Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][C:27](SC)=[CH:26][CH:25]=4)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH:32]1C=C(Cl)C=C(C(OO)=O)C=1.[S:43](=[O:47])(=O)(O)[O-:44].[Na+]>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][C:14]2[C:23]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][C:27]([S:43]([CH3:32])(=[O:47])=[O:44])=[CH:26][CH:25]=4)[CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(=O)([O-])O
Reactant: CSc1ccc(-c2cccc3c(OC4CCN(C(=O)OC(C)C)CC4)ccnc23)cc1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(Oc2ccnc3c(-c4ccc(S(C)(=O)=O)cc4)cccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 25 mL round-bottomed flask immersed in an ice-bath was placed a stir bar and Compound F2 (16 mg, 0.037 mmol) in CH2Cl2 (5 mL). A solution of mCPBA (19 mg, 0.081 mmol) dissolved in CH2Cl2 (1 mL) was added at 0° C. The mixture was stirred at 0° C. for 30 min. A solution of sodium bisulfate was added. The organic phase was separated, dried and concentrated to give the crude product. The crude was purified by HPLC. 1H NMR (CDCl3, 400 MHz) δ 1.29 (d, 6H), 2.04 (m, 2H), 2.20 (m, 2H), 3.16 (s, 3H), 3.59 (m, 2H), 3.85 (m, 2H), 4.97 (m, 1H), 5.14 (m, 1H), 7.23 (s, 1H), 7.66 (d, 2H), 7.92 (m, 2H), 8.12 (d, 2H), 8.48 (d, 1H), 9.08 (d, 1H). Exact mass calculated for C25H28N2O5S 468.17, found 469.2 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.C[C:16]([CH3:19])([O-])[CH3:17].[K+].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CS(C)=O.O1CCCC1>[CH2:21]([C:5]1([CH2:4][CH2:3][CH2:2][CH2:14][CH2:13][CH2:17][CH2:16][CH3:19])[C:4]2[CH:3]=[C:2]([I:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCI
Reactant: Ic1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(I)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
20 parts of 2-iodofluorene was dissolved in a mixed solution of 114 parts of dimethyl sulfoxide (DMSO) and 23 parts of tetrahydrofuran (THF), and the thus obtained mixture was then stirred at 25° C. for 10 minutes. Thereafter, while stirring, 8.7 parts of potassium-tert-butoxide was added to the mixture. Twenty minutes later, 19.2 parts of n-octyl iodide was added to the mixture, and further twenty minutes later, 8.7 parts of potassium-tert-butoxide was added thereto. Further, twenty minutes later, 19.2 parts of n-octyl iodide was added thereto, and the obtained mixture was then stirred at 25° C. for 2 hours. After completion of the stirring, THF was distilled away from the reaction solution, and it was then extracted with toluene-water. The toluene phase was dried over magnesium sulfate, and the toluene was then distilled away, thereby obtaining a brown tarry solid. This brown tarry solid was separated and purified by column chromatography (hexane-ethyl acetate) to obtain 30 parts of 9,9-di-n-octyl-2-iodofluorene in the form of a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20](O)=[O:21])[C:6]2=[O:17].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:47][OH:48].O>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:7]2[C:3]=1[CH2:4][N:5]([C@@H:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH2:32][CH3:33])[CH:24]=1)[CH2:19][C:20](=[O:21])[NH:47][OH:48])[C:6]2=[O:17]
