agent: Cl
Product: CC(C)NCCN1C(=O)/C(=N/NC(N)=O)c2ccccc21
Yield: 49.8 %

Procedure:
By using 1-(2-isopropylaminoethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 10 was carried out, and the reaction product was recrystallized from ethanol to obtain (E)-1-(2-isopropylaminoethyl)isatin 3-semicarbazone having a melting point of 169°-172° C. (decomposition) (yield: 49.8%).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>O>[S:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][C:14](=[O:16])[CH3:15])=[CH:5][CH:6]=1)(=[O:11])(=[O:12])[NH2:13]
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 55.8 %

Procedure:
A solution of sodium hydroxide (116 mg, 2.9 mmoles) in water (10 ml) was added to a stirred solution of 4-hydroxy-benzenesulphonamide (500 mg, 2.9 mmoles) in water (30 ml). This mixture was treated with acetic anhydride (295 mg, 2.9 mmoles) and stirred at room temperature for 4.5 hours. The reaction mixture was filtered off and the resulting solid washed with water to afford acetic acid 4-sulphamoyl-phenyl ester (33)(348 mg) as a yellow solid. LC/MS System A; Rt 2.06 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][S:31]([C:34]2[S:35][C:36](Br)=[CH:37][CH:38]=2)(=[O:33])=[O:32])=[CH:24][CH:23]=1>>[N:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:30][S:31]([C:34]2[S:35][C:36]([C:21]#[C:20][C:19]3[CH:18]=[N:17][N:11]4[C:12]([CH:14]5[CH2:16][CH2:15]5)=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[N:9][C:10]=34)=[CH:37][CH:38]=2)(=[O:33])=[O:32])=[CH:26][CH:27]=1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: O=S(=O)(NCCc1ccncc1)c1ccc(Br)s1
Product: O=S(=O)(NCCc1ccncc1)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (147 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-pyridin-4-yl-ethyl)-amide (example B.60) (174mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (112 mg, 40%). MS (ISP) 560.2 [(M+H)+]; mp 172–174° C.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[C:4]1/[C:5]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=2[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/1=2.[N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[NH:25][CH:24]=1.N1C2C(=CC=CC=2)C=C1>>[N:25]1([CH2:2]/[CH:3]=[C:4]2/[C:5]3[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=3[O:7][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/2=3)[C:24]2[C:30](=[CH:29][CH:28]=[CH:27][N:23]=2)[CH:31]=[CH:26]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COC(=O)c1ccc2c(c1)/C(=C/CCl)c1ccccc1CO2
Agent: c1ccc2[nH]ccc2c1
Product: COC(=O)c1ccc2c(c1)/C(=C/Cn1ccc3cccnc31)c1ccccc1CO2

Procedure:
In Examples 40 through 49, the products were prepared in a manner similar to Example 23, using Compound h and the corresponding benzimidazole or indole derivatives.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:41]([C:35]1([CH3:34])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:42])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: CN[C@H](Cc1ccccc1)CN1CCC(c2cc(F)ccc2OC)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)C2(C)CCCCC2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Under a N2 atmosphere, a solution of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-ethyl}-methyl-amine (0.12 g. 0.33 mmole) and triethylamine (0.10 mL, 0.74 mmole) in dichloromethane (10 mL) was cooled to 0° C. To the solution, 1-methyl-1-cyclohexanecarboxylic acid chloride (93 mg, 0.58 mmole) in a minimal amount of dichloromethane was added. The resulting mixture was stirred at 0° C. overnight. The solvent was evaporated and the residue dissolved in EtOAc (50 mL) and water (50 mL). The layers were separated, the organics washed with water (2×50 mL) and brine and dried over Na2SO4, filtered and concentrated. Flash chromatography (elution with 1:3 EtOAc-hexane) gave 0.14 g (88% yield) of 1-methyl-cyclohexanecarboxylic acid {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-ethyl}-methylamide. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid. m.p. 160-165° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:22](=[O:23])[N:21]([CH3:24])[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH:10]=2)=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)[CH:6]=[CH:7][CH:8]=1)#N.CC(O)=[O:27].[PH2]([O-])=O.[Na+]>[Ni].N1C=CC=CC=1>[CH3:24][N:21]1[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH:1]=[O:27])[C:22]1=[O:23])=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3
Reactant: Cc1ccc2[nH]c3c(cc(-c4cccc(C#N)c4)c(=O)n3C)c2c1
Reactant: CC(=O)O
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc2[nH]c3c(cc(-c4cccc(C=O)c4)c(=O)n3C)c2c1
Temperature: 60 °C

