Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].C([O:12][C:13](=[O:34])[C:14]([S:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23][CH2:24][NH:25][C:26]2[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=2)[N:22]=1)([CH3:16])[CH3:15])(C)(C)C.CC(C)CCCO.[BrH:42].C(O)(=O)C>C(OCC)C>[BrH:42].[CH2:32]([C:29]1[CH:28]=[N:27][C:26]([N:25]([CH2:2][CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:24][CH2:23][C:21]2[N:22]=[C:18]([S:17][C:14]([CH3:15])([CH3:16])[C:13]([OH:34])=[O:12])[S:19][CH:20]=2)=[N:31][CH:30]=1)[CH3:33]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: CC(C)CCCI
Agent: Br
Agent: CC(C)CCCO
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCc1cnc(N(CCCC(C)C)CCc2csc(SC(C)(C)C(=O)O)n2)nc1

Procedure:
A compound obtained using 1-iodo-4-methylpentane, which is synthesized using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 4-methylpentanol as starting materials and in reference to non-patent reference [Tetrahedron, 38, 11461 (1998)], and by an operation similar to that of Example 326, was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:16]2[CH:17]=[CH:18][C:19]([O:21][CH2:22][O:23][CH3:24])=[CH:20][C:15]=2[O:14][CH2:13][C:12]1([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[CH3:25].ClCCl.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>N1C=CC=CC=1>[CH3:24][O:23][CH2:22][O:21][C:19]1[CH:18]=[CH:17][C:16]2[CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:45]([C:42]3[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=3)(=[O:47])=[O:46])[C:12]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:30][CH:31]=3)([CH3:25])[CH2:13][O:14][C:15]=2[CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
(3RS,4RS)-4-(9-Hydroxynonyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran (90 mg, 0.19 mmol) was dissolved in pyridine (2 ml) and dichloromethane (0.5 ml) and then cooled to 0° C. p-Toluenesulfonylchloride (0.12 g, 0.63 mmol) was added dropwise thereto, and the mixture was stirred for 3 hours at room temperature, quenched with water and then extracted with ethyl acetate. The extracted organic substance was washed with 2N hydrochloric acid, dried over magnesium sulfate and then concentrated. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 105 mg (yield: 88%) of the title compound as a colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[N:16]=[C:15]2[C:11]([NH:12][CH:13]=[N:14]2)=[C:10]([Cl:17])[N:9]=1.[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30]Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[NH2:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH2:30][O:29][CH2:28][CH2:27][O:26][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:10]([Cl:17])[N:9]=1
Reactant: O=C(OCCOCCl)c1ccccc1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2ncn(COCCOC(=O)c3ccccc3)c2n1
Reaction time: 0.33 h
Yield: 19.6 %

Procedure:
A suspension of potassium carbonate (4.1 g) and 2-amino-6-chloropurine (5.0 g) in dry dimethylformamide (120 ml) was stirred for 20 minutes. 2-Benzoyloxyethoxymethyl-chloride (6.3 g) was added and the resulting pink suspension stirred at room temperature for 6 days. The reaction mixture was then poured into a mixture of ice and water (210 ml) with vigorous stirring. The aqueous mixture, was extracted with chloroform (3×200 ml), and the chloroform solution obtained was washed with a 5% acetic acid solution and then twice with water. The chloroform solution was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was redissolved in a minimal amount of chloroform and the resulting solution applied to a column containing silica gel (200 g) in chloroform. The column was eluted with 2% methanol/98% chloroform and the eluant collected in 30 ml cuts. The fractions containing 2-amino-6-chloro-9-(2-benzoyloxyethoxymethyl)purine (determined by TLC) were combined, evaporated and the residue recrystallized from benzene to give 2-amino-6-chloro-9-(2-benzoyloxyethoxymethyl)purine (2.0 g., m.p. 130°-133.5° C.).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=[O:3])[CH3:2].[CH:24]([S:27]([NH:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)(=[O:29])=[O:28])([CH3:26])[CH3:25]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)/[C:6](=[C:13](/[NH:35][C:34]2[CH:36]=[CH:37][C:31]([NH:30][S:27]([CH:24]([CH3:26])[CH3:25])(=[O:29])=[O:28])=[CH:32][CH:33]=2)\[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:5]1=[O:23])(=[O:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)Nc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Product: CC(=O)N1C(=O)/C(=C(\Nc2ccc(NS(=O)(=O)C(C)C)cc2)c2ccccc2)c2ccccc21

