Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C[Li].[F:8][C:9]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12].Cl>O1CCCC1>[F:8][C:9]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:10]=1[C:11](=[O:12])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3]
Reactant: COc1ccc(C(=O)Cl)c(F)c1
Reactant: CS(C)(=O)=O
Agent: Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CS(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
To a solution of 4.15 g (44.07 mmol) of dimethylsulfone in 140 ml of anhydrous tetrahydrofuran are added dropwise at −10° C. under argon 24 ml of methyllithium solution (1.6M in diethyl ether, 38.2 mmol). The reaction mixture is stirred for 15 min at room temperature, the reaction mixture is then cooled to −60° C. A solution of 5.54 g (29.38 mmol) of 2-fluoro-4-methoxybenzoyl chloride dissolved in 60 ml of tetrahydrofuran is then added dropwise to the reaction mixture. This mixture is stirred for 4 h at between −60° C. and 0° C., then a 1M hydrochloric acid solution is added. The product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is triturated in minimum methanol and the solid is filtered to yield 3.33 g (46%) of 1-(2-fluoro-4-methoxyphenyl)-2-(methylsulfonyl)ethanone in the form of a white solid.
Reaction SMILES: [N:1]1([C:6]([CH:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][CH2:10][NH:9]2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[N:1]1([CH2:6][CH:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][CH2:10][NH:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CCCNC1C(=O)N1CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CCCNC1CN1CCCC1
Yield: 78.4 %

Procedure:
By reducing 2.6 g (0.013 moles) of 2-(pyrrolidin-1-yl) carbonyl-3,3-dimethyl piperidine with 0.52 g (0.013 moles) of LiAlH4 in 100 ml of dry THF, using an alkaline work-up, 2.0 g of the title compound were obtained. The compound was sufficiently pure for the following step.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([CH:10]2C(=O)OC(C)(C)O[C:11]2=[O:19])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][NH2:21]>C(O)C>[CH:1]1([CH2:6][CH2:7][C:8]2[CH2:10][C:11](=[O:19])[NH:21][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C(C(=O)CCC2CCCC2)C(=O)O1
Reactant: NN
Solvent: CCO
Product: O=C1CC(CCC2CCCC2)=NN1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
A solution of 5-(3-cyclopentylpropionyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (900 mg, 3.3 mmol) in ethanol (5 ml) containing hydrazine (0.43 ml, 8.84 mmol) was stirred at ambient temperature for 20 minutes followed by stirring for 2 hours at 75° C. The volatiles were removed under vacuum and the residue was triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to give 3-(2-cyclopentylethyl)-4,5-dihydro-1H-pyrazol-5-one (250 mg, 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[N:7]([N:11](C)[C:12](=O)OCC)[CH:8]=[CH:9][CH:10]=1)=[O:5].O.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[N:7]([NH:11][CH3:12])[CH:8]=[CH:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)N(C)n1cccc1C(=O)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNn1cccc1C(=O)c1ccccc1Cl
Yield: 93.9 %

Procedure:
[2-(2-Chlorobenzoyl)-1H-pyrrol-1-yl]-methyl-carbamic acid, ethyl ester (39.2 g, 0.127 mol) was dissolved in 100 ml of ethanol and 200 ml of H2O containing sodium hydroxide (25 g, 0.625 mol). The reaction was refluxed for 18 hours followed by evaporation of the ethanol. The aqueous solution was extracted with three 300 ml portions of ethyl acetate, dried (MgSO4), filtered, and evaporated to give 28 g of an oil. This oil was distilled via Kugelrohr apparatus 125° (0.15 mmHg) to give 26.3 g of a solid. This solid was triturated with hexane to give 25.5 g (85%) of crystals, m.p. 56°-58°.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH3:21])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])=O)(C)(C)C.[ClH:38]>CCO>[ClH:38].[C:32]1([S:29]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[C:12]([O:17][CH2:18][CH2:19][NH:20][CH3:21])[CH:13]=[CH:14][CH:15]=3)(=[O:31])=[O:30])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN(CCOc1cccc2c1cc(S(=O)(=O)c1ccccc1)n2C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CNCCOc1cccc2[nH]c(S(=O)(=O)c3ccccc3)cc12
Temperature: 100 °C

