Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12][N:11]2[CH2:23][CH:24]=[CH2:25])=[CH:6][CH:5]=1.C1(C)C=CC=CC=1.[OH-].[Na+].[C:35](Cl)(=[O:39])[O:36][CH2:37][CH3:38]>O.CCCCCC>[CH2:37]([O:36][C:35]([N:14]1[CH2:13][CH2:12][N:11]([CH2:23][CH:24]=[CH2:25])[C@H:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[CH2:15]1)=[O:39])[CH3:38]
Reactant: C=CCN1CCN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCN1CCN(C(=O)OCC)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.3 %

Procedure:
In distilled water (5 mL), (R)-2-(4-Chlorophenyl)-4-(phenylmethyl)-1-(2-propenyl)hexahydropyrazine dihydrochloride (400 mg, 1.0 mmol) produced in Example 18 was dissolved. To the solution, toluene (5 mL) and 30 wt % aqueous solution of sodium hydroxide (401 mg, 3.0 equivalents) were added. After the organic layer and aqueous layer were separated, the organic layer was washed twice with distilled water (5 mL) and then concentrated. To the concentrate, hexane (5 mL) and ethyl chlorocarbonate (163 mg, 1.5 equivalents) were added. The mixture was stirred at 25° C. for 24 hours. Further, ethyl chlorocarbonate (328 mg, 3.0 equivalents) was added, and the mixture was stirred at 40° C. for 24 hours. After the mixture was cooled to 5° C., the precipitated crystals were collected by filtration under reduced pressure, washed with hexane (2 mL), and dried under vacuum, to obtain 22.5 mg of the title compound as while crystals (yield: 7%, chemical purity: 92.5 area %). Further, the filtrate was concentrated. To the concentrate, toluene (5 mL) was added and the toluene was distilled away. The operation was repeated 3 times. The obtained concentrate was dried under vacuum, to obtain 212 mg of the title compound as while turbid oil (yield: 69%, chemical purity: 95.9 area %). The retention time in the chemical purity analysis method was 22.7 min.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Br:11]C1C(=O)C(Br)=CC(Br)(Br)C=1>C(Cl)Cl>[Br:11][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Solvent: ClCCl
Product: Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
A solution of 2-nitroaniline (5 g, 36.2 mmol) in CH2Cl2 (100 ml) was cooled to -10° C., and treated by 90% 2,4,4,6-tetrabromo-2,5-cyclohexadienone (19.8 g, 43.5 mmol) in 5 portions. The mixture was stirred at -10° C.-0° C. for 1 hr. After being warmed to room temperature, the reaction mixture was washed by 2N NaOH (60 ml) and brine (50 ml), dried over Na2SO4 and evaporated. Flash chromatography on silica gel (5% EtOAc/Hexane) gave 7.40 g (94%) of 17 as a yellow solid: mp 109-110 (lit. mp 112-113° C.); 1H NMR δ 8.27 (1H, d, J=2.3), 7.43 (1H, dd, J=8.9, 2.4), 6.73 (1H, d, J=8.8), 6.09 (NH, brs).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O.[CH3:23][N:24](C)C=O>O.C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[C:23]([C:8]1[CH:7]=[CH:6][C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][C:3]=1[O:2][CH3:1])#[N:24]
Reactant: CCOC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(C#N)c(OC)c1
Temperature: 80 °C

Procedure:
Ethyl (3-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)acetate (16.6 g) was dissolved in anhydrous dimethylformamide (100 mL). Zinc cyanide (3.4 g, 29 mmol) was added, and the solution was purged thoroughly with nitrogen. Tetrakis(triphenylphosphine)palladium (0) (5.6 g, 4.9 mmol) was then added and the reaction mixture was heated to 80° C. for 4 h. After allowing the reaction mixture to cool to ambient temperature and diluting with water (200 mL), ethyl acetate (400 mL) was added and the mixture was filtered to remove any solids. The filtrate was transferred to a separatory funnel, and the layers separated. The aqueous layer was re-extracted with ethyl acetate (2×100 mL). The organic layers were combined and dried over magnesium sulfate. The dry organics were then filtered and evaporated to dryness under reduced pressure and excess dimethylformamide was removed by evaporation in vacuo at 65° C. for 1.5 h to yield crude product. The crude product was purified through silica gel chromatography (ethyl acetate/hexanes, 2:3) to yield ethyl (4-cyano-3-methoxyphenyl)acetate. 1H NMR (500 MHz, DMSO-d6), δ 7.67 (d, J=8.0 Hz, 1H), 7.18 (s, 1H), 7.0 (d, J=8.0 Hz, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.89 (s, 3H), 3.78 (s, 2H), 1.19 (t, J=7.1 Hz, 3H); LC/MS (M+1)+=220.17; tR=1.36 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH3:12])[C:5]=2[C:4](=[O:13])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1>CN(C=O)C.[Cu]Br>[CH2:11]([C:6]1[C:5]2[C:4](=[O:13])[CH2:3][C:2]([CH3:1])([CH3:14])[CH2:10][C:9]=2[N:8]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:7]=1)[CH3:12]
Reactant: CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: Clc1ncccn1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cn(-c2ncccn2)c2c1C(=O)CC(C)(C)C2
Reaction time: 24 h
Yield: 25 %