Procedure:
Prepared analogously to Example 1c from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-isopropylsulphonylamino-aniline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]([N:14]=[C:15]=[S:16])=[O:13])[CH3:10]>O1CCOCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([NH:14][C:12](=[O:13])[O:11][CH2:9][CH3:10])=[S:16])=[N:3][CH:4]=1
Reactant: CCOC(=O)N=C=S
Reactant: Nc1ccc(Br)cn1
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a solution of 2-amino-5-bromopyridine (5.0 g, 29 mmol) in dioxane (60 mL) was added ethoxycarbonylisothiocyanate (3.4 mL, 29 mmol) in a dropwise manner and the mixture was allowed to stir for 18 h at room temperature. The mixture was then concentrated and the residue triturated with 10% ethyl acetate in hexanes. The solid was collected by filtration and dried to afford ethyl {[(5-bromopyridin-2-yl)amino]carbonothioyl}carbamate (6.2 g, 69%) as a colorless solid. MS (EI) for C9H10BrN3O2S: 305 (MH+).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].BrC[CH:16]1[CH2:20][CH:19]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>CN(C=O)C>[CH:19]1([CH:21]([C:4]2[CH:5]=[CH:6][C:1]([CH2:7][N:11]3[CH:10]=[CH:9][N:8]=[C:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:2][CH:3]=2)[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17][CH2:16][CH2:20]1
Reactant: CC(C)(C)OC(=O)CC1CCC(CBr)C1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccc(Cn2ccnc2-c2ccccc2)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.44 g (10 mmol) of 2-phenylimidazole are dissolved in 10 ml of DMF, deprotonated (50° C.) using 330 mg (11 mmol) of NaH (80% strength) and the solution is then treated with 3.5 g (10 mmol) of tert-butyl 4-bromomethyl-2-cyclopentyl-acetate (DE 42 00 954 A1) and stirred overnight at RT. It is concentrated, the residue is dissolved in CH2Cl2, the solution is washed with H2O and concentrated and the residue is chromatographed on silica gel (cyclohexane/EA=8:2).
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]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][C:22]1[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=1)=[N:8][CH:7]=[CH:6]2.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[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]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([C:22]1[NH:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=1)=[O:39])=[N:8][CH:7]=[CH:6]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2ccnc(-c3ccccc3Sc3nc4ccccc4[nH]3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2ccnc(-c3ccccc3S(=O)c3nc4ccccc4[nH]3)c2cc1OC

Procedure:
The product of step (f) above was dissolved in 1:1 CH2Cl2 -CHCl3 (10 ml), treated with 85%m-Chloroperbenzoic acid (24 mg) at -5°, and worked up in aqueous NaHCO3 to give the title compound. NMR (CDCl3)d, 8.5 (d,1H), 8.35 (dd,1H), 7.26 (1H,s), 7.21 (1H,s), 7.7-7.2 (complex,8H), 4.30 (s,3H), 3.85 (s,3H)ppm, mp 250° (d).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[OH-].[Na+].[NH2:16][CH:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20]>O>[CH3:20][CH:19]([CH3:21])[CH2:18][CH:17]([NH:16][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[C:22]([OH:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)CC(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Yield: 42.4 %

Procedure:
A solution of 2-nitrobenzenesulfonylchloride (11 g; 50 mmol) and NaOH (2.1 g; 53 mmol) in H2O (100 ml) was added DL-leucine (6.55 g; 50 mmol) and left over night with stirring at rt. The reaction mixture was added 4 M NaOH (12.5 ml) and filtered. The filtrate was acidified with 1 M HCl (50 ml) and extracted with EtOAc. The combined organic fractions were dried (Na2SO4) and evaporated to dryness to give 6.7 g (42%) product.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH3:14][C:15]1[C:20]([F:21])=[C:19]([Cl:22])[CH:18]=[CH:17][N+:16]=1[O-].CO>ClCCl>[OH:4][CH2:14][C:15]1[C:20]([F:21])=[C:19]([Cl:22])[CH:18]=[CH:17][N:16]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1c(F)c(Cl)cc[n+]1[O-]
Solvent: CO
Solvent: ClCCl
Product: OCc1nccc(Cl)c1F
Reaction time: 72 h

