Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]([NH2:27])=[S:26])=[CH:14][CH:13]=2)(C)(C)C.C(N(CC)CC)C.ClC(O[CH2:45][CH:46]1[C:58]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[C:52]2[C:47]1=[CH:48][CH:49]=[CH:50][CH:51]=2)=O.O>Cl.C(OCC)(=O)C>[CH:48]1[C:47]2[CH:46]([CH2:45][O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]3[N:10]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:11](=[O:28])[C:12]4[C:17]([C:18]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][C:15]([C:25]([NH2:27])=[S:26])=[CH:14][CH:13]=4)[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:52]=2[CH:51]=[CH:50][CH:49]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(N)=S)ccc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)c(-c2ccccc2)c2cc(C(N)=S)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Tert-butyl[6-(aminothiocarbonyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.26 g, 7 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was suspended in tetrahydrofuran (20 ml). To the obtained mixture were added triethylamine (2.0 ml, 14 mmol) and 9-fluorenylmethyl chloroformate (2.72 g, 10.5 mmol) and the mixture was stirred with heating at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (3.21 g, 78.1%) as an amorphous.
Reaction SMILES: CC([NH:5][C:6]([C:8]1[N:9]=[CH:10][N:11]2[CH2:16][N:15]([CH3:17])[N:14]=[N:13][C:12]=12)=[O:7])(C)C.[OH:18]S(O)(=O)=O>>[CH3:17][N:15]1[C:16](=[O:18])[N:11]2[CH:10]=[N:9][C:8]([C:6]([NH2:5])=[O:7])=[C:12]2[N:13]=[N:14]1
Reactant: CN1Cn2cnc(C(=O)NC(C)(C)C)c2N=N1
Reactant: O=S(=O)(O)O
Product: Cn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl-Temozolomide 8 (4.01 g, 16.023 mmol) and conc. H2SO4 (8 mL) (Fisher Scientific) were placed into a 50 mL flask equipped with a stirrer bar. The mixture was stirred for 2 hours at room temperature and then slowly poured into ice-cold EtOH (160 mL). A white precipitate formed, which was collected by vacuum filtration and washed with ice-cold EtOH (10 mL). The solid was dried under vacuum (20 mm Hg, room temperature, 72 hours) to yield 2.63 g of 9 (13.546 mmol, 98.4% pure against a standard sample by HPLC analysis)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].B(O)(O)[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>CN(C=O)C.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:22][CH:23]=1
Reactant: OB(O)c1ccncc1
Reactant: Brc1cnc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2ncc(-c3ccncc3)cc2c1
Temperature: 80 °C
Yield: 65.7 %

Procedure:
3-Bromo quinoline (0.2 g, 0.00096 mol) was dissolved in DMF:water (3:1, 4 mL). To this was added potassium phosphate (0.611 g, 0.00288 mol) and pyridyl-4-boronic acid (0.141 g, 0.00115 mol) at RT. The reaction mixture was degassed for 5 min, and to this was added Pd(PPh3)4 (0.055 g, 0.000048 mol). The reaction mixture was heated by microwave at 80° C. for 1.5 h. After completion of reaction (monitored by TLC), the mixture was diluted with water (20 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum, and the residue purified by column chromatography (45% ethylacetate:hexane in silica 100-200 mesh, diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound (0.13 g, 63% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+:15]([CH:18]=[C:19](SC)SC)([O-:17])=[O:16].[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>C(O)C>[CH3:24][O:25][CH2:26][CH2:27][NH:28][C:19]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[S:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)=[CH:18][N+:15]([O-:17])=[O:16]
Reactant: COCCN
Reactant: CN(C)Cc1ccc(CSCCN)s1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: COCCNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)s1

Procedure:
2-[[[5-(N,N-Dimethylaminomethyl)2-thienyl]methyl]thio]ethanamine (4.3 g) and 1-nitro-2,2-bis(methylthio)ethylene (3.3 g) in ethanol (50 ml) were heated at reflux for 51/2 hr. Methoxyethylamine (1.8 ml) was added and the reaction heated at reflux for 22 hr. The solvent was removed and the residual oil was purified by column chromatography (silica/methanol). The resultant solid was recrystallised from isopropyl acetate to give the title compound as a white solid (1.04 g). m.p. 79°-80°. TLC silica/ethyl acetate, water, isopropanol, 0.88 ammonia 25:8:15:2, Rf 0.7.