Procedure:
A solution of 6,6-dimethyl-3-ethyl-4,5,6,7-tetrahydro-1H-indole-4-one (100 mg, 0.52 mmol), K2CO3 (87 mg, 0.63 mmol), copper (I) bromide (15 mg, 0.1 mmol) and 2-chloropyrimidine (71 mg, 0.63 mmol) in DMF (1 mL) were heated at 180° C. for 24 h. More copper (I) bromide (16 mg, 0.1 mmol) and 2-chloropyrimidine (50 mg) were added and heating continued for a further 24 h. The DMF was evaporated and the residue partitioned between water and DCM. The organic layer was separated and the aqueous phase extracted with DCM (2×). The combined organic layers were washed with water, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel, eluting with 4:1 isohexane: EtOAc, to afford the title compound (35 mg, 25%) as a yellow solid. mp 111-114° C. Found: C, 71.07; H, 6.98; N, 15.20%. Calc C16H19N3O: C, 71.35; H, 7.11; N, 15.60%. 1H NMR (360 MHz, d6-DMSO) δ 1.06 (6H,s), 1.15 (3H,t, J=7.4 Hz), 2.30 (2H,s), 2.67 (2H,q, J=7.3 Hz), 3.23 (2H,s), 7.44 (1H,t, J=4.8Hz), 7.47 (1H,s), 8.86 (2H,d, J=4.8Hz). MS (ES+) 270 (+1).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:33]1([CH2:36][N:37]([CH2:45]OC)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:35][CH2:34]1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[C@@H:15]([C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[CH2:45][N:37]([CH2:36][CH:33]1[CH2:34][CH2:35]1)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:41])[CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: COCN(CC1CC1)C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
(R)-4-Benzyl-3-(2-(4-chlorophenyl)acetyl)oxazolidin-2-one (2.0 g, 6.06 mmol) was added to a flask in DCM (75 ml) followed by TiCl4 (1.38 g, 7.28 mmol) and DIEA (0.823 g, 6.37 mmol). The reaction was allowed to stir for about 15 to about 20 minutes at −78° C. at which point tert-butyl cyclopropylmethyl(methoxymethyl)carbamate (1.57 g, 7.28 mmol) was added. The reaction allowed to stir for 5 minutes, and the −78° C. bath was replaced with a 0° C. bath. The reaction was then allowed to stir for 3 hours at room temperature. After the reaction was determined to be complete by HPLC, the reaction was cooled to 0° C. and quenched by the slow addition of aqueous NaHCO3 while stirring for 10 minutes. The organic layer was separated, and the aqueous layer was re-extracted (3×EtOAc). The combined organics were dried with MgSO4, filtered and concentrated. The crude residue was purified by column chromatography, eluting 6:1 to 2:1 hexane/EtOAc to give tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(4-chlorophenyl)-3-oxopropyl(cyclopropylmethyl)carbamate (2.70 g, 87%) as light brown oil. (LCMS (APCI+) [M-Boc+H]+ 412.9; Rt: 4.42 min)
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([OH:11])=O.C(N(CC)C(C)C)(C)C.[CH3:21][C:22]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:25]=[C:24]([C:34]([F:37])([F:36])[F:35])[C:23]=1[NH2:38].C(OCC)(=O)C>CN(C)C=O>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([NH:38][C:23]1[C:24]([C:34]([F:35])([F:36])[F:37])=[CH:25][C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:27][C:22]=1[CH3:21])=[O:11]
Reactant: Cc1cc(N2CCOCC2)cc(C(F)(F)F)c1N
Reactant: O=C(O)CC1CC2CCC1C2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCOCC2)cc(C(F)(F)F)c1NC(=O)CC1CC2CCC1C2
Reaction time: 0.03 h
Yield: 5.8 %

