Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][OH:5])(=[O:3])[CH3:2].[C:6]([N:10]=[C:11]=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(N(CC)CC)C.C(Cl)Cl>[CH3:7][C:6]([NH:10][C:11]([N:4]([O:5][C:11]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[C:1](=[O:3])[CH3:2])=[O:12])([CH3:9])[CH3:8]
Reactant: CC(=O)NO
Reactant: CC(C)(C)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(OC(=O)NC(C)(C)C)C(=O)NC(C)(C)C

Procedure:
Acetohydroxamic acid (7.5 grams), tert-butyl isocyanate (22 grams) and a few drops of triethylamine were stirred in 80 ml of methylene chloride for about 48 hours. After stirring, the solvent was removed under vacuum leaving a residue which was recrystallized from a solution containing methylene chloride and hexane. A subsequent recrystallization from methylene chloride left the desired, N-(((1,1-dimethylethyl)amino)carbonyl)-N-((((1,1-dimethylethyl)amino)carbonyl)oxy)acetamide, m.p. 111°-113° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[CH2:12]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:13]1[O:15][CH2:14]1>>[CH2:17]([O:16][CH2:12][C@H:13]([OH:15])[CH2:14][O:8][C@@H:6]1[CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[CH:9]([CH3:11])[CH3:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC[C@@H](O)COCc1ccccc1

Procedure:
That is, (2S)-3-l-menthoxypropane-1,2-diol can be obtained by adding (1R, 2S, 5R)-5-methyl-2-(1-methylethyl)cyclohexyl alcohol (hereinafter, is referred to as "l-menthol") to (R)-(-)-benzyl glycidyl ether [the compound of formula (II)]in the presence of a Lewis acid catalyst to provide (2S)-1-benzyloxy-2-hydroxy-3-{(1R, 2S, 5R)-[5-methyl-2-(1-methylethyl)cyclohexyl]oxy}propane [the compound of formula (III)], and hydrogenolyzing the compound in the presence of a palladium-carbon catalyst to eliminate the benzyl group.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:31][C@H:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1>C(Cl)Cl.CN(C=O)C>[CH:32]1([NH:31][C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][CH:5]=2)=[O:9])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: Cc1nocc1C(=O)O
Reactant: N[C@@H]1CCCc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nocc1C(=O)NC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
To a solution of 3-Methyl-isoxazole-4-carboxylic acid (0.52 g, 4.06 mmol) in DCM (15 mL) and DMF (2 mL), was added HOBt (1.1 g, 8.14 mmol) and EDCI (0.896 g 4.67 mmol). The clear yellow solution was cooled to 0 C and allowed to stir under Ar for 15 minutes. To the solution was added (R)-1-Amino-1,2,3,4-tetrahydronaphthalene (0.73 mL, 5.04 mmol and the reaction mixture was allowed to slowly warm to ambient temperature and was stirred for overnight. Dilution with DCM (50 mL) was followed by aqueous extraction (NaHCO3 water, brine (50 mL), drying over MgSO4, filtration and removal of solvent in vacuo. Silica gel chromatography (0-25% Hexane:EtOAc) afforded the title compound (650 mg; 62.5%) as a sticky solid. 1H NMR (CDCl3) δ 1.88 (m, 3H), 2.12 (m, 1H), 2.51 (s, 3H), 2.81 (m, 2H), 5.32 (m, 1H), 5.99 (bd, 1H), 7.13 (m, 1H), 7.20 (m, 2H) 7.20 (m, 2H); 13C NMR (CDCl3) δ 11.22, 20.15, 29.41, 30.35, 47.93, 116.73, 126.72, 127.88, 128.88, 129.65, 136.25, 138.00, 158.45, 160.28. ESIMS: 257 (M+H) EA calc'd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93; found C, 70.61; H, 6.11; N, 11.09.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:5][N:6]=1.[OH:15][CH:16]=[C:17]([O:24][CH3:25])[C:18](OCCC)=O.O>C(Cl)(Cl)Cl>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][CH:18]=[C:17]([O:24][CH3:25])[C:16](=[O:15])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCSc1nnc(N)s1
Reactant: CCCOC(=O)C(=CO)OC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCSc1nn2c(=O)c(OC)cnc2s1
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
A mixture of 4.7 g of 2-amino-5-heptylthio-1,3,4-thiadiazole, 3.3 g of propyl 3-hydroxy-2-methoxy-2-propenoate and 12 g of polyphosphoric acid was heated to 130°~135° C. and stirred for 30 minutes. After cooling, water and chloroform were added to the mixture and extraction was carried out. The organic layer was washed with a sodium hydrogen carbonate aqueous solution and water respectively, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was separated by silica gel column chromatography using an ethyl acetate/toluene mixture as an eluent. Thus 4.0 g of 2-heptylthio-6-methoxy-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 68°~71° C. Yield 64%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:5]=1[CH2:6][OH:7].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18].CC(=O)OCC>CN(C=O)C>[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:7][CH2:6][C:5]2[CH:8]=[C:9]([F:13])[CH:10]=[C:11]([F:12])[C:4]=2[F:3])[C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(F)cccc1F
