Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1.CO.[OH-].[K+].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([N:16]3[CH2:22][C:21]4[CH:23]=[C:24]([C:27]5[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=5)[CH:25]=[CH:26][C:20]=4[O:19][CH2:18][CH2:17]3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)CN(c2ncnc(C)c2Cc2ccc(F)cc2)CCO3)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ncnc(N2CCOc3ccc(-c4ccc(C(=O)O)cc4)cc3C2)c1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.3 %

Procedure:
To a solution of methyl 4-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate (1.0 g, 2.0 mmol) in 1:1 methanol and THF (10 mL) was added drop wise 2N aqueous potassium hydroxide (8 mL). The reaction mixture was stirred at room temperature for 18 h and then refluxed for 90 min. The mixture was cooled by adding ice, and the pH adjusted to 6 with 2N aqueous hydrochloric acid. The precipitate was filtered, washed with water, azeotroped with toluene (20 mL), and dried to afford 4-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoic acid (0.97 g, 100% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([OH:12])=[C:9]([Br:11])[CH:10]=1)=[O:4].[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([Br:11])[C:8]([O:12][CH2:19][C:15]2[N:14]([CH3:13])[CH:18]=[CH:17][N:16]=2)=[N:7][CH:6]=1
Reactant: Cn1ccnc1CO
Reactant: COC(=O)c1cnc(O)c(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OCc2nccn2C)c(Br)c1
Reaction time: 1 h
Yield: 27.1 %

Procedure:
5-Bromo-6-hydroxy-3-pyridinecarboxylic acid methyl ester (1.0 g, 4.3 mmol) was suspended in tetrahydrofurane, 1-methyl-1H-imidazole-2-methanol (0.72 g, 6.5 mmol) and triphenylphosphine was added (1.70 g, 6.5 mmol). To this mixture was added with stirring diisopropyl-azodicarboxylate (1.35 mL, 6.5 mmol) at room temperature. Stirring was continued for 1 h at room temperature, solvent was removed and the residue was purified by chromatography with heptane/ethylacetate/methanol on silica gel to yield 0.38 g of the title compound as a colorless solid, MS (ISP) 326.0, 328.0 (M+H)−.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]([C:11]1[S:12][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][N:15]=1)[NH2:10].O>CO>[C:16]([C:13]1[S:12][C:11]([NH:9][N:10]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:15][N:14]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)c1nnc(NN)s1
Solvent: CO
Solvent: O
Product: CC(C)(C)c1nnc(NN=Cc2ccccc2)s1
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
A solution of benzaldehyde (5.3 g) in methanol (25 ml) was added to a solution of 2-hydrazino-5-t-butyl-1,3,4-thiadiazole (8.5 g) in methanol (40 ml). The mixture was stirred for 30 minutes, poured into water (100 ml) and filtered. The solid was crystallised from ethanol to give benzaldehyde 5-t-butyl-1,3,4-thiadiazolyl hydrazone (8.2 g, 63%) as a white powder, mp 195°-196° C.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]([CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:15]2[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=O)C1C=CC=CC=1.C(O)C>O1CCCC1.[C].[Pd]>[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[N:17]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:16]([CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])=[C:15]2[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(NC(=O)OCc3ccccc3)ccc2c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(N)ccc2c1=O
Yield: 87 %

Procedure:
To a mixed solution of 6-benzyloxycarbonylamino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (synthesized according to the method similar to that in Example 110 (1)) (0.45 g, 0.81 mmol) in tetrahydrofuran (20 ml) and ethanol (20 ml) was added 5% palladium-carbon (0.1 g). The obtained mixture was hydrogenated, at ambient temperature and atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration to give 6-amino-3-tert-butoxycarbonylaminomethyl-2isobutyl-4-phenyl-1(2H)-isoquinolinone (0.31 g, 87.0%) as crystals.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([CH3:17])=[CH:12][N:11]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:9][C:10]1[N:15]=[C:14]([NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])[C:13]([CH3:17])=[CH:12][N:11]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CNc1nc(Cl)ncc1C
Temperature: 40 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
Glycine ethyl ester hydrochloride (157 mg) was added to a solution of 2,4-dichloro-5-methylpyrimidine (184 mg) and diisopropylethylamine (486 μL) in acetonitrile (3 mL) while the solution was cooled with ice. The mixture was stirred at 40° C. overnight. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 to 1:1) to give 205 mg (81% yield) of the desired product as a white amorphous.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4](Cl)=[N:3]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.[I-].[Na+]>Cl>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:5][C:4]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:3]1
Reactant: CN(C)Cc1cccc(OCCCNc2nc(Cl)nn2C)c1
Reactant: C1CCNC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Product: CN(C)Cc1cccc(OCCCNc2nc(N3CCCC3)nn2C)c1
Yield: 61 %

