Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])([O-:3])=O.[C:5]([O-:8])([O-])=[O:6].OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[F:19][S:20]([C:23](C(F)=O)([F:25])[F:24])(=[O:22])=[O:21]>C(Cl)(F)(F)C(Cl)(Cl)F>[F:25][C:23]([F:24])([S:20]([F:19])(=[O:21])=[O:22])[C:1]([O:4][O:8][C:5](=[O:6])[C:23]([F:25])([F:24])[S:20]([F:19])(=[O:22])=[O:21])=[O:3]
Reactant: O=C([O-])[O-]
Reactant: O=C(F)C(F)(F)S(=O)(=O)F
Agent: OO
Agent: [Na+]
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: O=C(OOC(=O)C(F)(F)S(=O)(=O)F)C(F)(F)S(=O)(=O)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
A round-bottom flask is charged with 50 ml of CFC-113 and 2.0 g of sodium percarbonate (13 mmoles or 19 mmoles of H2O2 equivalent). After chilling the contents of the flask to 0° C., 2.83 ml of FSO2CF2(C═O)F (25 mmoles) is added and the resulting slurry is stirred magnetically for 3 hours. The reaction mixture is filtered through a pad of Drierite® on glass wool, washing through with fresh CFC-113, an operation assumed to remove any unreacted percarbonate and any free H2O2. The filtrate, now measuring 52 ml in volume, is found to be 0.10 M in peroxide for a 42% yield based on starting FSO2CF2(C═O)F.
Reaction SMILES: [NH2-].[Na+].Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Br[CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][CH:19]=1>O1CCCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:18][CH:19]=2)[NH2:12])=[CH:7][CH:6]=1
Reactant: BrCc1coc(-c2ccccc2)n1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NN(Cc1coc(-c2ccccc2)n1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
A flask containing tetrahydrofuran (2.0 mL) was charged with sodium amide (152 mg, 3.69 mmol; Aldrich) and chilled to 0° C. (4-Fluorophenyl)hydrazine hydrochloride (400 mg, 2.46 mmol; Aldrich) was added in portions. After 5 minutes, the solid had completely dissolved and the ice bath was removed. Stirring was continued for 1 hour, then the solution was chilled again in an ice bath and 4-(bromomethyl)-2-phenyloxazole (586 mg, 2.46 mmol; Anichem) was added dropwise. After 30 minutes, the ice bath was removed and the reaction was heated to 50° C. overnight. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: LC/MS (DCI/NH3) m/z 267 (M+H−NH3)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24]>CCCCCC>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH2:25])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Nc1ccccc1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
The title compound was prepared according to General Method C using 4-phenoxyphenylsulfonyl chloride (969 mg, 3.6 mmol) and o-phenylenediamine (300 mg, 2.77 mmol). The reaction mixture was partitioned between water (200 ml) and toluene:methylene chloride (1:3). The organic phase collected and the methylene chloride evaporated leaving the toluene. Hexane added and the product precipatated from solution. (317 mg, 34%) EI-MS m/z 341 (M+H)+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[CH3:17][N:18]([CH3:25])[CH2:19][CH2:20][CH2:21]C(Cl)=O.[CH2:26]([N:28]1[C:40]2[CH:39]=[CH:38][C:37]([NH2:41])=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH3:27]>>[CH3:17][N:18]([CH3:25])[CH2:19][CH2:20][CH2:21][C:6]([N:8]1[CH2:15][C:14](=[CH2:16])[CH2:13][C@H:9]1[C:10]([NH:41][C:37]1[CH:38]=[CH:39][C:40]2[N:28]([CH2:26][CH3:27])[C:29]3[C:34]([C:35]=2[CH:36]=1)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:12])=[O:7]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CN(C)CCCC(=O)Cl
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: C=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(=O)CCCN(C)C)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-methyleneproline, 4-(dimethylamino)butanoyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=433.6.