Procedure:
2-Benzenesulfonyl-4-[2-(tert-butoxycarbonyl-methyl-amino)-ethoxy]-indole-1-carboxylic acid tert-butyl ester (0.250 g., 0.5 mmol) from Step 3 was dissolved in 5 mL EtOH. To this solution was added 1 mL of 2M ethanolic hydrogen chloride solution. The reaction mixture was heated at 100° C. for 35 minutes. Upon cooling to ambient temperature, a fine white precipitate was observed. After filtration and drying in vacuo at 60° C., [2-(2-benzenesulfonyl-1H-indol-4-yloxy)-ethyl]-methyl-amine hydrochloride was obtained. MS: 330 (M+H)+, mp=250.7–252.1° C.
Reaction SMILES: [CH3:1][O:2]C1C=CC(N)=C([N+]([O-])=O)C=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:23]2[CH:24]=[CH:25][C:26](C(F)(F)F)=[CH:27][C:22]=2[N:21]=[C:20]1/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42]>C(OCC)(=O)C>[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[C:23]2[CH:24]=[CH:25][C:26]([O:2][CH3:1])=[CH:27][C:22]=2[N:21]=[C:20]1/[CH:32]=[CH:33]/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: FC(F)(F)c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-methoxy-2-nitroaniline according to the preparation of (E)-1-(2-pyridyl)-2-styryl-5-trifluoromethyl-1H-benzimidazole (Example 57). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound. MW: 417.42; mp: 187.0-188.0° C.; 1H-NMR (DMSO-d6) δ: 8.76 (1H, dd, J=5.0, 1.3 Hz), 8.17 (1H, td, J=7.8,2.0 Hz), 7.85 (1H, d, J=15.8 Hz), 7.72 (1H, d, J=8.1 Hz), 7.65-7.58 (3H, m), 7.42-7.30 (4H, m), 7.26 (1H, d, J=2.2 Hz), 7.17 (1H, d, J=16.1 Hz), 6.90 (1H, dd, J=8.8, 2.6 Hz), 3.83 (3H, s).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:3]=1.CCO.O.[NH2:23][NH2:24]>O>[F:8][C:7]1[C:2]([NH:23][NH2:24])=[N:3][C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][CH:6]=1
Reactant: NN
Reactant: COc1cccc(COc2ncc(F)c(Cl)n2)c1
Solvent: CCO
Solvent: O
Product: COc1cccc(COc2ncc(F)c(NN)n2)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A 125 mL Erlenmeyer flask was charged with 4-chloro-5-fluoro-2-(3-methoxybenzyl-oxy)pyrimidine (1.50 g, 5.58 mmol) and EtOH (50 mL). Hydrazine monohydrate (900 μL, 18.5 mmol) was added, and the resulting mixture was allowed to stir at room temperature. After 22 h, the reaction was transferred to a 500 mL Erlenmeyer flask and diluted with water (200 mL), whereupon a white solid began to precipitate from solution. After stirring for 7 h, solid product was collected in a fritted funnel and rinsed with excess water. After drying on the frit, the title compound was obtained (1.23 g, 83%) as a white solid: mp 103-106° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.92 (bs, 1H), 7.86 (d, J=3.6 Hz, 1H), 7.27 (t, J=8.1 Hz, 1H), 6.94-7.01 (m, 2H), 6.87 (dd, J=2.4, 7.9 Hz, 1H), 5.24 (s, 2H), 4.46 (bs, 2H), 3.74 (s, 3H); MS (ESI) m/z 265.2 (M+H)+, 263.2 (M−H)−.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)=[O:17].[N-:30]=[N+:31]=[N-:32].[Na+].Cl.[NH+]1C=CC=CC=1.O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:27]=[CH:28][CH:29]=1)[C:16]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]2[NH:32][N:31]=[N:30][N:24]=2)=[CH:25][CH:26]=1)=[O:17]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CC(=O)c2cccc(OCc3ccc4ccccc4n3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(-c2nnn[nH]2)cc1)c1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A heterogenous mixture of 4-(3-(2-quinolinylmethyloxy)benzoylmethyl)benzonitrile (1.35 mmol). NaN3 (6.77 mmol), pyridinium hydrochloride (6.77 mmol) in DMF (3 ml) is heated at 100° C. for 3 hours under nitrogen. The reaction mixture is poured into water and the product is collected on a filter. Recrystallization from EtOAc-DMF gives 5-(4-(3-(2-quinolinylmethyloxy)benzoylmethyl)phenyl)tetrazole.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].[Cl:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH2:32][N:33]([CH3:44])[C:34]([C:36]1[CH2:37]N(C)[C:39](=[O:42])[C:40]=1[OH:41])=[O:35]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH2:32][N:33]([CH3:44])[C:34]([C:36]1[CH2:37][N:23]([CH2:24][C:25]([OH:27])=[O:26])[C:39](=[O:42])[C:40]=1[OH:41])=[O:35]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: NCC(=O)O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CC(=O)O)C1