Procedure:
A mixture of 1-methyl-3-chloro-N5 -[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-1H-1,2,4-triazole-5-amine (0.4 g), pyrrolidine (0.71 g) and sodium iodide (0.3 g) was heated at 180° in an autoclave for 16 hr. The reaction mixture was dissolved in dilute hydrochloric acid, washed with ethyl acetate, basified with sodium hydroxide and extracted with toluene. The toluene extracts were fractionally distilled to give the title compound as a pale yellow oil (0.27 g) b.p. 210° (0.04 mm). TLC silica; ethyl acetate:isopropanol: water:0.88 ammonia 25:15:8:2; Rf 0.6.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:9][CH:8]=2)=[O:4].[Li+].[OH-].O>C1COCC1>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:15][O:14][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[NH:6]2
Reactant: COC(=O)c1cc2c(OCC(C)(C)C)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)COc1cccc2[nH]c(C(=O)O)cc12
Reaction time: 48 h

Procedure:
4-(2,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid methyl ester 90 (270 mg, 1.03 mmol) is dissolved in 20 ml of THF. A 2M-solution of LiOH in water (5.2 ml, 11 mmol) is added and the mixture is stirred for 48 hours. The solvent is then evaporated and the residue is partitioned between water and ether. The water layer is acidified with HCl and extracted twice with EtOAc. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:23][N:24](C)C)[C:14](=O)[CH:15]3[CH2:20][CH3:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:28]N>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:23]=[N:24][NH:28][C:14]=2[CH:15]3[CH2:20][CH3:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCC1C(=O)C(=CN(C)C)C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCC1c2[nH]ncc2C2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 9-(4-chloro-benzenesulfonyl)-2-dimethylaminomethylene-4-ethyl-9-aza-bicyclo[3.3.1]nonan-3-one crude mixture in glacial acetic acid (1 mL) followed by hydrazine monohydrate (0.5 mL). The reaction mixture was stirred at 100° C. for 1 h after which the solution was cooled to room temperature and quenched by the addition of a saturated aqueous NaHCO3 solution (until pH>7). The resulting solution was extracted with EtOAc (3×20 mL), the organic extracts were combined, dried (Na2SO4), filtered, concentrated and purified by silica gel column chromatography and preparative HPLC to give 12-(4-chloro-benzenesulfonyl)-7-ethyl-4,5,12-triaza-tricyclo[6.3.1.02,6]dodeca-2(6),3-diene as a white solid. Retention time (min)=1.896, Method [1], MS (ESI) 366.1 (M+H); 1H-NMR (300 MHz, CDCl3) δ 7.81-7.78 (m, 2H), 7.47-7.43 (m, 2H), 7.25 (s, 1H), 5.15 (b s, 1H), 4.27 (d, J=4.95 Hz, 1H), 2.56 (dd, J=9.34, 5.49 Hz, 1H), 2.10-1.22 (m, 8H), 1.02 (t, J=7.14 Hz, 3H) (major diastereomer); 1H-NMR (300 MHz, CDCl3) δ 7.68-7.66 (m, 2H), 7.35-7.32 (m, 2H), 7.22 (s, 1H), 5.28 (b s, 1H), 4.31 (d, J=5.5 Hz, 1H), 2.80-2.73 (m, 1H), 2.05-1.21 (m, 8H), 1.06 (t, J=7.69 Hz, 3H) (minor diastereomer).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)NCCCSc1ccncc1
Yield: 72.2 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 1.15 ml (4.96 mmol) of lauroyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.05 g of the desired compound (72.2%, colorless powder), mp: 71.0°-72.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C1(=O)O[CH2:20][CH2:19][O:18]1>CN(C=O)C>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([O:1][CH2:20][CH2:19][OH:18])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc2cc[nH]c2c1
Temperature: 125 °C