Reaction SMILES: [CH2:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.C([Li:18])CCC>CCCCC>[CH-:10]1[C:11]2[CH2:12][C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH2:7][CH2:8][CH2:9]1.[Li+:18]
Reactant: c1ccc2c(c1)CC1=C2CCCC1
Reactant: [Li]CCCC
Solvent: CCCCC
Product: [Li+]
Product: c1ccc2c(c1)CC1=C2CCC[CH-]1
Reaction time: 8 h
Yield: 70 %

Procedure:
10 g of tetrahydofluorene (59 mmol) was dissolved in 75 ml of pentane. To this solution 21 ml of n-butyl lithium (n-BuLi) (2.65M) was added dropwise over a 20 min period. The solution was stirred overnight with deposition of a white solid. The solid was collected by filtration, washed with pentane and dried under reduced pressure to give 7.14 g (70 percent yield) of product.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[Na+].Cl[CH2:8][C:9]([OH:11])=[O:10]>C(O)(C)(C)C>[C:2]([O:4][CH2:8][C:9]([OH:11])=[O:10])([CH3:5])([CH3:3])[CH3:1]
Reactant: O=C(O)CCl
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OCC(=O)O
Yield: 69.6 %

Procedure:
A suspension of sodium t-butoxide (24.1 g) in t-butanol (150 ml) was cooled in a water bath and treated drop-wise with a solution of chloroacetic acid (11.4 g) in t-butanol (30 ml). The mixture was heated under reflux for 5 h then concentrated in vacuo. The resultant white solid was dried in vacuo for 16 h then water (10 ml) was added and the mixture was filtered. The filtrate was treated with diethyl ether (150 ml), then cooled in an ice bath, stirred and acidified to pH1 with 2N sulphuric acid. The layers were separated and the aqueous layer was further extracted with diethyl ether. The combined organic extracts were dried MgSO4) and concentrated in vacuo to afford Intermediate 32 (11.1 g). 1H NMR (400 MHz, CDCl3, δ ppm) 1.27 (9H, s), 4.04 (2H, s).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[OH-].[Na+].O>CCO>[O:7]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][Br:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCCBr
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: BrCCCCCCCOc1ccccc1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
Phenol (3.10 g, 33 mmol), 1,7-dibromoheptane (7.74 g, 30 mmol) and NaOH (1.34 g, 33 mmol) were refluxed in EtOH (40 mL) for 30 h. After cooling to room temperature, water (150 mL) was added and the mixture was extracted with ethyl acetate (4×50 mL). The organic phase was washed with water (50 mL) and brine (50 mL), and the mixture was dried over Na2SO4. After evaporation of solvent, the residue was purified by Kugelrohr distillation to give 7-phenoxyheptyl bromide (2.46 g, 30%), bp 126-130° C./0.10 torr, 1H-NMR: 1.2-1.9 (m, 10H), 3.36 (t, 2H), 3.91 (t, 2H), 6.7-7.2 (m, 5H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.N1C(C)=CC=CC=1C.[N+:22]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[S:34](Cl)(=[O:36])=[O:35])([O-:24])=[O:23].Cl>ClCCl.O>[N+:22]([C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[S:34]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:36])=[O:35])([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](NS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (5 g, 27 mmol) was added to a solution of 2,6-lutidine (6.2 mL, 54 mmol) in dichloromethane (150 ml) under nitrogen. The reaction mixture was cooled down to 0° C. and a solution of 2,4-dinitrobenzenesulphonyl chloride (7.15 g, 27 mmol) in dichloromethane (100 ml) was slowly added over 15 minutes at 0° C. The reaction mixture was then stirred at room temperature for 48 hours under nitrogen. Water (100 ml) was added followed by 2N aqueous hydrogen chloride until the aqueous layer reached pH 2. The layers were then separated and the aqueous layer extracted with more dichloromethane (100 ml). The organic phases were combined, washed twice with water (100 ml), dried over magnesium sulfate and concentrated in vacuo to provide the title compound as a gum, 10 g (89%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])[CH2:5][CH:6]([NH:20][CH3:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](Cl)=[O:29].