Procedure:
Trifluoroacetic anhydride (16.18 ml) was added dropwise at 10°-15° to a solution of 2-methyl-3-fluoro-4-chloropyridine-N-oxide (6.17 g) in dichloromethane (50 ml). After three days at room temperature, methanol (30 ml) was added to the cooled solution. The excess solvent was removed and the residue dissolved in water. After basifying (NaOH), the solution was extracted with dichoromethane. The extracts were dried (K2CO3) and evaporated to dryness to give a solid which was purified by column chromatography (silica gel; 1% MeOH/CHCl3) to give 2-hydroxymethyl-3-fluoro-4-chloropyridine (3.8 g) m.p. indeterminate)
Reaction SMILES: [BH4-].[Na+].C(O)(C)C.COS([O-])(=O)=O.[CH3:13][N+:14]1[N:15]([CH3:31])[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH3:31][N:15]1[CH:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]1[CH3:13]
Reactant: Cn1c(-c2ccccc2)cc(-c2ccccc2)[n+]1C
Agent: COS(=O)(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CN1C(c2ccccc2)CC(c2ccccc2)N1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Sodium borohydride (19 g, 0.5 mole) is added portionwise to an isopropanol (1 liter) solution of 1,2-dimethyl-3,5-diphenylpyrazolium methyl sulfate (40.1 g, 0.25 mole). The reaction is allowed to stir at room temperature for 3 days; then additional sodium borohydride (9 g, 0.25 mole) is added, and the reaction is heated to reflux with stirring and maintained there for 7 hours. The reaction mixture is cooled to room temperature and water (100 ml) is added over a 11/2-hour period. After stirring for 2 hours, the isopropanol is removed on a rotary evaporator, and the resulting paste slurried in water and extracted with diethyl ether. Evaporation of the ether layer gives the pyrazolidine as a viscous oil; 48.3 g, 72%, and analyzed as its HCl salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(O)C(O)C(F)(F)F
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: OC(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (8.50 g; 48.0 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (10.59 g; 73.52 mmoles) were suspended in 6N HCl (19 mL; 114 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (200 mL) and with ethyl acetate (200 mL), then sodium bicarbonate (6.05 g; 72.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×80 mL). The extracts were combined, washed with water (60 mL) and brine (60 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (84 mg, 63%).
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=O)([O-])[O-].[Cs+].[Cs+].BrCCl>C(#N)C>[CH2:11]1[O:10][C:9]2[C:2](=[C:3]([CH:6]=[CH:7][CH:8]=2)[CH:4]=[O:5])[O:1]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(O)c1O
Agent: ClCBr
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1cccc2c1OCO2
Temperature: 25 °C

Procedure:
To a mechanically stirred degassed mixture of 2,3-dihydroxy benzaldehyde (7.80 g, 56 mmol) and cesium carbonate (16.20 g, 84 mmol) in acetonitrile (110 ml) was added bromochloromethane (5.46 g, 84 mmol) and the resulting suspention was heated to reflux. After 5 hours the reaction was cooled to room temperature and filtered through celite with ethyl acetate washings. The filtrate was concentrated and directly chromatographed on silica gel using 9:1 hexane:ethyl acetate as eluent.
Reaction SMILES: [N:1]1([CH2:10][C:11]([C:13]2[CH:14]=[C:15]([C:19]3[CH:23]=[C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:21][C:20]=3[S:28]([NH:31]C(C)(C)C)(=[O:30])=[O:29])[CH:16]=[CH:17][CH:18]=2)=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1(OC)C=CC=CC=1.N1(C2C=CC=CN=2)CCCC1.Cl[C:56]([O:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:57].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)(C(F)(F)F)=O>[CH2:59]([O:58][C:56]([NH:31][S:28]([C:20]1[S:21][C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:23][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11](=[O:12])[CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[CH:14]=1)(=[O:29])=[O:30])=[O:57])[CH2:60][CH2:61][CH3:62]
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)Cn3cnc4ccccc43)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(C(=O)Cn2cnc3ccccc32)c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 36 %

Procedure:
To a solution of 3-[3-(2-benzoimidazol-1-ylacetyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (54.4 mg, 0.107 mmol; see step (b)) in TFA (3 mL) was added anisole (150 μL) and the reaction mixture was stirred for 28 h at ambient temperature. The reaction mixture was concentrated in vacuo and dried in vacuo overnight. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (31.6 mg, 0.214 mmol) and butyl chloroformate (135.7 μL, 1.07 mmol), and the reaction mixture was stirred overnight. Another portion of pyrrolidinopyridine (31.6 mg, 0.214 mmol) and butyl chloroformate (135.7 μL, 1.07 mmol) was added and the reaction mixture was stirred overnight. Citric acid (10 mL, 10% aq) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the title compound in 36% yield, over two steps, (21 mg, 0.038 mmol).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13](Br)[CH:14]=[CH2:15]>CN(C=O)C>[CH2:15]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH:14]=[CH2:13]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCBr
Agent: [K]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 93.5 %

