Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])O.[Na+].COCCOC>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.O>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:32]2[C:27]([Cl:26])=[N:28][CH:29]=[CH:30][CH:31]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN(Cc1cc(-c2cccnc2Cl)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-chloropyridin-3-yl)boronic acid (237 mg), sodium hydrogencarbonate (126 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 100° C. for 3 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:4) to give the title compound as a colorless oil (yield 280 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22]Br.CCOC(C)=O>CN(C=O)C.O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc(O)c(Cl)c1N
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(COc1ccc(C(C)=O)c(N)c1Cl)OC
Temperature: 65 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
1-(2-Amino-3-chloro-4-hydroxyphenyl)ethanone (40 g, 215 mmol) was dissolved in DMF (360 ml). Cesium carbonate (140 g, 430 mmol) was added, followed by bromoacetaldehyde dimethyl acetal (54.5 g, 323 mmol). The mixture was then vigorously stirred at 65° C. for 24 h. Upon cooling to room temperature, EtOAc (1 L) and H2O (1 L) were added to the mixture. The organic layer was extracted with EtOAc (1×400 ml). The combined organic layer was washed with aqueous 3% LiCl solution (2×1 L), brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography to give 1-[2-amino-3-chloro-4-(2,2-dimethoxyethoxy)phenyl]-ethanone as a white solid (39 g, 67% yield).
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1C(=O)C2=CC=CC=C2C1=O>CN(C=O)C>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: Sc1nc2ccccc2o1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCCCCCCCCSc1nc2ccccc2o1
Temperature: 60 °C

Procedure:
To a round bottom flask with 2-mercaptobenzoxazole (2.14 g, 14.2 mmol) and DMF (100 mL) at room temperature was added K2CO3 (2.61 g, 18.9 mmol) followed by N-(8-bromooctyl)phthalimide (4.00 g, 11.8 mmol). The resulting solution was heated to 60° C. for 0.5 h and then cooled back to room temperature. At this point, the reaction mixture was quenched with H2O (100 m]L) and then diluted with EtOAc (600 mL). The organic layer was washed with 1 N HCl (60 mL), sat. aq. NaHCO3 (60 mL), and brine (60 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 20% EtOAc/petroleum ether gradient) to afford the thioether intermediate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][CH:11]([OH:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:13][CH:11]([CH2:10]/[CH:9]=[CH:8]/[C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH3:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)C/C=C/c1cncc(Br)c1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)C/C=C/c2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring solution of (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol (3.14 g, 13.0 mmol) in dry pyridine (30 mL) at 0° C. was added p-toluenesulfonyl chloride (3.71 g, 19.5 mmol). The reaction mixture was stirred for 24 h at ambient temperature. The pyridine was removed by rotary evaporation. Toluene (50 mL) was added to the residue and subsequently removed by rotary evaporation. The crude product was stirred with a saturated solution of sodium bicarbonate (100 mL) and extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give (4E)-5-(5-bromo-3-pyridyl)-4-penten-2-ol p-toluenesulfonate. The resulting tosylate was treated with excess methylamine (40% solution in water), ethyl alcohol (10 mL), and stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate and filtered. Removal of solvent by rotary evaporation followed by column chromatography over silica gel eluting with chloroform-methanol (95:5, v/v) produced 1.50 g (45.0%) of a pale-yellow oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>N1CCNCC1.O>[CH2:24]([O:23][C:21]([N:1]1[CH2:4][CH:3]([C:5]([OH:7])=[O:6])[CH2:2]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CNC1
Agent: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