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:22])[CH2:5][CH:6]([N:20]([C:28](=[O:29])[C:27]1[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=[C:25]([C:24]([F:23])([F:38])[F:39])[CH:26]=1)[CH3:21])[CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNC(CC(=O)OC)C(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 6.8 g (21 mmol) of 3-methylamino-4,4-diphenyl-butanoic acid methyl ester hydrochloride in 100 ml of methylene chloride is added to a solution of 4.2 ml (22 mmol) of 3,5-bistrifluoromethyl-benzoyl chloride in 100 ml of methylene chloride. Then, at 0° C., 6.6 ml (46 mmol) of triethylamine and 0.26 g (2.1 mmol) of 4-dimethylaminopyridine are added. After 6 hours the reaction mixture is diluted with ethyl acetate and washed twice with water and once with brine. The organic phase is dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride/methanol (99:1 to 95:5). The title compound is obtained in the form of a light-yellow solid. TLC: methylene chloride/methanol (95:5) Rf =0.88; Rt (HPLC)=21.4 min; 1H-NMR (400 MHz, d6 -DMSO, 150° C.) d 7.97 (br, 1H), 7.45-7.19 (m, 12H), 5.46 (br, 1H), 4.46 (d, 1H), 3.54 (s, 3H), 2.87 (dd, 1H), 2.72 (s, 3H), 2.47 (dd, 1H); FAB-MS (M+H)+ =524.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4](Cl)=[N:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1F.NC(N)=[S:22].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]1[S:22][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([F:12])[C:6]=2[N:5]=1
Reactant: NC(N)=S
Reactant: Fc1cncc(F)c1N=C(Cl)c1c(F)cccc1Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Fc1cccc(Cl)c1-c1nc2c(F)cncc2s1
Temperature: 150 °C
Reaction time: 18 h
Yield: 41.3 %

Procedure:
A stirred suspension of 2-chloro-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzimidoyl chloride (12.0 g, 39.4 mmol), thiourea (9.0 g, 118 mmol) and pyridine (12.7 mL, 198 mmol) in isopropanol (200 mL) was heated at 150° C. for 3.5 hours. After stirring for one additional hour, the resulting precipitate was collected by filtration. The filtrate was treated with Et3N (27 mL, 0.197 mol) and heating was continued at 150° C. for 18 hours. After cooling to room temperature, the volatiles were removed under reduced pressure and the resultant residue was partitioned between EtOAc (300 mL) and water (500 mL). The aqueous phase was extracted with EtOAc (2×300 mL) and the combined organic layers were dried and concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-100% Et2O in petroleum ether and then triturated with a mixture 3:1 diethyl ether:pentane (25 mL) to afford the title compound as a cream coloured solid (4.6 g, 41%). LCMS (Method F): RT=3.39 min, m/z: 283 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[S:11].[C:16](=O)([O-])[O-].[Na+].[Na+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10](=[N:12][C:13](=[O:15])[CH3:14])[S:11][CH3:16]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NC(=S)Nc1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Product: CSC(=NC(C)=O)Nc1c(Cl)cccc1Cl
Reaction time: 10 h

Procedure:
5.2 g (0.02 M) of N-(2,6-dichlorophenyl)-N'-acetylthiourea, 1.3 g (0.012 M) of sodium carbonate, 1.5 ml (0.024 M) of methyliodide and 200 ml of acetone are boiled under energetic shaking for 10 hours. The acetone is distilled off and the residue is washed and then filtered. After drying 4.9 g (88.5% from the theoretical yield of N-(2,6-dichlorophenyl)-N'-acetyl-S-methylisothiourea are obtained with a melting point 135-139° C. After recrystallization from ethanol, the melting point of the product is 139°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.[C:38](OC(=O)CN)(C)(C)C.CN[C:49]1[CH:54]=CC=[CH:51][CH:50]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:20]([N:22]([CH3:38])[C:23]2[CH:51]=[CH:50][CH:49]=[CH:54][CH:24]=2)=[O:21])[CH2:31][CH3:32])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: CNc1ccccc1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)N(C)c1ccccc1