Reactant: OCc1cc(F)cc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(F)cccc1OCc1cc(F)cc(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a cold (ice water) suspension of sodium hydride (407 mg; 10 mmol) in anhydrous DMF (4 is added a solution of 2,3,5-trifluorobenzyl alcohol (1.62 g; 10 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 1 hour, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1.56 gm; 11 mmol) in anhydrous DMF (5 mL), and allowed to room temperature over 3 hours. TLC (25% EA/Hex) was incomplete so the reaction was continued at room temperature for an additional 2 hours. The reaction mixture is poured into ice water with vigorous stirring and the resulting solid is filtered, washed with water, and dried under vacuum at 40° C. for 4.5 hours to give 2.05 grams of 2-fluoro-6-(2,3,5-trifluorobenzyloxy)-benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3[OH:22])[N:4]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31].Cl>O1CCCC1>[C:30]([O:22][CH:17]1[C:16]2[C:21](=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[CH:13]=[CH:14][CH:15]=2)[C:19](=[O:20])[O:18]1)(=[O:32])[CH3:31]
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3OC(C)=O)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.3 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-hydroxy-phthalide (see Example 84) are dissolved in 30 ml of tetrahydrofuran, and 0.6 ml of triethylamine is added to the solution which is then treated dropwise at 25° C. (internal temperature) with 0.5 ml of acetyl chloride. After subsequently stirring for 2 hours at room temperature, the reaction mixture is treated with ice-water and dilute hydrochloric acid and extracted with ethyl acetate, and the organic phase is washed with sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. Column chromatography on silica gel [eluant: ethyl acetate/n-hexane (2:3)] yields 3-acetoxy-7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-phthalide in the form of white crystals, m.p. 119°-120° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH2:18][SH:19])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>C1COCC1>[C:27]([S:19][CH2:18][CH2:17][NH:16][C:14](=[O:15])[CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: O=C(CCNC(=O)OCc1ccccc1)NCCS
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)SCCNC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
To the stirred solution of 3-(benzyloxycarbonylamino)-N-(2-mercaptoethyl)propionamide (2 g) and triethylamine (0.8 g) in anhydrous THF (15 ml), acetyl chloride (0.6 g) is added dropwise under ice-water cooling. After the addition, the mixture is stirred for 30 minutes under ice-water cooling and additional 30 minutes at room temperature. The solution is filtered and the filtrate is concentrated in vacuo. The residue is dissolved in ethyl acetate (30 ml) and the solution is washed with saturated sodium bicarbonate solution, N hydrochloric acid and then saturated sodium chloride solution. The ethyl acetate solution is dried over anhydrous magnesium sulfate and concentrated in vacuo to give 1.6 g (70%) of the titled compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[S:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.Cl.C(O)(=[O:31])C>O>[C:12]1([C:11]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH:2]=[O:31])[C:8]=3[S:9][CH:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)O
Reactant: BrCc1cccc2c(-c3ccccc3)csc12
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: O=Cc1cccc2c(-c3ccccc3)csc12
Reaction time: 3.5 h

Procedure:
7-Bromomethyl-3-phenylbenzo[b]thiophene (13.5 g; 44.6 mmole) was added to a solution of hexamine (14.0 g; 0.1 mole) in a mixture of acetic acid (50 ml) and water (25 ml) and the mixture refluxed with stirring for 3.5 hours. Concentrated hydrochloric acid (25 ml) was added and the mixture refluxed for a further 20 minutes. The solution was cooled, poured into water and extracted with diethyl ether. The combined ether extracts were dried over magnesium sulphate and evaporated. The crude product was purified by column chromatography on silica eluting with a mixture of methylene chloride and hexane. The relevant fractions were combined and evaporated to yield 3-phenylbenzo[b]thiophene-7-carboxaldehyde as an oil. (4.9 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]([CH2:22][NH2:23])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.N1C=CC=CC=1>[F:2][C:3]1[CH:4]=[C:5]([S:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][NH:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:17][CH2:16][CH2:15]3)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC[C@@H]1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.6 %

Procedure:
C-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-methylamine hydrochloride (0.5 gms, 1.41 mmole) was dissolved in 20 mL methylene chloride and 0.5 mL pyridine, and the mixture was cooled in an ice bath. Methanesulfonyl chloride (0.16 g, 1.41 mmol) was added dropwise, and the reaction mixture was stirred for five minutes at ice bath temperature, then allowed to warm to room temperature. The reaction mixture was quenched by addition of water, and was extracted with methylene chloride. The organic layer was washed with water, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 0.39 g of (R)-N-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-methanesulfonamide, M+H=398.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@H:26]([NH2:28])[CH3:27]>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@H:26]([NH:28][CH2:16][CH2:15][C:2]1([OH:1])[CH2:3][CH2:4][C:5]2([O:6][CH2:7][C:8]([CH3:11])([CH3:12])[CH2:9][O:10]2)[CH2:13][CH2:14]1)[CH3:27]
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Reactant: C[C@H](N)c1ccc(F)cc1F
Product: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(F)cc1F
Yield: 66 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and (S)-1-(2,4-difluoro-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 66% of theory; LC (method 5): tR=0.99 min; Mass spectrum (ESI+): m/z=384 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C(=O)N([I:26])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([I:26])[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3ccnc3s2)cc1OC
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nn3c(I)cnc3s2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
2-(3,4-Dimethoxy-phenyl)-imidazo[2,1-b][1,3,4]thiadiazole (from the previous step, 0.65 g, 2.50 mmol, 1 eq) was dissolved in DMF (9 mL), and NIS (0.41 g, 1.75 mmol, 0.7 eq) was added. The mixture was stirred at RT in an argon atmosphere. After 2 hours HPLC-MS analysis indicated incomplete conversion; 0.1 g of NIS was added, and the reaction mixture was stirred at RT overnight. Another 0.08 g of NIS was added, and after another 2 h of stirring at RT the reaction mixture was poured into 20 mL of aq. sodium thiosulfate (10%) and extracted with EtOAc. The combined organic layers were washed with water, dried (Na2SO4) and concentrated, and the residue (0.888 g) was purified by column chromatography (SiO2, cyclohexane/20-100% EtOAc) to afford the desired product (white solid, 0.336 g, 36% yield, 2 steps). HPLC-MS: (10-95% B in 4 min, 0.5 mL/min+2 min 100% B, 0.7 mL/min): tR=4.42 min, [M+H]+ m/z 387.9; 1H NMR (300 MHz, DMSO) δ/ppm 7.50 (dd, J=2.2, 8.4, 1H), 7.42 (d, J=2.1, 1H), 7.37 (s, 1H), 7.16 (d, J=8.5, 1H), 3.89 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:15]2[O:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][S:5][C:6]2[C:15]3[O:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:12]([CH3:22])[C:11](=[O:23])[C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:33]1
Reactant: Cc1c(-c2ccccc2)oc2c(SCCCCl)cccc2c1=O
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCSc2cccc3c(=O)c(C)c(-c4ccccc4)oc23)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
A mixture of 4.4 g of Intermediate XXXIV, 2.5 g of 1-(2-methoxyphenyl)-piperazine, 1 g of potassium iodide and 1.8 g of anhydrous potassium carbonate in 40 ml of dimethylformamide was stirred at 100° C. for 3 hours. After cooling to 20°-25° C., the reaction mixture was poured into 350 ml of water and extracted with dichloromethane. The organic extracts were washed with water and dried on anhydrous sodium sulfate, and the solvent was then evaporated off in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate: petroleum ether 3:2, and by crystallization from ethanol, yielding 3.9 g of the title compound, m.p. (70) 96°-99° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]1(Br)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:9]1([S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: BrC1CCCCC1
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(SC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
To a stirred solution of 3-bromobenzenethiol (5.00 g) in DMF (100 ml) was added cyclohexyl bromide (4.31 g) and potassium carbonate (7.31 g). The mixture was stirred at room temperature under nitrogen for 18 h. The reaction mixture was partitioned between 2N HCl and EtOAC. The organic phase was washed with brine and dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave the title compound (3.89 g). Tlc (silica) (4:1 cyclohexane-diethyl ether) Rf=0.90.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]=C)=[CH:19][CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])C.C[N+]1([O-])CC[O:30]CC1>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:11]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:25])=[CH:18][CH:19]=1)=[O:30]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc(CN(CCCCCCC(=O)OCC)S(C)(=O)=O)cc1
Agent: O=[Os](=O)(=O)=O