Procedure:
A mixture of 6-hydroxyindole (2.66 g, 20 mmol) and K2CO3 (3.04 g, 22 mmol) was stirred in DMF (10 mL) at 80° C. for 10 min. A solution of ethylene carbonate (1.94 g, 22 mmol) in DMF (4 mL) was added and the mixture was heated at 125° C. for 3 h. The mixture was concentrated, diluted with water, and extracted with toluene. The organic phase was washed with 1 M aqueous Na2CO3 and brine. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica using EtOAc/toluene (1:4→36:65) as eluent. Yield 1.02 g (29%); mp 74-77° C.; HRMS m/z calcd for C10H11NO2(M)+177.0790, found 177.0784. Anal. (C10H11NO2) C, H, N.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1CCNC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCCC1
Yield: 16 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of pyrrolidine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH2:21][OH:22])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=1.Cl[C:24]1[CH:25]=[C:26]2[N:33]([CH3:34])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=1)[CH2:21][O:22][C:24]1[CH:25]=[C:26]2[N:33]([CH3:34])[CH2:32][CH2:31][N:27]2[C:28](=[O:30])[N:29]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccnc(C(F)(F)F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccnc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (9.37 mg, 0.234 mmol), (3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol (44.9 mg, 0.156 mmol) in THF (8 mL) and 7-chloro-1-methyl-2,3-dihydroimidaz-o[1,2-c]pyrimidin-5(1H)-one (29 mg, 0.156 mmol).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br)([O-:11])=[O:10]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)[CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Product: O=[N+]([O-])c1cccc(CN(Cc2cccc([N+](=O)[O-])c2)c2ccc(F)cc2)c1

Procedure:
4-Fluoroaniline and 3-nitrobenzyl bromide were processed using the method described in Example 32A to afford the title compound. LC/MS Rt 2.15 m/z 423 (M+CH3CN)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].OO.S([O-])([O-])(=[O:29])=S.[Na+].[Na+].C(O)C.O>C(O)C>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:29])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 0.17 h
Yield: 287 %

Procedure:
Vanadium(IV) acetylacetonate (40 mg) was dissolved in ethanol (150 ml), to which 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylthio]benzimidazole (monohydrate) (20.0 g) was added and then 35% aqueous solution of hydrogen peroxide (6.14 g) was added dropwise at 20°-25° C., and the mixture was allowed to react at 20°-25° C. for about 5 hours. After completion of the reaction, a solution of sodium thiosulfate (2.7 g/16 ml) was added to the reaction mixture and stirred vigorously for about 10 minutes. The crystals were collected by filtration and washed with an ice-cooled mixture of ethanol-water (8:2). The crystals thus obtained were treated with a mixture of ethanol-water (9:1, 90 ml), heated (60°-70° C.), and stirred so that the crystals were dissolved, then the insoluble matters were removed by hot filtration. The filtrate was ice-cooled for crystallization and the crystals were collected by filtration, washed with ice-cooled ethanol-water mixture (8:2) and dried in vacuo, to give white needles of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylsulfinyl]benzimidazole (18.1 g). (yield: 91.0%).
Reaction SMILES: [CH2:1]([CH:9]([C:15](OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].IC[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29]>>[F:32][C:27]([F:33])([C:28]([F:29])([F:30])[F:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:15][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C=CCCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: FC(F)(F)C(F)(F)CCCCCCI
Product: C=CCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with the diethyl 2-(7-octenyl)malonate prepared in Example 5 and the 1-iodo-7,7,8,8,8-pentafluorooctane prepared in Example 4, the same procedure as shown in Example 5 was repeated to give ethyl 2-(7,7,8,8,8-pentafluorooctyl)-9-decenoate.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:12]=[CH:11][NH:10][C:4]=2[N:5]=[C:6]([O:8][CH3:9])[N:7]=1.[CH:13]1([C@H:18]([N:22]2[CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=[N:23]2)[CH2:19][C:20]#[N:21])[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH:13]1([C@H:18]([N:22]2[CH:26]=[C:25]([C:2]3[C:3]4[CH:12]=[CH:11][NH:10][C:4]=4[N:5]=[C:6]([O:8][CH3:9])[N:7]=3)[CH:24]=[N:23]2)[CH2:19][C:20]#[N:21])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1nc(Cl)c2cc[nH]c2n1
Reactant: CC1(C)OB(c2cnn([C@H](CC#N)C3CCCC3)c2)OC1(C)C
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(-c2cnn([C@H](CC#N)C3CCCC3)c2)c2cc[nH]c2n1
Temperature: 100 °C