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and glycine as described in the preparation of Compound 12. The title compound was isolated as a white solid (80 mg, 43% yield). Mp=178–180° C. 1H NMR (300 MHz, DMSO) δ: 12.97 (bs, 1H), 11.07 (s, 1H), 7.62 (d, 1H, J=8.41), 7.53 (s, 1H), 7.25 (d, 1H, J=6.95), 4.59 (s, 2H), 4.15 (s, 2H), 4.10 (s, 2H), 2.98 (s, 3H). HRMS (M−H) calcd for C15H13N2Cl2O5: 371.0201. found: 371.0216.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11](O)=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].S(Cl)([Cl:19])=O>>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([Cl:19])=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: CC(C)C(C(=O)O)c1ccc(N=[N+]=[N-])cc1
Reactant: O=S(Cl)Cl
Product: CC(C)C(C(=O)Cl)c1ccc(N=[N+]=[N-])cc1

Procedure:
2-(4-Azidophenyl)-3-methylbutanoic acid, 3.68 g, was dissolved in 15 ml of thionyl chloride. After 45 minutes the solution was heated to a boil, then evaporated in vacuum to a residual oil. The oil was twice dissolved in diethyl ether and evaporated in vacuum to a residual oil, and further dried under a nitrogen stream. The infrared spectrum of the oil showed absorption peaks at 2120 cm-1 (azide) and 1810 cm-1 (acid chloride).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6]O.P(Br)(Br)[Br:13]>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6][Br:13]
Reactant: OCC=Cc1ccccc1Br
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCC=Cc1ccccc1Br
Temperature: 0 °C
Yield: 85 %

Procedure:
All of the o-bromocinnamylalcohol (159 mM) from Step A was dissolved in 300 ml of carbon tetrachloride under nitrogen and chilled to 0°. Then 100 ml of carbon tetrachloride containing phosphorous tribromide (5.62 ml; 59.8 mM) was added dropwise. After stirring at 0° for an additional hour the reaction was poured into ice water and partitioned. The aqueous layer was extracted once with methylene chloride and the combined organic layers were washed with cold 1.5N aqueous sodium hydroxide. Drying over magnesium sulfate followed by solvent removal gave a pale yellow oil, which was purified by short path distillation at 0.2 torr. The o-bromocinnamyl bromide was distilled at 105° and 37.3 g (85% yield) was isolated. NMR (CDCl3): δ 6.8-7.7 (m; 5H); 6.33 (AB: 1H); 4.15 (d; 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C(O)(=O)C>C(OCC)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:15][CH:16]=1
Reactant: COC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C(C)Oc1ccc(N)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-(4-nitrophenoxy)propionate (10 g, 0.044 mol) in ethyl acetate is added dropwise to a mixture of iron dust (7.37 g, 0.132 mol) in a 5% acetic acid solution at 65° C. The reaction mixture is stirred at 65° C. for 30 minutes, cooled to room temperature and filtered through diatomaceous earth. The resultant filtrate is diluted with water and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as an oil which is identified by NMR spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:19]1([CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:26]([CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NCc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Cc1ccccc1)NCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a solution of (4-bromophenyl)methanamine (2.5 g, 13 mmol) in dichloromethane (45 mL) was added N,N-diisopropylethylamine (3.5 mL, 20 mmol), followed by phenylmethanesulfonyl chloride (3.1 g, 16 mmol) and the reaction was stirred at ambient temperature for 1 hour. The precipitate was then collected by filtration, washed with dichloromethane and dried under reduced pressure to give N-[(4-bromophenyl)methyl]-1-phenyl-methanesulfonamide (2.79 g, 61% yield). LCMS (m/z) ES+ 340.0 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]=1Br)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].C([O-])(O)=O.[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(OCC)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]=1[CH:29]=[CH:28][C:27]([O:31][CH2:32][CH3:33])=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: O=C(OCc1ccccc1)N1CCCC1Cc1c(Br)oc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1oc2ccccc2c1CC1CCCN1C(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 70.5 %