Reaction SMILES: [OH-].[Na+].O.Cl.[C:5]([NH2:13])(=[NH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]([CH2:22][C:23](OCC)=[O:24])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C>O>[C:6]1([C:5]2[N:13]=[C:23]([OH:24])[CH:22]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Oc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To a ice cooled solution of sodium hydroxide (2.4 g, 60 mmol) in water (30 ml) was added benzamidine hydrochloride hydrate (9.4 g, 60 mmol) and ethyl benzoylacetate (12.1 g, 63 mmol). Ethanol (ca 30 ml) was added and the mixture was stirred at room temperature overnight. The solid was filtered off, washed with water and diethyl ether and dried which gave the title compound (9.0 g, 60%), (M+H)+1 249.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[CH2:27]([N:29]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([NH2:38])=[CH:35]2)=[N:30]1)[CH3:28]>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:38]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][N:29]([CH2:27][CH3:28])[N:30]=4)[CH:35]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CCn1cc2cc(N)ccc2n1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CCn1cc2cc(N3CCC4(CCN(S(=O)(=O)c5ccccc5Cl)CC4)C3=O)ccc2n1

Procedure:
Off-white crystalline solid. MS (ESI): 473.1 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 2-ethyl-2H-indazol-5-ylamine (for synthesis: Kamel et al.; Journal fuer Praktische Chemie, 31; 1966; 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[O-]CC.[Na+].[Na].Cl[CH2:23][CH:24]([OH:26])[CH3:25]>C(O)C>[CH3:23][CH:24]([OH:26])[CH2:25][O:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]2[CH:3]=[C:2]([F:1])[CH:15]=[C:14]([F:16])[CH:13]=2)=[CH:11][CH:10]=1
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: CC(O)CCl
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CC(O)COc1ccc(Oc2cc(F)cc(F)c2)cc1
Yield: 59.2 %

Procedure:
4-(3,5-Difluorophenoxy)phenol (3.0 g, 13.5 mmol) was added to an ethanolic solution of sodium ethoxide prepared from ethanol (15 ml) and sodium (313 mg, 13.6 mmol). To the resultant solution, 1-chloro-2-propanol (1.60 g, 16.9 mmol) was dropwise added with stirring under reflux. After completion of the addition, the resultant mixture was stirred under reflux for 5 hours. After allowed to cool, ethanol was removed, and the residual oil was dissolved in toluene. The toluene layer was washed with water once, a 20% aqueous potassium hydroxide solution two times and a saturated aqueous sodium chloride solution once in order and dried over anhydrous magnesium sulfate. Removal of the solvent gave 1-methyl-2-[4-(3,5-difluorophenoxy)phenoxy]ethanol (2.24 g).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[C@@H:3]1[C:10]([O:12][CH:13]1[CH:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][CH:15]([CH3:22])[CH2:14]1)=[O:11].[C:23](=O)([O-])[O-].[K+].[K+]>CO.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH3:23][O:8][C:6]1[CH2:7][C@H:2]([CH3:1])[C@@H:3]([C:10]([O:12][C@H:13]2[C@H:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][C@@H:15]([CH3:22])[CH2:14]2)=[O:11])[C:4](=[O:9])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CC1CCC(C(C)C)C(OC(=O)[C@H]2C(=O)CC(=O)C[C@@H]2C)C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [K+]
Solvent: CO
Product: COC1=CC(=O)[C@H](C(=O)O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)[C@@H](C)C1
Temperature: 23 °C
Reaction time: 12 h
Yield: 713.6 %

Procedure:
A solution of (1R, 3R, 4S)-p-menth-3-yl (1R, 2S)-2-methyl-4,6- dioxocyclohexanecarboxylate (2, 24.0 g, 77.8 mmol, 1 equiv) in methanol (300 mL) was treated with camphorsulfonic acid (ca. 800 mg, 3.9 mmol, 0.05 equiv) and the resulting solution was stirred at 23° C. for 12 h. The reaction mixture was neutralized by the addition of solid potassium carbonate (1.08 g, 7.78 mmol, 0.10 equiv) and the resulting suspension was filtered and the filtrate was concentrated. The residue was concentrated from toluene (2×15 mL) and then was purified by flash column chromatography (20% ethyl acetate-hexanes) to afford (1R, 3R, 4S)-p-menth-3-yl (1R, 6S)-4-methoxy-6-methyl-2-oxo-3-cyclohexene-1-carboxylate (4) as a white solid (mp 78°-80° C., 17.9 g, 71%). The regioisomeric enone, (1R, 3R, 4S)-p-menth-3-yl (1R, 6S)-2-methoxy-6-methyl-4-oxo-2-cyclohexene-1-carboxylate (5) was isolated in separate fractions and was resubjected to the reaction conditions to establish the equilibrium mixture of enones, in which the desired product 4 is strongly favored.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].C(O)CO.[CH3:18][NH2:19].O>C(#N)C>[NH2:12][C:5]1[C:6]([CH3:11])=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([NH:19][CH3:18])=[O:2]
Reactant: CN
Reactant: COC(=O)c1cc(Cl)cc(C)c1N
Solvent: CC#N
Solvent: OCCO
Solvent: O
Product: CNC(=O)c1cc(Cl)cc(C)c1N
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
The solution prepared in Step B (96.2 g, 200 mmol) was diluted with acetonitrile (60.0 g) and ethylene glycol (180 g) and dried azeotropically by distilling at atmospheric pressure under a Claisen distillation head to take off ˜72 mL of volatiles. Then the distillation head was replaced with a dry-ice-cooled condenser, the remaining solution was cooled to 0-5° C., and methylamine gas (31.1 g, 1000 mmol) was added below the surface of the reaction mixture. The mixture was heated at 70° C. for 17.5 h, and then water (400 mL) was added slowly to precipitate the product. The mixture was cooled slowly to 5° C., stirred for 15 minutes at this temperature, filtered, and the solids were washed with water and dried under nitrogen to afford the subject compound (36.36 g, 91.5% yield). HPLC showed 99.3 area % purity.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[Cl-:12].[NH4+]>O1CCCC1.CO.O>[ClH:12].[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH2:9]
Reactant: [Cl-]
Reactant: Cc1ccc(I)c([N+](=O)[O-])c1
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(I)c(N)c1
Product: Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 1-iodo-4-methyl-2-nitrobenzene (5.00 g, 19 mmol) in tetrahydrofuran (12.5 ml), methanol (25 ml) and water (6.3 ml) were added reduced iron (5.30 g, 95 mmol) and ammonium chloride (6.10 g, 114 mmol), and the mixture was stirred overnight at 70° C. The reaction mixture was allowed to cool to room temperature, tetrahydrofuran (50 ml) was added to the reaction mixture. After filtration through celite, the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (20 ml) was added 4N HCl-ethyl acetate solution (10 ml). The precipitated solid was collected by filtration, washed with ethyl acetate, and dried in vacuo to give 2-iodo-5-methylphenylamine hydrochloride (2.56 g, yield 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][CH:16]([CH3:31])[CH2:17][S:18]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([CH2:21][S:18]([CH2:17][CH:16]([OH:15])[CH3:31])(=[O:20])=[O:19])=[CH:23][CH:24]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(O)CS(=O)(=O)Cc1ccc(C(=O)O)cc1
Product: CC(O)CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
1 g of methyl 4-(bromomethyl)benzoate was reacted with 1-mercaptopropan-2-ol via Procedure Q. 1 g of methyl 4-((2-hydroxypropylthio)methyl)benzoate was oxidized with 2 g of MCPBA in DCM at −78° C. to form crude methyl 4-((2-hydroxypropylsulfonyl)methyl)benzoate. The reaction was evaporated and purified by ISCO Combi-Flash to yield 567 mg of pure methyl 4-((2-hydroxypropylsulfonyl)methyl)benzoate which was subsequently hydrolyzed via Procedure M to give 328 mg of 4-((2-hydroxypropylsulfonyl)methyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((2-hydroxypropylsulfonyl)methyl)benzoic acid via Procedure G. The crude product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-hydroxypropylsulfonyl)methyl)benzamide. MS (Q1) 445.3 (M)+.