To azetidine-3-carboxylic acid (0.50 g), potassium carbonate (0.82 g), dioxan (5 mL), water (10 mL) was added benzyl chloroformate (0.74 mL) at room temperature for 6 h under nitrogen. Piperazine (5 drops) was then added. After ½ h, the dioxan was removed in vacuo and the residue diluted with 2M hydrochloric acid (25 mL). After extracting with ethyl acetate (35 mL), the organic layer was washed with brine (10 mL) and dried (MgSO4). Solvent removal in vacuo gave Intermediate 13 as a colourless oil (1.07 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.56 g of a 50% oil dispersion, 33.0 mmol) is suspended in tetrahydrofuran (85 mL). To this is added a solution of N-[4-methoxybenzenesulfonyl]-benzylamine (9.0 g, 32.5 mmol) also in tetrahydrofuran (85 mL), and the reaction is stirred for 30 minutes at room temperature. Then ethyl bromoacetate (5.40 mL, 48.8 mmol) is added, and the reaction is stirred overnight at room temperature. The reaction is quenched with a small amount of water, and all the solvent is removed. The crude mixture is partitioned between ethyl acetate and water, the aqueous phase is extracted several times with ethyl acetate, the combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (30% ethyl acetate/hexane) to give ethyl 2-[[4-methoxybenzenesulfonyl](benzyl)amino]acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([NH2:10])=[S:9])[CH:2]=1.Br[CH2:12][C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=O>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[S:9][CH:12]=[C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[N:10]=2)[CH:2]=1
Reactant: NC(=S)Nc1cccnc1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2csc(Nc3cccnc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Pyridin-3-yl-thiourea (2.06 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.06 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with a small amount of diethylether and dried. m/z=298.0 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][OH:8])=[CH:2]1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:9][S:10]([O:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:12])=[O:11]
Reactant: OCCc1ccsc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCCc1ccsc1
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 65 %

Procedure:
To a solution of 5.0 g (7.8×10-3 mol) of 2-(3-thienyl)-ethanol (Aldrich Chemical) in 10 ml of dry, freshly distilled pyridine was added 3.62 ml (1.2 equiv.) of methanesulfonyl chloride in 20 ml of pyridine at 5°-10° C. The addition was carried out gradually, over a period of about 15-20 min. The reaction mixture was stirred overnight at room temperature and was quenched by pouring into a separatory funnel containing water and ether. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic extracts were extracted once with 10% hydrochloric acid, followed by water and drying over Na2SO4. Evaporation of the solvent afforded 5.3 g of a light brown oil (65% yield), and tlc (CHCl3) showed a single spot. Chromatographic purification on silica gel afforded a light yellow oil. Nmr (CDCl3, δ rel TMS) 2.9s, 3H; 3.1t, 2H; 4.4t, 2H; 7.0-7.4m, 3H. Ir (neat, ν, cm-1) 3100w, 2930w, 29202, 1415w, 1355s, 1335s, 1245w, 1173s, 1080w, 1055w, 970s, 955s, 903m, 850m, 825w, 795s, 775s, 740w. MS, 206.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
4-Nitrobenzenesulfonyl chloride (4.4 g) was added to a stirred solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (4.0 g) and pyridine (2.25 ml) in methylene chloride (80 ml) and stirred at ambient temperature for 16 hours. The reaction mixture was poured into saturated sodium bicarbonate solution. The organic layer was separated, washed with brine and dried over sodium sulfate. The solution was evaporated under vacuum and triturated with diethylether and filtered to remove undesired solids. The diethylether liquors were evaporated under vacuum and dissolved in methylene chloride before purification by column chromatography on silica eluting with ethyl acetate/isohexane (20/80). The fractions containing the expected product were combined and evaporated under vacuum to give tert-butyl 3-[(4-nitrophenyl)sulfonyloxy]piperidine-1-carboxylate as a yellow crystalline solid (6.77 g); 1H NMR Spectrum: (CDCl3) 1.43 (s, 9H), 1.40-1.54 (m, 1H), 1.70-1.94 (m, 3H), 3.22-3.60 (m, 4H), 4.67 (m, 1H), 8.11 (s, 2H), 8.40 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](OCC)=[O:4].FC(F)(CCC1C=CC=CC=1)CO>>[F:1][C:2]([F:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)(F)c1ccccc1
Agent: OCC(F)(F)CCc1ccccc1
Product: OCC(F)(F)c1ccccc1

Procedure:
Obtained from Intermediate 5 (13.2 g, 66 mmol) by the procedure described in Intermediate 2. The title compound was obtained (6.88 g, 66%) as oil.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1)#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Reaction time: 16 h