Reactant: CCOc1cc([C@@H](CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc([C@@H](CC(=O)NO)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a solution of (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid (1.3 g, 2.8 mmol) in tetrahydrofurane (10 ml) was added carbonyldiimidazole (0.7 g, 4.2 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added hydroxylamine HCl salt (0.4 g, 5.6 mmol). The resulted mixture was stirred at room temperature for 4 hours. Water (20 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was added ethyl acetate (30 ml). The mixture was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulted oil was stirred with ether (5 ml) for 2 hours and filtered to give (1R)-cyclopropanecarboxylic acid {7-chloro-2-[1-(3-ethoxy-4-methoxy-phenyl)-2-hydroxycarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (1.2 g, 86%): mp 142–144° C.; 1HNMR (DMSO-d6): δ 0.87–0.89 (m, 4H, c-CH2), 1.28–1.33 (t, J=7.5 Hz, 3H, OCH2CH3), 1.78–1.83 (m, 1H, c-CH), 2.85–2.91 (m, 2H, CH2CO), 3.73 (s, 3H), 4.00 (t, J=7.5 Hz, 2H, OCH2CH3), 4.11 (d, J=17 Hz, 1H, NCHH), 4.60 (d, J=17 Hz, 1H, NCHH), 5.53–5.69 (m, 1H, CHN), 6.92–6.94 (m, 3H, Ar), 7.58 (d, J=10 Hz, 1H, Ar), 8.26 (d, J=10 Hz, 1H, Ar), 8.84 (s, 1H), 10.46 (s, 1H), 10.57 (s, 1H); 13C NMR (DMSO-d6): δ 8.4, 8.5, 15.2, 15.9, 35.4, 46.2, 52.2, 55.9, 64.3, 74.6, 112.4, 112.7, 119.7, 119.8, 121.5, 131.7, 132.9, 136.4, 140.2, 148.4, 149.1, 166.3, 167.6, 172.4; Anal. Calcd. for C26H28ClN3O7+0.5 H2O: C, 58.01; H, 5.48; N, 8.46. Found: C, 57.97; H, 5.29; N, 8.53, H2O, 1.5.
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6](/[CH:14]=[C:15]1/[C:16](=[O:36])[N:17]([C@@H:20]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]4[O:30][C:31](=[O:35])[O:32][C:33]=4[CH3:34])=[O:26])[CH2:21]3)[CH2:18][CH2:19]/1)=[C:7]2[C:11]([OH:13])=[O:12].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.Cl.[C:50]([O:69][N:70]=[C:71]([C:75]1[N:79]=[C:78]([NH2:80])[S:77][N:76]=1)[C:72](Cl)=[O:73])([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.O>ClCCl.CO>[NH2:80][C:78]1[S:77][N:76]=[C:75](/[C:71](=[N:70]/[O:69][C:50]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)/[C:72]([NH:1][C@@H:2]2[C:9](=[O:10])[N:8]3[C@@H:3]2[S:4][CH2:5][C:6](/[CH:14]=[C:15]2/[C:16](=[O:36])[N:17]([C@@H:20]4[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]5[O:30][C:31](=[O:35])[O:32][C:33]=5[CH3:34])=[O:26])[CH2:21]4)[CH2:18][CH2:19]/2)=[C:7]3[C:11]([OH:13])=[O:12])=[O:73])[N:79]=1
Reactant: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](N)[C@H]4SC3)C2=O)C1
Reactant: Nc1nc(C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)Cl)ns1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(c5ccccc5)(c5ccccc5)c5ccccc5)c5nsc(N)n5)[C@H]4SC3)C2=O)C1