Reaction SMILES: [F:1][C:2]([F:23])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][NH:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[F:24][C:25]([F:30])([F:29])[CH:26]1[O:28][CH2:27]1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C>[F:1][C:2]([F:23])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:27][CH:26]([OH:28])[C:25]([F:30])([F:29])[F:24])[C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: FC(F)(F)C1CO1
Reactant: N#Cc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: N#Cc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Temperature: 50 °C
Yield: 75.6 %

Procedure:
The benzonitrile (1.58 g, 4.88 mmol) from EX-576A and 1,1,1-trifluoro-2,3-epoxy-propane (546 mL, 6.34 mmol) were dissolved in 4 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (304 mg, 0.49 mmol) was added, and the stirred solution was warmed to 50° C. overnight. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine, dried over MgSO4 and evaporated. The crude product was purified by MPLC on silica gel eluting with dichloromethane to give 1.61 g (76%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]-(3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile product as a clear oil, greater than 98% by reverse phase HPLC. HRMS calcd. for C19H15F7N2O2: 437.1100 [M+H]+, found: 437.1097. 1H NMR (CDCl3) δ3.60-3.69 (m, 1H), 3.86 (d, 1H), 4.32 (bs. 1H), 4.69 (q, 2H), 5.86 (dt, 1H), 6.85-6.95 (m, 2H), 6.97-7.01 (m, 2H), 7.04-7.12 (m, 2H), 7.23-7.37 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:39])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[CH2:35][C@H:34]([OH:36])[CH2:33][C@H:32]3[CH2:37][OH:38])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N1C=CC=CC=1.[C:49](OC(=O)C)(=[O:51])[CH3:50]>ClCCl.Cl>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:40])[C:14]([N:16]([CH3:17])[C:18]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[CH:22][C:21]([N:31]3[CH2:35][C@H:34]([OH:36])[CH2:33][C@H:32]3[CH2:37][O:38][C:49](=[O:51])[CH3:50])=[N:20][CH:19]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(N2C[C@H](O)C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC[C@@H]1C[C@@H](O)CN1c1cc(-c2ccccc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.9 %

Procedure:
To a solution of 1.5 g (2.4 mmol) (2S,4R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide and 0.4 ml (5 mmol) pyridine in 24 ml dichloromethane were added dropwise at room temperature 0.22 ml (2.4 mmol) acetic anhydride. After stirring at room temperature for 20 h the reaction mixture was diluted with a 0.1 M aqueous hydrochloric acid solution and extracted with 3 portions of dichloromethane. The combined organic extracts were washed with a 2 M aqueous sodium carbonate solution, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 1.1 g (71%) of the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]([O:16][C:17]([NH:19][C@H:20]([C:22](O)=[O:23])[CH3:21])=[O:18])([CH3:15])([CH3:14])[CH3:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[C:12]([O:16][C:17]([NH:19][C@H:20]([C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)=[O:23])[CH3:21])=[O:18])([CH3:14])([CH3:15])[CH3:13]
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 5-amino-2-oxindole (800 mg, 5.4 mM) and N-tert-butoxycarbonylalanine (1020 mg, 5.4 mM) in dichloromethane (50 ml) were added benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (2800 mg, 5.6 mM) and N-methylmorpholine (1.2 ml, 11 mM). The mixture was stirred for 15 h at room temperature. Then the solvent was evaporated under vacuum, the residue suspended in water and extracted 3 times with ethyl acetate. The collected extracts were evaporated and then purified by flash chromatography on silica gel using as eluant cyclohexane/ethylacetate 1:9. Thus pure 5-(N-tert-butoxycarbonylalanylamino)-2-oxindole was obtained (600 mg). A solution of the above compound (250 mg, 0.97 mM) in trifluoroacetic acid (15 ml) was maintained for 1 h at room temperature. Then the solution was concentrated under vacuum and ether added to precipitate 5-(alanylamino)-2-oxindole.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](O)=[O:9])[CH:2]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl>[CH3:16][O:15][N:14]([CH3:13])[C:8](=[O:9])[CH2:7][C:3]1[CH:2]=[C:1]([CH3:11])[CH:6]=[CH:5][CH:4]=1