Procedure:
A solution containing crude 46 (5.0 g, 12.1 mmol), ethyl acrylate (2.7 g, 27.7 mmol), tetrabutylammonium chloride (3.5 g, 12.6 mmol), NaHCO3 (2.0 g, 23.8 mmol), and Pd(OAc)2 (0.107 g, 0.46 mmol) in DMF (40 mL) was heated at 100° C. for 16 h. After cooling to ambient temperature, the reaction mixture was diluted with diethyl ether and washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (EtOAc/hexane, 1:3) to afford 3.7 g (70%) of 47 as an orange-colored oil. 1H NMR (CDCl3, 300 MHz) δ7.81 & 6.99 (rotamer, app d, J=7.5 Hz, app t, J=7.5 Hz, 111), 7.61 (dd, J=15.9, 18.3 Hz, 1H), 7.47-7.20 (m, 8H), 6.58 (dd, J=5.7, 15.6 Hz, 1H), 5.27-5.16 (m, 2H), 4.24 (q, J=7.2 Hz, 2H), 4.17-4.08 (m, 1H), 3.51-3.35 (m, 2H), 3.38 & 3.17 (rotamer, 2 dd, J=3.6, 14.1 Hz, 1H), 2.89-2.69 (m, 1H), 1.94-1.64 (m, 4H), 1.36 (t, J=7.2 Hz, 2H) ppm.
Reaction SMILES: [CH3:1]S(C1N(CCCCC2C=CC=CC=2)C(=O)C1)=O.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:47])[CH2:33][N:34]2[CH:37]([S:38]([CH2:40]CCCCC)=[O:39])[CH2:36][C:35]2=[O:46])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.OCCS(C1N(CC(=O)CCC2C=CC=CC=2)C(=O)C1)=O>>[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:47])[CH2:33][N:34]2[C@@H:37]([S:38]([CH3:40])=[O:39])[C@H:36]([CH3:1])[C:35]2=[O:46])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)C1CC(=O)N1CCCCc1ccccc1
Reactant: CCCCCCS(=O)C1CC(=O)N1CC(=O)NCCCCCCc1ccccc1
Agent: O=C(CCc1ccccc1)CN1C(=O)CC1S(=O)CCO
Product: C[C@@H]1C(=O)N(CC(=O)NCCCCCCc2ccccc2)[C@H]1S(C)=O