Procedure:
0.5 g of (6R, 7R)-7-amino-3[E-(R)-1′-(5-methyl-2-oxo-[1,3]-dioxol-4-ylmethoxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid were dissolved in 20 ml of dichloromethane at 0°. 0.7ml of bis(trimethylsilyl)acetamide were then added and 0.46 g of 2-trityloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)-acetic acid chloride hydrochloride (J. Antibiotics 37:557-571, 1984) were metered in portions. The mixture was poured onto 15 ml of water/15 ml of MeOH and the phases were separated. The water phase was washed once again with 15 ml of dichloromethane and the combined organic phases were dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[CH2:29][OH:30])=[O:23])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([C@H:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[CH2:29][O:30][C:38](=[O:40])[CH3:39])=[O:23])[N:16]3[CH2:21][CH2:20][O:19][CH2:18][C:17]=23)=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2CO)n2c1COCC2)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2COC(C)=O)n2c1COCC2)c1ccccc1
Yield: 55 %

Procedure:
A mixture of 6-((R)-2-hydroxymethyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 16ei) (0.213 mmol), triethylamine (31 mg, 0.31 mmol), acetyl chloride (24 mg, 0.31 mmol) and 4-dimethylamino-pyridine (ca. 1 mg) in dry dichloromethane was stirred overnight. After addition of aqueous sodium hydrogencarbonate, extraction (3 times with dichloromethane), and drying of the combined organic layers over sodium sulfate, the solvents were evaporated and the residue was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give acetic acid (R)-1-[8-((R)-1-phenyl-propylcarbamoyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-6-carbonyl]-pyrrolidin-2-ylmethyl ester (54 mg, 55%). LC/MS (method 4): Rt=1.23 min; m/z=454.31 (M+H+).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].Br[CH2:7][CH2:8][O:9][CH2:10][CH2:11]Br.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[O:9]1[CH2:10][CH2:11][C:2]([C:1]#[N:5])([C:3]#[N:4])[CH2:7][CH2:8]1
Reactant: BrCCOCCBr
Reactant: N#CCC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: N#CC1(C#N)CCOCC1
Temperature: 85 °C
Yield: 80.8 %

Procedure:
A mixture of malononitrile (0.991 g, 15 mmol), 1-bromo-2-(2-bromoethoxy)ethane (3.83 g, 16.50 mmol) and DBU (4.97 ml, 33.0 mmol) in DMF (6 ml) was heated at about 85° C. for 3 hours, and then cooled to ambient temperature. The mixture was concentrated in vacuo, the resulting residue was diluted with ethyl acetate, washed three times with water and dried overnight under high vacuum to yield the desired product as a light brown solid (1.65 g). GC-MS: 136 [M]; Retention time=5.76 min. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.14-2.32 (m, 4H) 3.77-3.96 (m, 4H).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:5][C:3]1=[O:4].C(=O)([O-])[O-:17].[K+].[K+]>Cl>[OH:17][CH:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[O:5][C:3]1=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCC1CC(Cl)C(=O)O1
Agent: Cl
Agent: [K+]
Product: CCCCCCCCC1CC(O)C(=O)O1
Temperature: 25 °C
Yield: 78 %