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, N-methylaniline was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].[F:7][C:8]([F:20])([F:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](Cl)(=[O:17])=[O:16].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:20][C:8]([F:7])([F:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:16])=[O:17]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CC(O)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(O)CCOS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of 1,3-butane diol (2.18 g, 24 mmol) and TEA (1.64 g, 16 mmol) in CH2Cl2 (15 mL) at 0° C. was added o-(trifluoromethyl)benzenesulfonyl chloride (2 g, 8 mmol) dissolved in CH2Cl2 (20 mL). The solution was stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (15 mL) was added to the solution and mixture was stirred at rt for 45 min. The organics were extracted with CH2Cl2 (150 mL) and washed with 0.5 M HCl (2×80 mL) and saturated aqueous NaCl (1×50 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography (50% ethyl acetate in hexanes) yielded the desired product (2 g, 84%). 1H NMR (400 MHz CDCl3) δ 8.23 (m, 1H), 7.92 (m, 1H), 7.74 (m, 2H), 4.34 (m, 1H), 4.24 (m, 1H), 3.95 (m, 1H), 1.89 (m, 1H), 1.73 (m, 1H), 1.20 (d, 3H, J=6.3 Hz). Anal. Calcd. For C11H13F3O4S: C, 44.29; H, 4.39. Found: C, 44.29; H, 4.28.
Reaction SMILES: OC[CH2:3][C:4]1([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])[N:28]=4)=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12].I([O-])(=O)(=O)=O.[Na+].O.C(#N)C.[C:49]([O:52]CC)(=[O:51])[CH3:50]>O.[Ru](Cl)(Cl)Cl>[C:49]([CH2:50][CH2:3][C:4]1([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])[N:28]=4)=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:5](=[O:12])[NH:6][C:7](=[O:11])[NH:8][C:9]1=[O:10])([OH:52])=[O:51]
Reactant: CCOC(C)=O
Reactant: O=C1NC(=O)C(CCO)(Oc2ccc(Oc3ccc(-c4nc(-c5ccccc5F)no4)cc3)cc2)C(=O)N1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C(O)CCC1(Oc2ccc(Oc3ccc(-c4nc(-c5ccccc5F)no4)cc3)cc2)C(=O)NC(=O)NC1=O
Reaction time: 4 h

Procedure:
A mixture of 5-(2-hydroxy-ethyl)-5-{4-[4-(3-(2-fluorophenyl)-[1,2,4]oxadiazol-5-yl)-phenoxy]-phenoxy}-pyrimidine-2,4,6-trione (518 mg, 1.0 mmol), sodium periodate (875 mg, 4.1 mmol), ruthenium trichloride hydrate (7 mg, 0.025 mmol), water (3 mL), acetonitrile (2 mL), and ethyl acetate (2 mL) was stirred vigorously for 4 hours. The mixture was filtered through diatomaceous earth which was then rinsed with ethyl acetate. The filtrate was washed with 10% sodium dithionite solution and brine and then dried over sodium sulfate. Filtration and concentration yielded 418 mg of the title compound as a white solid. LC-MS (m/z, APCI): 533 [M+H]+.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[C:13]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:14]=2[S:15][C:16]=1[C:17](Cl)=[O:18].