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)N(CCCCCCC(=O)O)Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of ethyl-7-[(4-vinyl-benzyl)-methanesulfonyl-amino]-heptanoate (2.2 g, 6.0 mmol) in dioxane (45 mL) was added to a solution of N-methylmorpholine N-oxide (1.47 g, 12.5 mmol) in water (45 mL). Osmium tetroxide (4.6 mL, 2.5 wt % in 2-methyl-2-propanol) was added and the mixture was stirred at room temperature for 1 h. The reaction was quenched with 1N HCl (50 mL) and the aqueous solution was extracted with CH2Cl2. The organic layer was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 35% aqueous THF (100 mL) and NalO4 (1.41 g, 6.59 mmol) was added. The mixture was stirred at room temperature for 2 h and was diluted with EtOAc and water. The organic solution was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound (1.9 g) which was used without further purification. 1H NMR (400 MHz, CDC13) δ 10.0 (s, 1H), 7.82-7.90 (d, 1H), 7.50-7.59 (d, 2H), 5.30 (s, 2H), 4.45 (s, 2H), 4.05-4.18 (m, 2H), 3.12-3.22 (m, 2H), 2.86 (s, 3H), 2.19-2.30 (m, 2H), 1.42-1.62 (m, 6H), 1.18-1.80 (m, 3H); MS 387 (M+18).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH:10]([CH:13]([OH:20])[CH:14]([OH:19])[CH:15]([OH:18])[CH2:16][OH:17])[CH2:11][NH-:12].[O:21]([C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][CH:32]=1)[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>>[OH:9][CH:10]([CH:13]([OH:20])[CH:14]([OH:19])[CH:15]([OH:18])[CH2:16][OH:17])[CH2:11][NH-:12].[OH:9][CH:10]([C:11]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[CH2:13][CH2:14][CH:15]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH2:1][NH:8][C:35]([C:34]3[CH:33]=[CH:32][C:31]([O:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:29][CH:30]=4)=[CH:39][CH:38]=3)=[O:37])=[CH:3][CH:4]=2)[C:16]1=[O:17]
Reactant: O=C(O)c1ccc(Oc2ccc(C(=O)O)cc2)cc1
Reactant: NCc1ccccc1
Agent: [NH-]CC(O)C(O)C(O)C(O)CO
Product: O=C(O)c1ccc(Oc2ccc(C(=O)NCc3ccc(N4C(=O)C(CCC(O)c5ccccc5)C4c4ccccc4)cc3)cc2)cc1

Procedure:
The benzylamine from ha was reacted with the 2,3,4,5,6-pentahydroxyhexylamide of 4,4′-oxybisbenzoic acid from If as described in Example I. This produced the 2,3,4,5,6-pentahydroxyhexylamide of 4-(4-{4-[3-(3-hydroxy-3-phenylpropyl)-2-oxo-4-phenylazetidin-1-yl]benzylcarbamoyl}phenoxy)benzoic acid (9) of molecular weight 789.89 (C45H47N3O10); MS (ESI): 790.26 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](O)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([S:23]([CH3:22])(=[O:25])=[O:24])[CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C1CCN(C(=O)OC(C)(C)C)C1)S(C)(=O)=O
Reaction time: 24 h

Procedure:
To a solution of 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g) in dichloromethane (10 ml) was added triethylamine (0.38 ml) followed by methanesulfonic acid (0.21 ml). After stirring for 24 hours, the reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 3-(methanesulfonyl-methyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.52 g). Treatment of this compound with HCl in dichloromethane/methanol yielded N-Methyl-N-pyrrolidin-3-yl-methanesulfonamide hydrochloride salt (0.41 g).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:35]=4[N:34]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:35]=4[N:34]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
A solution of 1.4 g (2.4 mMol) of tert.butyl 4'-[(2-ethyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and 15 ml of trifluoroacetic acid in 30 ml of methylene chloride is stirred for 14 hours at ambient temperature, then concentrated by evaporation, the residue is mixed with about 30 ml of water and made alkaline with 2N sodium hydroxide solution. After extracting twice with 30 ml of diethyl ether, the aqueous phase is acidified with 20% citric acid. The crude product precipitated is suction filtered and purified by column chromatography (100 g silica gel; eluant:methylene chloride/ethanol=96:4).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COc1cc(O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1C
Temperature: 115 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of 4-methyl-3-(methyloxy)phenol (Reference Intermediate R2, 400 mg) in dry N,N-dimethylformamide (15 mL), potassium carbonate (1200 mg, 8.69 mmol) and then 2-chloro-5-nitropyridine (551 mg, 3.47 mmol) were added and the reaction mixture was stirred for 2 hours at 115° C. The reaction was quenched with water (10 mL), diluted with brine (20 mL) and extracted with ethyl acetate (3 times 30 mL). The organic layer was washed with ice cold brine (2 times 30 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography (Biotage system, 100 g SNAP column) with a gradient cyclohexane/ethyl acetate from 10/0 to 8/2. Evaporation afforded the to title compound as a light yellow oil (570 mg).