Procedure:
450 mg of 3-(3-cyanophenyl)-1,6-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one, 10 ml of AcOH, 20 ml of pyridine, 2.6 g of sodium hypophosphite and 434 mg of Raney Ni are mixed and then the mixture is heated at 60° C. for 4 hours. The reaction medium is filtered and the filtrate is evaporated; the residue is taken up in 50 ml of AcOEt/CH2Cl2 (1/1; v/v) and the organic phase is washed with water, dried and evaporated to produce the expected compound, M.p.=280° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:16])[N:7]=1)=[O:5])[CH3:2].[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:38][CH3:39])=[C:24]([C:26]([CH3:37])([CH3:36])[CH2:27][C:28]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH:29]=O)[CH:25]=1>O1CCCC1.[Ti]>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]=[CH:29][C:28]([OH:35])([C:31]([F:32])([F:34])[F:33])[CH2:27][C:26]([C:24]2[CH:25]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=2[O:38][CH3:39])([CH3:36])[CH3:37])[N:7]=1)=[O:5])[CH3:18]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: CCN(CC)C(=O)c1ccc2c(N)cccc2n1
Agent: [Ti]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution that consists of 210 mg (0.86 mmol) of 5-aminoquinoline-2-carboxylic acid diethylamide, 266 mg (0.86 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 0.36 ml (1.73 mmol) of titanium tetraethylate in 15 ml of tetrahydrofuran is stirred for one hour at room temperature and then for 3 hours at 80° C. After removal of the solvent and purification on silica gel with hexane-ethyl acetate (0-70%), 230 mg (52% of theory) of the product is obtained.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:33]=[C:32]([C:34]([O:36][CH3:37])=[O:35])[CH:31]=[CH:30][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1)=[O:21].[OH-].[Na+]>C(Cl)Cl.O.N1C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20](=[O:21])[C:19]2[CH:30]=[CH:31][C:32]([C:34]([O:36][CH3:37])=[O:35])=[CH:33][C:18]=2[NH:17][C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]2)=[O:12])=[N:24][CH:25]=1
Reactant: CC(C)N1CCC(C(=O)O)CC1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)C2CCN(C(C)C)CC2)c1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
A solution of 1-isopropylpiperidine-4-carboxylic acid (2.0 g, 9.6 mmol) in methylene chloride (70 mL) was treated dropwise with thionyl chloride (0.70 mL, 9.6 mmol). After heating to reflux for 1 h, 2-amino-N-(5-chloropyridin-2-yl)-4-methoxycarbonylbenzamide (1.5 g, 4.8 mmol) was added. After 0.5 h, pyridine (0.80 mL) was added and the resulting mixture heated at reflux. After 12 h, the mixture was cooled, treated with water, 1 N NaOH (20 mL), and concentrated. The residue was purified by column chromatography (SiO2: 5% methanol:methylene chloride) affording 1.14 g (52%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH3:31][O:32][C:33](=[O:39])[CH2:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C(Cl)Cl>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:35]([CH2:34][C:33]([O:32][CH3:31])=[O:39])(=[O:37])=[O:36])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Reactant: COC(=O)CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 25 °C
Reaction time: 72 h
Yield: 7.1 %

Procedure:
To product of example 205 (21.5 mg, 0.05 mmol) in methylene chloride (1 mL) was added chlorosulfonyl-acetic acid methyl ester (35 mg, 0.2 mmol) and triethylamine (30 μl, 0.22 mmol) and the resulting mixture was stirred at room temperature for 3 days. Upon completion of the reaction, the solvent was removed under reduced pressure. The residue was chromatographedon silica gel eluting with 199:1 dichloromethane:methanol. The product was dissolved in dichloromethane and added two drops of acetic acid, then stirred at rt for 10 min, washed with water. The organic layer was dried with magnesium sulfate and evaporated in vacuo to give the title compound (2 mg, 7%). 1H NMR (300 MHz, DMSO-d6): δ 0.99 (d, J=6.62 Hz, 6 H) 1.57 (m, 2 H) 1.70 (m, 1 H) 3.65 (s, 3 H) 4.40 (s, 2 H) 4.49 (m, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.59 (dd, J=8.82, 2.57 Hz, 1 H) 7.66 (d, J=2.57 Hz, 1 H) 7.76 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=8.09, 1.84 Hz, 1 H) 8.90 (dd, J=4.41, 1.84 Hz, 1 H) 10.73 (s, 1 H) 14.15 (s, 1 H). MS (ESI−) m/z 562 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:7]([O:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:6]([O:19][CH3:20])[CH:5]=1)([OH:3])=[O:2].O.[C:22]1(C)[CH:27]=CC(S(O)(=O)=O)=C[CH:23]=1.C(O)C=C>>[C:1]([C:4]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:7]([O:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:6]([O:19][CH3:20])[CH:5]=1)([OH:3])=[O:2].[CH3:27][CH:22]=[CH2:23]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCC(=O)O
Solvent: C=CCO
Solvent: O
Product: C=CC