[CH2:26]([OH:28])[CH3:27].O>O1CCCC1>[CH2:1]([O:8][C:12]1[C:13]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:14]=2[S:15][C:16]=1[C:17]([O:28][CH2:26][C:27]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: COc1ccc2sc(C(=O)Cl)c(Cl)c2c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2sc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 13.1 g (120.8 mmol, 2.8 equiv) of benzyl alcohol in 35 ml of dry tetrahydrofuran is added dropwise over 10 minutes to a room temperature slurry of 4.3 g (107.5 mmol, 2.5 equiv) of 60% NaH oil dispersion in 65 ml of tetrahydrofuran under nitrogen atmosphere. The reaction is stirred for 15 minutes then cooled in an ice-water bath. A hot solution of 11.4 g (43.7 mmol) 3-chloro-5-methoxybenzo[b]thiophene-2-carbonylchloride (prepared by the method described by Sudabeh Pakray and Raymond N. Castle in J. Heterocyclic Chem., 1986, 23, 1571) in 95 ml of tetrahydrofuran is added rapidly to the 0° C. reaction mixture. The reaction is stirred at 0° C. for 15 minutes, warmed at reflux for three hours and allowed to cool to room temperature before pouring onto 700 g of ice-water. The resulting mixture is extracted with diethyl ether (4×200 ml). The combined extracts are washed with saturated aqueous NaHCO3 (100 ml), water (100 ml) and saturated aqueous NaCl, dried over Na2SO4 and concentrated in vacuo to give a brownish yellow solid. The material was used as is in the subsequent reaction. A sample of the residue is rccrystallized from ethanol-water to give analytically pure benzyl 3-benzyloxy-5-methoxybenzo[b]thiophene-2-carboxylate as a white crystalline solid: mp 66°-67° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1([F:12])[CH2:9][CH:8]1[CH2:10][OH:11].C(N(CC)CC)C.O>C1COCC1>[CH3:1][S:2]([O:11][CH2:10][CH:8]1[CH2:9][C:7]1([F:12])[F:6])(=[O:4])=[O:3]
Reactant: OCC1CC1(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)OCC1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (1.43 mL) was added to a solution of (2,2-difluorocyclopropyl)methanol (1.00 g) and triethylamine (2.58 mL) in THF (10 mL) dropwise at 0° C. The mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.47 g) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:23])([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:24].[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:23])([C:7]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:25](=[O:32])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:17]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:24]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(N)c4)cc3CC[C@@H]12
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(NC(=O)c5ccccc5)c4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-(3-aminophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (50 mg, 0.16 mmol), N,N-dimethylaminopyridine (3 mg, 0.024 mmol), benzoic acid (21 mg, 0.18 mmol), and 0.4 mL of dichloromethane. 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCI) hydrochloride (120 mg, 0.64 mmol) was added in one portion, and the mixture was stirred at room temperature for 10 min. The mixture was diluted with dichloromethane, and the organic phase was washed with water followed by brine. The organic phase was dried over sodium sulfate, concentrated, and chromatographed on silica gel (0-50% methanol/ethyl acetate eluent gradient) to give 50 mg (76%) of the title compound as an amorphous foam. mp 257°-262° (decomp.) FDMS m/e=424. α[D]589 =+62.50 (c=0.61, chloroform).
Reaction SMILES: [OH:1][CH:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C=O)C>[Si:14]([O:1][CH:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: COC(=O)CC(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)CC(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
5.91 Grams (50 mmol) of methyl 3-hydroxybutyrate and 3.74 g (55 mmol) of imidazole were dissolved in 20 ml of DMF and thereto 8.29 g (55 mmol) of t-butyldimethylsilylchloride was added in several portions. After stirring the mixture at room temperature for 30 minutes, ice water was added and extraction with diethyl ether was conducted three times. The extract was washed with a saturated solution of NaCl, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was distilled (62° to 68° C./5 mmHg) to give 10.51 g of methyl (-)-3-t-butyldimethylsilyloxybutyrate (yield: 91%).