Procedure:
In a 50 ml flask with a cooling column, 3.5 g (15 mmol) of α-chloro-γ-octyl-γ-butyrolactone and 20 ml of 2N aqueous potassium carbonate were kept at 80° C. for 40 hours under stirring. The reaction mixture was cooled to room temperature and poured into 10 ml of 12N hydrochloric acid. The reaction product was extracted with ether and the ether extract was dried over anhydrous sodium carbonate. The ether was removed and the residue was distilled under reduced pressure to give α-hydroxy-γ-octyl-γ-butyrolactone (Yield 78%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21](=[O:33])[C:22]1[CH:31]=[C:30]([NH2:32])[CH:29]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:28][O:27][C:25](=[O:26])[C:24]1[CH:29]=[C:30]([NH:32][S:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:31]=[C:22]([C:21]([O:20][CH3:19])=[O:33])[CH:23]=1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(OCc3ccccc3)cc2)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Benzyloxy-benzenesulfonyl chloride (7.35 g, 26.0 mmol) was added in small portions to a suspension of 5-amino isophtalic acid dimethyl ester (5.23 g, 25.0 mmol) in DCM (100 ml) and pyridine (10 ml). The resulting clear yellow solution was stirred for 2 hours at room temperature, the volatile solvents were removed under reduced pressure, the solid residue was suspended in MeOH (125 ml) and the mixture was heated to reflux for 10 minutes. The off white solid was filtered off, washed with water and cold MeOH and dried under high vacuum. Yield 10.93 g (96%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH3:12])=[CH:4][CH:3]=1.[Br:13]Br>CC(O)=O.C1(C)C=CC=CC=1>[Br:13][C:4]1[CH:3]=[C:2]([Cl:1])[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]=1[CH3:12]
Reactant: BrBr
Reactant: Cc1ccc(Cl)c2c1CCCO2
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1c(Br)cc(Cl)c2c1CCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
A mixture of the 8-chloro-5-methyl-3,4-dihydro-2H-1-benzopyran (7d) (5.74 g, 31.4 mmol) and acetic acid (75 mL) is treated with bromine (1.93 mL, 37.7 mmol) in AcOH (35 mL). The mixture was stirred at room temperature for 15 minutes, then diluted with toluene (100 mL). The mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (70 mL) and successively washed with a 15% sodium thiosulfate solution (50 mL) and a saturated solution of sodium hydrogenocarbonate (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The product was recrystallized in ethanol, to provide 6-bromo-8-chloro-5-methyl-3,4-dihydro-2H-1-benzopyran (7e) (4.44 g, 17.0 mmol, 54%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:16])[CH2:14][OH:15])[CH:7]=[CH:6]2.I([O-])(=O)(=O)=[O:18].[Na+]>C(Cl)(Cl)(Cl)Cl.C(#N)C.O.O.[Ru](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:16])[C:14]([OH:18])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(C)CO)ccc2c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
To a solution of 0.21 g 2-(6-methoxy-2-naphthyl)propan-1-ol in 2 ml of carbon tetrachloride, 2 ml acetonitrile, 3 ml of water, and 0.877 g of sodium metaperiodate is added 5 mg of ruthenium trichloride hydrate. After 4 hours at ambient temperature the mixture is extracted with 4 portions of 10 ml of methylene chloride. The combined organic extracts are dried over MgSO4, filtered, and concentrated to give the product 2-(6-methoxy-2-naphthyl)propionic acid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:23]1(C(O)=O)[NH:28][C:27](=[O:29])[CH:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:25]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:24]1=[O:42])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O[N:47]1[C:51](=[O:52])CCC1=O.N[C:55]1[S:56][C:57]2[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=2[N:59]=1>O1CCOCC1.C(OCC)(=O)C>[S:56]1[C:57]2[CH:63]=[CH:62][CH:61]=[CH:60][C:58]=2[N:59]=[C:55]1[C:23]1([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:28]([C:51](=[O:52])[NH2:47])[C:27](=[O:29])[CH:26]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:25]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:24]1=[O:42]
Reactant: Nc1nc2ccccc2s1
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)CC1C(=O)NC(Cc2ccccc2)(C(=O)O)C(=O)N1OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)CC1C(=O)N(C(N)=O)C(Cc2ccccc2)(c2nc3ccccc3s2)C(=O)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
1.09 g of dicyclohexylcarbodiimide was added to 25 ml of a solution of 2.17 g of (3RS,6SR)-3-benzyl-1-benzyloxy-3-carboxy-6-isobutylpiperazine-2,5-dione and 0.63 g of N-hydroxysuccinimide in anhydrous dioxane. The mixture was stirred at room temperature for 2 hours. Thereto was added 0.80 g of 2-aminobenzothiazole. The mixture was stirred at room temperature for 23 hours. The reaction mixture was diluted with 200 ml of ethyl acetate. The resulting solution was washed with an aqueous solution saturated with sodium hydrogen carbonate and an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent. The residue was crystallized using ethyl acetate, to obtain 2.77 g of (3RS,6SR)-3-(benzothiazol-2-yl)-carbamoyl-3-benzyl-1-benzyloxy-6-isobutylpiperazine-2,5-dione as a white solid.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:21][CH2:22][CH2:23][N:24]=[C:25]=[O:26]>>[Cl:21][CH2:22][CH2:23][NH:24][C:25]([N:20]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:26]
Reactant: NCc1ccccc1
Reactant: O=C=NCCCl
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: O=C(NCCCl)N(Cc1ccccc1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 65.4 %

Procedure:
3.6 g of D-galactose, 3.2 g of benzylamine and 3.0 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 23-(1). 4.9 g of 1-(2-chloroethyl)-3-benzyl-3-(D-galactopyranosyl)urea are thereby obtained as colorless caramel.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][CH2:39][C@@H:40]([NH2:44])[C:41]([OH:43])=[O:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[N:19]([C:31]4[CH:36]=[CH:35][C:34]([NH:44][C@H:40]([CH2:39][CH3:38])[C:41]([OH:43])=[O:42])=[CH:33][CH:32]=4)[CH:20]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=4[Cl:30])[N:22]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(I)cc3)cc2)cc1
Reactant: CC[C@@H](N)C(=O)O
Product: CC[C@@H](Nc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O