Reactant: CNOC
Reactant: Cc1cccc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1cccc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A mixture of 2-m-tolylacetic acid (1 g, 6.7 mmol), N,O-dimethylhydroxylamine hydrochloride (654 mg, 6.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.28 g, 6.7 mmol), hydroxybenzotriazole (910 mg, 6.7 mmol) and triethylamine (3.38 g, 33.5 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. When TLC indicated that 2-m-tolylacetic acid was consumed, the reaction mixture was diluted with water (30 mL), and extracted with EtOAc (30 mL×3). The combined organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE: EtOAc=10:1) to afford N-methoxy-N-methyl-2-m-tolylacetamide (900 mg, yield 70%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14]C(C)(C)C)=[O:13])[N:11]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1
Reactant: CC(C)(C)OC(=O)c1csc(-c2ccccn2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1csc(-c2ccccn2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-(pyridin-2-yl)thiazole-4-carboxylate 7.3 (340 mg, 1.3 mmol) in commercial anhydrous CH2Cl2 (5 mL) at RT was added TFA (0.93 mL, 13 mmol) under N2. The mixture was stirred at RT overnight. The mixture was diluted with CH2Cl2 (25 mL), washed with an aqueous solution of NaHSO3 10% (5×25 mL), brine (25 mL) and then water (25 mL). The organic layer was dried over MgSO4 and evaporated to afford title product as a yellow oil. Yield: 250 mg (94%). LCMS: P=93%, rt=3.03 nm, m/z=207.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[C:5]([CH:6]=[O:7])=[C:4]([OH:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C=O)C>[Cl:10][C:8]1[CH:9]=[C:2]([Cl:1])[CH:3]=[C:4]([O:11][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cc(Cl)cc1OCc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
A solution of 13.77 g (72.5 mmol) of 4,6-dichloro-2-hydroxybenzaldehyde in 100 ml of DMF was stirred and 12.02 g (87 mmol) of K2CO3 was added. This mixture was heated to ~70° C. for 60 minutes, then 11.7 ml of 4-fluorobenzyl bromide was added. The resulting solution was stirred at 70° C. for 3.5 hours, then this was poured onto ice H2O (1.5 l), filtered and washed with H2O, and recrystallized from Et2O/petroleum ether. Yield: 17.88 g (83%) of off-white crystals, m.p. 107°-108° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21](=[O:26])(=[O:25])[N:22]([CH3:24])[CH3:23])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:31][NH2:32]>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:31][NH:32][C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:21](=[O:25])(=[O:26])[N:22]([CH3:23])[CH3:24])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:3]
Reactant: CCOC(=O)c1nc(-c2ccccc2S(=O)(=O)N(C)C)n(C)c(=O)c1O
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: CN(C)S(=O)(=O)c1ccccc1-c1nc(C(=O)NCc2ccc(Cl)c(Cl)c2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 2-(2-dimethylsulfamoyl-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.076 g, 0.2 mmol) and 3,4-dichlorobenzylamine (0.13 mL, 1.0 mmol). The title product was obtained as white needles (0.0569 g, 56% yield). 1HNMR (500 MHz, CDCl3) δ: 11.93 (1H, s), 7.91 (1H, dd, J=7.32 Hz), 7.74 (1H, t, J=5.80 Hz), 7.72–7.67 (2H, m), 7.38 (2H), d, J=7.93 Hz), 7.32 (1H, d, J=1.83Hz), 7.11 (1H, dd, J=8.24, 1.83 Hz), 4.60 (1H, dd, J=15.26, 7.02 Hz), 4.41 (1H, dd, J=15.26, 5.80 Hz), 3.24 (3H, s), 2.69 (6H, s). HRMS (ESI) calcd for C21H21SCl2N4O5 (M+H): 511.0610; found: 511.0612.