Procedure:
4-Chloro-2-methoxy-7H-pyrrolo[2,3-d]pyrimidine (0.4 g, 2.18 mmol, Toronto Research Chemicals) and (R)-3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile (0.824 g, 2.61 mmol, prepared as described in Org. Lett., 2009, 11(9), 1999-2002.) were dissolved in 1,4-dioxane (4 mL) and potassium carbonate (0.903 g, 6.54 mmol) in water (2 mL) was added. The mixture was degassed and tetrakis(triphenylphosphine)palladium(0) (0.126 g, 0.109 mmol) was added. The reaction mixture was heated to 100° C. for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate three times. The combined extracts were dried over sodium sulfate, decanted and concentrated. Flash column chromatography, eluting with a gradient from 0-10% MeOH in methylene chloride was used to purify the product (670 mg, 91%). 1H NMR (300 MHz, CD3OD): δ 8.59 (s, 1H), 8.35 (s, 1H), 7.24 (d, 1H), 6.81 (d, 1H), 4.47 (dt, 1H), 4.04 (s, 3H), 3.21 (dd, 1H), 3.10 (dd, 1H), 2.62-2.44 (m, 1H), 2.02-1.86 (m, 1H), 1.81-1.20 (m, 7H); LCMS (M+H)+: 337.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[C:13](=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S.CI.[N:30]1C=CC=CC=1>CCN(CC)CC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24](=[NH:30])[NH2:25])=[CH:22][CH:23]=2)[C:13](=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Reactant: c1ccncc1
Agent: S
Solvent: CCN(CC)CC
Solvent: CI
Product: N=C(N)c1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Reaction time: 16 h

Procedure:
A solution of 4-(4-cyanobenzyl)-3-oxopiperazine-1-carboxylic acid benzyl ester (2.4 g, 6.87 mmol) in 30 mL of pyridine and 3 ml of Et3N is saturated with H2S. The resulting mixture is sealed and stirred for 16 hours. After this time, the solution is concentrated. The residue is dissolved in 30 mL of acetone and methyl iodide (19.4 g, 137 mmol) is added. The solution is refluxed for 2 hours. After this time, the solution is concentrated. The residue is dissolved in MeOH (40 mL) and NH4OAc (5.0 g, 65 mol) is added. The solution is reluxed for 3 hours. After this time, the solution is concentrated. The crude product is purified by RP-HPLC eluting in a gradient of CH3CN to 60% CH3CN/H2O(0.1%TFA). The appropriate collected fractions are lyophilized to give the product as a white foam. MS (FAB) m/z 367, (M+H).
Reaction SMILES: [CH:1]1([OH:13])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH:26]([O:28][CH2:29][CH3:30])=[CH2:27]>CC(OC)(C)C>[CH2:26]([O:28][CH:29]([O:13][CH:1]1[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1)[CH3:30])[CH3:27]
Reactant: OC1CCC=CCCC=CCCC1
Reactant: C=COCC
Agent: CCOC(C)OC1CC/C=C/CC/C=C/CCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: OC1CC/C=C/CC/C=C/CCC1
Solvent: COC(C)(C)C
Solvent: O
Product: CCOC(C)OC1CCC=CCCC=CCCC1
Temperature: 40 °C

Procedure:
To a mechanically stirred mixture of E,E-4,8-cyclododecadien-1-ol (99% (E,E)/1% (E/Z), 2.0 g, 11 mmol), toluene sulphonic acid monohydrate (0.15 g, 2 mmol) and MTBE (methyl terbutyl ether, 20 mL) was added drop wise ethyl vinyl ether (5 g) over 15 minutes. The reaction mixture was heated at reflux at 40° C. for 1 hour, then diluted with MTBE, washed with aqueous NaHCO3, water and brine. The solvent was evaporated and the product (4.5 g) purified by flash distillation (Kugelrohr, 86° C., 0.1 mbar) and liquid chromatography (silica gel 100 g; eluent=heptane/ethyl acetate 95/5).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:26])[N:7]([CH:14]1[CH2:19][CH:18]([O:20][C:21](=[O:23])[CH3:22])[C:17](=[O:24])[NH:16][C:15]1=[O:25])[C:8]2=[O:13])([O-:3])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:47])(=O)=O)=CC=1>O1CCCC1>[F:47][C:14]1([N:7]2[C:6](=[O:26])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])[C:8]2=[O:13])[CH2:19][CH:18]([O:20][C:21](=[O:23])[CH3:22])[C:17](=[O:24])[NH:16][C:15]1=[O:25]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(=O)OC1CC(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)NC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC1CC(F)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 1-tert-butoxycarbonyl]-3-(4-nitro-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (2.0 g, 4.3 mmol) in tetrahydrofuran (20 mL) is added sodium bis(trimethylsilyl)amide (4.3 mL, 4.3 mmol, 1.0 M) in tetrahydrofuran at −78° C. After 10-30 minutes, N-fluorobenzenesulfonimide (1.1 g, 4.3 mmol) is added to the mixture. The mixture is warmed to room temperature and the solvent is removed in vacuo. The residue is stirred with ethyl acetate (10 mL) and hydrochloric acid (10 mL, 1N) for 1 hour, the organic layer is separated, and the solvent is removed in vacuo to give 3-fluoro-3-(4-nitro-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine which is further purified by column chromatography.