Procedure:
To a mixture of potassium phthalimide (310.39 g, 1.68 mol) in DMF (1.0 L) at 0° C. was added allyl bromide (290.4 mL, 3.36 mol) from a dropping funnel over 30 minutes. The reaction was then warmed to room temperature and allowed to stir for 5 days. The mixture was filtered to remove salts while washing the residue with ethyl acetate (1 L), and the filtrate concentrated under reduced pressure. The residue was then partitioned between saturated aqueous NaHCO3 (0.5 L) and CH2Cl2 (0.8 L) and the organic phase separated. The aqueous phase was extracted with CH2Cl2 (2×0.8 L), and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure to give N-allylphthalimide as a white powder (294 g, 94%). 1H NMR (CDCl3) δ 4.30 (d, 2H, J=6.0 Hz), 5.22 (m, 2H), 5.88 (m, 1H), 7.73 (m, 2H), 7.85 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][CH:15]=1.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]
Reactant: CN(C(=O)Oc1ccc(CCNC(=O)OC(C)(C)C)cc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Reaction time: 4 h

Procedure:
{2-[4-(Methyl-phenyl-carbamoyloxy)-phenyl]-ethyl}-carbamic acid tertbutyl ester(3.7 g; 10 mmol) from above was dissolved in CH2Cl2 (90 mL). Addition of TFA (6 mL) and stirring for 4 h. The reaction mixture was evaporated to dryness and dried in vacuo at 50° C. overnight producing the title compound as a TFA salt in quantitative yield as yellow hygroscopic crystals.
Reaction SMILES: [CH2:1]([CH:10]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[N:11]1[CH:14]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:17])[CH:13]([CH:28]([OH:30])[CH3:29])[C:12]1=[O:31])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Cl[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=1)=[O:43].O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:32]([CH:10]([CH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[N:11]1[CH:14]([CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:17])[CH:13]([CH:28]([O:30][C:42]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][C:49]([N+:52]([O-:54])=[O:53])=[CH:50][CH:51]=2)=[O:43])[CH3:29])[C:12]1=[O:31])[C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(COC(=O)CC2C(C(C)O)C(=O)N2C(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COC(=O)CC2C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2C(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
2.6 g of 1-(di-p-anisylmethyl)-3-(1-hydroxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone was dissolved in 15 ml of dried methylene chloride, and 1.22 g of 4-dimethylaminopyridine was added thereto. Under ice-cooling, a solution of 1.3 g of p-nitrobenzyl chloroformate in 7 ml of dried methylene chloride was added dropwise to the mixture, followed by stirring at room temperature for 1 hour. To the reaction mixture were added methylene chloride and water, and the methylene chloride layer was washed successively with a 1N hydrochloric acid aqueous solution, water, a 5% aqueous solution of sodium bicarbonate and water, and dried over sodium sulfate. The solvent was removed by distillation, and the residue was purified by silica gel chromatography to obtain 2.2 g of 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone.
Reaction SMILES: C(Cl)(Cl)Cl.[SH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.Br[CH2:17][CH2:18][CH2:19][OH:20]>C(N(CC)CC)C>[OH:20][CH2:19][CH2:18][CH2:17][S:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: OCCCBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(SCCCO)cc1
Yield: 67 %

Procedure:
To 40 ml of chloroform were added 4.0 g of methyl 4-mercaptobenzoate, 3.3 g of 3-bromo-1-propanol and 2.38 g of triethylamine, and the mixture was stirred for an hour and then evaporated under a reduced pressure. After adding 50 ml of ethyl acetate, the mixture was washed with 30 ml each of water, 1N hydrochloric acid and a saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate and evaporated under a reduced pressure. The residue was applied to a silica gel column and eluted with chloroform/methanol (100:3) to obtain 3.6 g of methyl p-(3-hydroxypropylthio)benzoate as a colorless crystal. To 3.0 g of this crystal was added 1.44 g of phosphorus tribromide, and the mixture was heated at 80° C. for 2 hours, poured into 50 ml of ice-water, and extracted three times with 20 ml of ethyl acetate. The extract was dried over magnesium sulfate, and evaporated under a reduced pressure. The residue was applied to a silica gel column and eluted with chloroform/hexane (1:1) to obtain 3.0 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].[N:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.Cl>O1CCCC1.O>[O:12]1[CH2:13][CH2:14][N:9]([C:15]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:16])[CH2:10][CH2:11]1
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)N1CCOCC1)C(=O)O
Temperature: 0 °C
Yield: 39.6 %

Procedure:
4 g(50 mmol) of L-alanine and 2 g(50 mmol) of NaOH were added to 30 ml of distilled water. The mixture was cooled to 0° C. and then stirred vigorously. To the mixture was added slowly a solution of 7.1 g(50 mmol) of morpholinecarbonyl-chloride in 30 ml of tetrahydrofuran, while adjusting the whole mixture to pH 8.5-pH 9.5 with the addition of 0.05N NaOH. After the reaction was completed, the reaction mixture was acidifiedto pH 2 with 6N HCl. The reaction mixture was extracted with a mixed solvent of ethyl acetate and THF(1:1) (30 ml×3) and the organic layer was concentrated under a reduced pressure to give 4 g of the title compound(yield: 40%).