Procedure:
4-Methylsulfinyl-1-(4-phenylbutyl)-azetidin-2-one; N-(6-Phenylhexyl )-(4-n-hexylsulfinyl-2-oxoazetidin-1-yl )acetamide; 4-(2-Hydroxyethylsulphinyl)-N-(4-phenyl-2-oxobutyl)azetidin-2-one (Diastereoisomer 2);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][S:16][C:17]1[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=1)=[N:8][CH:7]=[CH:6]2.C1C=C(Cl)C=C(C(OO)=[O:34])C=1.C([O-])(O)=O.[Na+].OS([O-])=O.[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][S:16]([C:17]1[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=1)=[O:34])=[N:8][CH:7]=[CH:6]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2ccnc(CSc3nc4ccccc4[nH]3)c2cc1OC
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2cc1OC
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To a solution of 246.0 mg of 2-[(6,7-dimethoxyisoquinolin-1-yl)methylthio]benzimidazole (Ia-1) (0.700 mmol) in 10 ml of CHCl3 was added 151.0 mg of 80% 3-CPBA (0.700 mmol) at -10°--15° C., and the mixture was stirred for 30 min. at the same temperature. The reaction mixture was mixed with 3 ml of saturated aqueous solution of NaHCO3 and 0.3 ml of 10% aqueous solution of NaHSO3. The reaction temperature was returned to room temperature, and the reaction mixture was mixed with 2 ml of water and extracted with CHCl3. The CHCl3 layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography, eluting with AcOEt-MeOH. The obtained crystals were washed with CH2Cl2 -benzene to give 216.2 mg of the objective compound 2-[(6,7-dimethoxyisoquinolin-1-yl)methylsulfinyl]benzimidazole (Ic-1) (Yield: 83.7%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:11]([N:12]([CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][N:9]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:8]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1COCC1.O>[NH2:1][CH2:4][CH2:5][CH2:6][C@H:7]1[C@H:11]([N:12]([CH2:25][CH2:26][CH:27]([CH3:28])[CH3:29])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:10][N:9]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:8]1
Reactant: CC(C)CCN([C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CCCN=[N+]=[N-])S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)CCN([C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CCCN)S(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of tert-butyl (3R*,4S*)-3-(3-azidopropyl)-4-{(3-methylbutyl)[(4-nitrophenyl)sulfonyl]amino}pyrrolidine-1-carboxylate (0.55 g, 1.05 mmol) in toluene (50 mL), PPh3 (0.28 g, 1.05 mmol) was added and the mixture was heated at reflux for 1.5 hours. The mixture was diluted with 10 mL THF, H2O was added (28 mg, 1.57 mmol) and the reaction was heated at reflux for additional 1.5 hours. The solvents were evaporated and the residue was purified by column chromatography on silica gel eluting with 5→10% MeOH in CH2Cl2 giving the title compound.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][NH:12][O:13][CH3:14].CCN(CC)CC.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=1)=[O:10]
Reactant: O=C(O)c1cccc(F)n1
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To a cooled mixture of 6-fluoro picolinic acid (1.19 g, 8.43 mmol), N,O-dimethylhydroxyl amine (860 mg, 8.82 mmol) and Et3N (3.27 mL, 23.52 mmol) in CH2Cl2 (10 mL) was added 1-propane phosphonic acid cyclic anhydride (4.49 mL, 7.05 mmol; 50 wt% solution in EtOAc) dropwise and stirred at room temperature for 3 h. The reaction mixture was filtered, washed with CH2Cl2 (2×10 mL), evaporated to dryness, and subjected to column chromatography (SiO2, 40% EtOAc-hexanes) to obtain 6-fluoro-pyridine-2-carboxylic acid methoxy-methyl-amide (1.19 g) in 73% yield. ESMS m/z (relative intensity): 185 (M+H)+ (100).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][C@@H:11]([C@@H:14]([F:17])[CH2:15][CH3:16])[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:21](CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:18])[NH:10][C@@H:11]([C@@H:14]([F:17])[CH2:15][CH3:16])[CH2:12][NH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC[C@H](F)[C@@H](CO)NC(=O)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC[C@H](F)[C@@H](CN)NC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of benzyl[(2R,3S)-3-fluoro-1-hydroxypentan-2-yl]carbamate (2.4 g) in chloroform (40 mL) was cooled in ice, triethylamine (2 mL) and methanesulfonyl chloride (0.8 mL) were added thereto, and the mixture was stirred for 30 min. Saturated sodium hydrogen carbonate was added thereto, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. After the desiccant was filterred off, the solvent was distilled off under reduced pressure, and the residue was dissolved in DMF (40 mL). Sodium azide (3.06 g) was added thereto, and the mixture was stirred at 60° C. for 2 hr. Water was added thereto, the resulting mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in THF (50 mL), triphenylphosphine (3.59 g) and water (10 mL) were added thereto, and the resulting mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, chloroform/methanol=98:2-80:20) to afford benzyl[(2R,3S)-1-amino-3-fluoropentan-2-yl]carbamate (2.34 g).
Reaction SMILES: [CH3:1][C:2]1([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>>[CH3:1][C:2]1([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:3]1=[S:36]
Reactant: CCOC(=O)CN1C(=O)C(C)(CC(=O)OCC)c2c1cccc2[N+](=O)[O-]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CCOC(=O)CN1C(=S)C(C)(CC(=O)OCC)c2c1cccc2[N+](=O)[O-]

Procedure:
A mixture of (±)-diethyl 2,2′-(3-methyl-4-nitro-2-oxo-2,3-dihydro-1H-indole-1,3-diyl)diacetate from Step B (2.30 g, 6.31 mmol) and Lawesson's reagent (1.53 g, 3.79 mmol) was heated at 150° C. in xylenes (120 mL) for 18 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=381 (M+1).