Procedure:
A solution of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, (Example 1) 5.63 g (0.048 mol), in 100 mL of methanol saturated with gaseous ammonia is treated with 0.5 g of Raney nickel 190 30 and hydrogen gas in a shaker at 50 pounds per square inch (psi) and 40° C. After 16 hours, thin layer chromatography indicates no starting nitrile present. The suspension is cooled, filtered through filter aid, and concentrated to an oil. This crude oil is purified by flash chromatography on silica gel with 30:20:1 (ethyl acetate:methanol:ammonium hydroxide) as eluant to give 4.93 g of (4R-cis)-1,1-dimethylethyl 6-(2-aminoethyl)- 2,2-dimethyl-1,3-dioxane-4-acetate (98.2 area %) as a clear oil.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:13]1[NH:14][CH:15]=[C:16]([CH2:18][OH:19])[N:17]=1)[CH2:10][CH2:11][CH3:12].C(OCC)(=O)C>CN(C1C=CN=CC=1)C.O1CCOCC1.COCCO>[CH2:9]([C:13]1[NH:17][C:16]([CH2:18][OH:19])=[C:15]([I:1])[N:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1I
Reactant: CCCCc1nc(CO)c[nH]1
Agent: CN(C)c1ccncc1
Solvent: COCCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCc1nc(I)c(CO)[nH]1
Temperature: 50 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
4-DMAP (1.2 g; 10 mmol) and N-iodosuccinimide (25 g; 111 mmol) were added to a solution of 2-butyl-4-hydroxymethyl-imidazole (15.4 g; 100 mmol) in dioxane (210 ml) and 2-methoxyethanol (140 ml) and the mixture was stirred overnight at 50° C. Concentration gave 44.4 g of a brownish-yellow magma (theory; 28 g), which was further reacted without further purification. For characterisation, 2 g of the crude product were dissolved using ethyl acetate and washed with 5% NaHCO3 solution and saturated sodium chloride solution. Drying and concentration of the organic phases gave 1.2 g of a yellow solid [97% of theory; m.p.: 135°-40° C. (dec.); Rf : 0.24 (methylene chloride:methanol=10:1)].
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]=C)=[CH:19][CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])C.C[N+]1([O-])CC[O:30]CC1>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:11]([S:12]([CH3:15])(=[O:14])=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:25])=[CH:18][CH:19]=1)=[O:30]
Reactant: C=Cc1ccc(CN(CCCCCCC(=O)OCC)S(C)(=O)=O)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)N(CCCCCCC(=O)O)Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of ethyl-7-[(4-vinyl-benzyl)-methanesulfonyl-amino]-heptanoate (2.2 g, 6.0 mmol) in dioxane (45 mL) was added to a solution of N-methylmorpholine N-oxide (1.47 g, 12.5 mmol) in water (45 mL). Osmium tetroxide (4.6 mL, 2.5 wt % in 2-methyl-2-propanol) was added and the mixture was stirred at room temperature for 1 h. The reaction was quenched with 1N HCl (50 mL) and the aqueous solution was extracted with CH2Cl2. The organic layer was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in 35% aqueous THF (100 mL) and NalO4 (1.41 g, 6.59 mmol) was added. The mixture was stirred at room temperature for 2 h and was diluted with EtOAc and water. The organic solution was washed with water (1×) followed by brine (1×), dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound (1.9 g) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 10.0 (s, 1H), 7.82-7.90 (d, 1H), 7.50-7.59 (d, 2H), 5.30 (s, 2H), 4.45 (s, 2H), 4.054.18 (m 3.12-3.22 (m, 2H), 2.86 (s, 3H), 2.19-2.30 (m, 2H), 1.42-1.62 (m, 6H), 1.1 3H); MS 387 (M+18).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:16])[C:14]=1[F:15])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:17][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].CCN=C=NCCCN(C)C.C1C(NN)=NN=C(N(CCO)CCO)C=1.Cl.Cl>N1C=CC=CC=1.C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:16][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][CH:25]=[N:26][C:18]=3[CH3:17])[C:14]=1[F:15])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Nc1c(F)c(Cl)cc2c1[nH]c1cnccc12
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NNc1ccc(N(CCO)CCO)nn1
Solvent: c1ccncc1
Solvent: O=CO
Product: Cc1ncccc1C(=O)Nc1c(F)c(Cl)cc2c1[nH]c1cnccc12
Temperature: 100 °C

Procedure:
A solution of 6-chloro-7-fluoro-9H-β-carbolin-8-ylamine (100 mg, 0.424 mmol) in pyridine (2.5 ml) was stirred at RT. 2-methyl nicotinic acid (70 mg, 0.509 mmol) was added, followed by EDCI (130 mg, 0.678 mmol). The suspension was stirred at 100° C. for a day. The pyridine was removed under reduced pressure and the resulting dark oil was triturated with saturated aqueous NaHCO3. The precipitate which formed was filtered and washed with MeOH. The material was treated with 2M HCl in Et2O to yield a gray solid, the di-HCl salt N-(6-chloro-7-fluoro-9H-β-carbolin-8-yl)-2-methyl-nicotinamide (110 mg). 1H-NMR (300 MHz, DMSO-d6): δ 13.15 (s, 1); 11.03 (s, 1); 9.33 (s, 1); 8.99-8.97 (m, 1); 8.92-8.89 (m, 1); 8.79-8.73 (m, 2); 8.50 (m, 1); 7.70 (m, 1); 2.80 (s, 3). HCOOH standard conditions. DAD Rf=0.91 min. MS (M+H+): 355.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][SH:5].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](S(C)(=O)=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([S:5][CH2:4][C:3]([O:7][CH3:8])=[O:6])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CSC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To sodium hydride (60% wt. suspension in mineral oil, 108 mg) in dry DMF (5 ml) was added methyl thioglycolate (160 ul) dropwise at 0° C. After 30 minutes added 4-methanesulfonyl-piperidine-carboxylic acid tert-butyl ester (500 mg) as a solution in DMF (1.5 ml) and the reaction mixture was warmed up to room temperature over 5 hours. Aqueous work-up and purification on silica yielded 4-methoxycarbonylmethylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (414 mg).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16]([C:20]1[O:24][N:23]=[C:22]([OH:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CS(C)=O.C(=O)(O)[O-].[Na+]>O.CO>[C:16]([C:20]1[O:24][N:23]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[C:22](=[O:25])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(O)no1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2oc(C(C)(C)C)cc2=O)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 93.2 %

Procedure:
413.3 g of ethyl 4-chloro-3-nitrobenzoate, 305 g of 5-t-butyl-3-hydroxyisooxazole and 1 liter of dimethyl sulfoxide were mixed, and stirred. Thereto was added 300 g of sodium bicarbonate, and the reaction was run at 90° C. for 8 hours. Thereafter, the reaction mixture was cooled, and thereto were added 1.5 liters of methanol, and further 3 liters of water to precipitate crystals. These crystals were filtered off. Yield: 560.7 g, Percent yield: 93.2%.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[Li]CCCC.CCCCCC.[CH2:30]([N:34]([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[O:44])=[CH:41][CH:40]=1)[CH2:31][CH2:32][CH3:33].[NH4+].[Cl-]>CCCCCC.C1COCC1>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][C:8]=2[C:9]=1[CH:43]([C:42]1[CH:41]=[CH:40][C:39]([O:38][CH2:37][CH2:36][CH2:35][N:34]([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:46][CH:45]=1)[OH:44])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Reactant: CCCCN(CCCC)CCCOc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(O)c1ccc(OCCCN(CCCC)CCCC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
2.67 g of N-(2-butyl-1-benzofuran-5-yl)methanesulfonamide (II) (0.01 mol, 1 eq) is dissolved in 35 mL of n-hexane and 7 mL of 2.5 M BuLi hexane solution is added in 30 min during which the temperature is kept at 20° C. The reaction mixture is stirred for 2 hours at room temperature and then it is added to the solution of 4.37 g of 4-(3-dibutylamino-propoxy)-benzaldehyde (V) (0.015 mol, 1.5 eq) in 80 mL of THF. The reaction mixture is stirred at room temperature for 2 hours and then 40 mL of NH4Cl solution is added. After 15 min of stirring, the product is extracted with 2×40 mL of diethyl ether. The organic phase is concentrated and the crude product is purified by column chromatography (spheric silica; eluent:toluene:MTBE:methanol=50:40:10) to obtain 2.24 g of compound (VI) (40%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].Cl[C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:27](=[O:32])[C:28]([O:30][CH3:31])=[O:29]
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)C(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added TEA (0.141 mL, 1 mmol) and methyl 2-chloro-2-oxoacetate (0.09 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in hexane) afforded the title compound as a solid (0.12 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 1H). 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.60 (d, J=4.4 Hz, 2H), 4.18 (m, 1H), 3.85 (s, 3H); ESIMS m/z 512.22 ([M−H]−); IR (thin film) 1740, 1701, 1114, 808 cm−1.