Procedure:
A mixture of 3-(4-carboxy-2-methoxy-5-nitrophenoxy)propanoic acid (153) (20 g, 74.3 mmol) and p-toluene sulphonic acid monohydrate (2.3 g, 7.4 mmol) in allyl alcohol (240 mL, 3.5 mol) was refluxed for 7 hours then allowed to cool. The allyl alcohol was then removed in vacuo, and the residue triturated with dilute HCl acid and collected by filtration. This solid was taken up in EtOAc, and the resulting solution washed with water and brine and dried over sodium sulphate. Evaporation in vacuo afforded 154 as a white solid (19.27 g, 84%): mp 128-130° C.; 1H-NMR (CDCl3): δ 2.92 (t, 2H, J=6.35 Hz); 3.94 (s, 3H); 4.38 (t, 2H, J=6.41 Hz); 4.65 (d, 2H, J=5.61 Hz); 5.27 (dd, 1H, J1=1.28 Hz, J2=19.42 Hz); 5.33 (dd, 1H, J1=1.28 Hz, J=17.04 Hz); 5.92 (m, 1H); 7.15 (s, 1H); 7.45 (s, 1H); 13C NMR (67.8 MHz, CDCl3): δ 34.1, 56.5, 65.0, 65.4, 108.5, 111.3, 118.3, 122.9, 131.8, 141.1, 149.1, 152.6, 167.1, 170.0; IR (Nujol); ν 1730, 1630, 1550, 1430, 1390, 1290, 1230, 1190, 1170, 1070, 1030, 1010 cm−1; MS (EI) m/z (relative intensity): 325 (M+., 19), 251 (3), 213 (2), 196 (3), 211 (3), 113 (19), 91 (4), 71 (9), 55 (6); HRMS: calcd. for C14H15NO6 325.0798, found 232.0773.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[NH:37])[NH2:36])=[CH:31][CH:30]=1.[OH-].[Na+].C(O)C.C(O)(=O)C>O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35](=[NH:36])[NH2:37])=[CH:33][CH:34]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cn1c(CCc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3ccccc3)ccc21

Procedure:
0.52 g (0.93 mmol) of 1-methyl-2-[2-(4-amidinophenyl)-ethyl]-5-[N-(ethoxycarbonylmethyl)-benzenesulphonylamino]-benzimidazole and 0.4 g (0.01 mol) of sodium hydroxide are stirred in 5 ml water and 10 ml ethanol for three hours at ambient temperature. Then the mixture is diluted with water and adjusted to pH 4 with glacial acetic acid. The crystalline precipitate is suction filtered and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>C(#N)C.O1CCCC1>[CH2:11]([S:8]([NH:7][CH2:6][C:5]1[CH:13]=[CH:14][C:2]([NH:1][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCS(=O)(=O)NCc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CC#N
Product: CCS(=O)(=O)NCc1ccc(NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
N-(4-Aminobenzyl)ethanesulfonamide (504 mg, 2.35 mmol) was dissolved in acetonitrile (3 mL) and tetrahydrofuran (4 mL). The reaction mixture was added pyridine (0.23 mL, 2.78 mmol) and phenyl chloroformate (0.31 mL, 2.43 mmol) and stirred at room temperature for 3 h under nitrogen atmosphere. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic part was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography to give phenyl 4-(ethylsulfonamidomethyl)phenylcarbamate (697 mg, 87%).
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]([CH2:20][CH3:21])([OH:19])[CH:6]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([O:9]CC)=[O:8])C.O.[OH-].[Na+].Cl>O1CCOCC1>[CH2:12]([CH:6]([C:7]([OH:9])=[O:8])[C:5]([CH2:20][CH3:21])([OH:19])[C:4]([OH:22])=[O:3])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(O)(CC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(O)(C(=O)O)C(Cc1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 15 h

Procedure:
The 3-Benzyl-2-ethyl-2-hydroxysuccinic acid diethyl ester thus obtained was dissolved in 1,4-dioxane (5 mL), added with water (5 mL) and 5 M sodium hydroxide aqueous solution (15 mL), and stirred at 100° C. for 15 h. The reaction mixture was cooled to room temperature, adjusted to pH 1 with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer having been washed with 1 M hydrochloric acid and brine was dried over anhydrous magnesium sulfate and then filtered. The organic layer was concentrated under reduced pressure to give 1.0 g (quantitative) of 3-benzyl-2-ethyl-2-hydroxysuccinic acid as a solid.