Procedure:
2-(4′-tert-Butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-1-(4-iodo-phenyl)-1H-imidazole (191 mg, 0.3 mmol) was treated as described in general procedure R using D-2-aminobutyric acid (310 mg, 3 mmol) to give (R)-2-{-4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-butyric acid, which was then treated as described in general procedure F to give (4R)-5-{-4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-ethyl-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(C1C(=O)CC(C2C=CC(F)=CC=2)CC1=O)(=O)C>>[C:16]([CH:11]1[C:12](=[O:14])[CH2:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][C:10]1=[O:15])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: O=C1CC(=O)CC(c2ccccc2F)C1
Agent: CC(=O)C1C(=O)CC(c2ccc(F)cc2)CC1=O
Agent: [Na+]
Product: CC(=O)C1C(=O)CC(c2ccccc2F)CC1=O

Procedure:
The title compound was prepared from 5-(2-fluoro-phenyl)-cyclohexane-1,3-dione (770 mg, 3.74 mmol), example 1/b stage 2, and sodium acetate (307 mg, 3.74 mmol), following the procedure describing the synthesis of 2-acetyl-5-(4-fluoro-phenyl)-cyclohexane-1,3 dione (example 3/a stage 1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C(O[I:16](OC(=O)C)([O-])(=O)=O)(=O)C.C([N+](CC)(CC)CC)C>ClCCl>[OH:1][C:2]1[C:9]([I:16])=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CC(=O)O[I+2]([O-])([O-])([O-])OC(C)=O
Reactant: COc1ccc(O)c(C=O)c1
Agent: CC[N+](CC)(CC)CC
Solvent: ClCCl
Product: COc1cc(I)c(O)c(C=O)c1
Reaction time: 8 h
Yield: 11.9 %

Procedure:
To a solution of 2-hydroxy-5-methoxy-benzaldehyde (15.97 g, 104.9 mmole) in 375 mL dichloromethane at −15° C. was added tetraethylammonium diacetoxyiodate (48.06 g, 128.1 mmole) over 15 minutes. After stirring overnight, an additional amount of tetraethylammonium diacetoxyiodate (46.93 g, 125.1 mmole) was added over 15 minutes. The reaction was stirred for an additional 12 hours, concentrated, and added to 2N HCl. The mixture was extracted into ethyl acetate and the combined organic phases were washed with saturated sodium bicarbonate, water, brine, and dried with magnesium sulfate. The organic phases were concentrated in vacuo and the residue was loaded on to silica gel and chromatographed with silica gel (hexanes:ethyl acetate, 9:1) to afford 3.47 g (11.9%) of iodide as a yellow solid: Mp=103-105° C.; 1H NMR (DMSO-d6) δ 11.3 (s, 1 H), 9.73 (s, 1 H), 7.60 (d, 1 H, J=3.0 Hz,), 7.07 (d, 1 H, J=3.1 Hz), 3.83 (s, 3 H).
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl.[CH:34](N(C(C)C)CC)(C)[CH3:35].C(Cl)(=O)C=C>O1CCOCC1.C(Cl)Cl>[CH2:24]([O:23][C:20]1[N:19]=[CH:18][C:17]([S:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH:7][C:6](=[O:5])[CH:34]=[CH2:35])[CH2:9][CH2:10]2)(=[O:15])=[O:16])=[CH:22][CH:21]=1)[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(OCCc3ccccc3)nc2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(OCCc3ccccc3)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.7 %

Procedure:
[1-(6-Phenethyloxy-pyridine-3-sulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.18 g, 0.39 mmol) was suspended in a 4M solution of HCl in Dioxane (10 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum and the resulting residue dissolved in THF (10 ml). To this solution was added diisopropylethylamine (0.34 ml, 1.99 mmol) was added in one portion, followed by the drop wise addition of acryloyl chloride (0.03 ml, 0.38 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 50% DCM, 50% EtOAc) to give the title compound (0.032 g, 19% yield) as a white solid.