Procedure:
Bicyclo[2.2.1]hept-2-yl-acetic acid (160 mg), N,N-diisopropyl-ethylamine (0.44 mL) and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-methyl-methanaminium hexafluoro-phosphate N-oxide (0.47 g) were mixed in dry N,N-dimethylformamide (3 mL) and stirred under argon for 2 minutes. 2-Methyl-4-morpholin-4-yl-6-trifluoromethyl-phenylamine (0.18 g) dissolved in dry N,N-dimethylformamide (2 mL) was added to the reaction mixture, which was stirred at 25° C. under argon for 16 hours. Ethyl acetate (20 mL) was added and the organic phase was washed with saturated aqueous ammonium chloride/water (1:1, 20 mL), water (20 mL), brine/water (1:1, 20 mL), dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 16 mg (6% yield) of the title compound as a white solid. LC-MS (m/z) 397 (MH+); tR=3.12, (UV, ELSD) 91%, 98%.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=O)[CH3:4].[C:25]([OH:28])(=[O:27])[CH3:26].O1CC[CH2:31][CH2:30]1>>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6](/[C:3](/[CH3:4])=[CH:26]/[C:25]([O:28][CH2:30][CH3:31])=[O:27])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C1CCOC1
Reactant: CCCCCCCc1ccc(-c2ccc(C(C)=O)cc2)cc1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCc1ccc(-c2ccc(/C(C)=C/C(=O)OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% in oil, 0.37 g) in tetrahydrofuran (40 ml) was added by portions 4-acetyl-4′-n-heptylbiphenyl (2.50 g) at ambient temperature. After stirring at ambient temperature for 1 hours, to the solution was added triethyl phosphonoacetate (1.9 ml) and the mixture was heated to reflux for 5 hours. After cooling to ambient temperature, to the mixture was added acetic acid (0.53 ml) and evaporated. The residue was taken up into a mixture of water and ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (200 ml) eluting with mixture of n-hexane and diisopropyl ether (99:1-20:1, V/V) to give Ethyl (E)-3-[4-(4-heptylphenyl)phenyl]-2-butenoate (2.19 g).
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](OCC)=O.[H-].[Na+].[C:15]1(/[CH:21]=[CH:22]/[C:23](=[NH:25])[NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C.CCO.O>[OH:6][CH2:5][CH2:4][CH2:3][C:2]1[C:1](=[O:7])[N:25]=[C:23](/[CH:22]=[CH:21]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:24][CH:8]=1
Reactant: O=C1CCCCO1
Reactant: CCOC=O
Reactant: N=C(N)/C=C/c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: O=c1nc(/C=C/c2ccccc2)[nH]cc1CCCO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 44.9 %

Procedure:
To δ-valerolactone (2.0 g; 20 mmol) in anhydrous diethyl ether (20 ml) was added ethyl formate (1.6 mL; 21 mmol) and sodium hydride (1.0 g of a 60% w:w dispersion in oil, 25 mmol). The reaction was allowed to stir at room temperature under nitrogen for 45 min. A solution of (2E)-3-phenyl-2-propenimidamide (2.92 g; 20 mmol) in EtOH (25 ml) was added, the mixture was then heated to 70° C. and stirred at this temperature for 4 hours. The reaction was cooled to room temperature, water was added (50 mL) and the mixture was extracted with EtOAc (2×200 mL). The combined organic extracts were dried with Na2SO4, the solvents were removed and the crude residues were purified by column chromatography on silica gel using a 0-10% MeOH/DCM gradient. Fractions containing product were concentrated to afford the desired compound (2.3 g, 45%).
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]2[O:8][C:7]([CH3:9])=[CH:6][C:5]2=[C:10]([CH:13]=O)[C:11]=1[OH:12].[CH:16](B(O)O)=[CH:17][CH2:18][CH2:19][CH3:20].C(NCC1C=CC=CC=1)C1C=CC=CC=1.O>O1CCOCC1>[F:15][C:3]1[C:2]([F:1])=[C:11]2[C:10]([CH:13]=[CH:16][CH:17]([CH2:18][CH2:19][CH3:20])[O:12]2)=[C:5]2[CH:6]=[C:7]([CH3:9])[O:8][C:4]=12
Reactant: Cc1cc2c(C=O)c(O)c(F)c(F)c2o1
Reactant: CCCC=CB(O)O
Agent: c1ccc(CNCc2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCCC1C=Cc2c(c(F)c(F)c3oc(C)cc23)O1

Procedure:
4.0 g (18.9 mmol) of 6,7-difluoro-5-hydroxy-2-methylbenzofuran-4-carbaldehyde are stirred for 20 h at 90° C. together with 2.79 g (24.5 mmol) of 1-penteneboronic acid and 0.72 ml (3.73 mmol) of dibenzylamine in 95 ml of 1,4-dioxane. Water is added to the reaction mixture, which is then extracted with MTBE. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The crude product is firstly purified by column chromatography (SiO2, 1-chlorobutane) and subsequently crystallised from methanol, giving 4,5-difluoro-2-methyl-7-propyl-7H-furo[3,2-f]chromene as a yellow, crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25]([O:27]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[CH:7]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:6]3=[N:31][NH:32][C:25](=[O:27])[C:4]([CH:3]=1)=[C:5]23
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccccc1)C(c1nccn1C)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1Nc2cc(F)cc3c(=O)[nH]nc(c23)C1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15 %

Procedure:
A mixture of ethyl 7-fluoro-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (250 mg, 0.636 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture wax filtered and washed water (20 mL) and methanol (5 mL) to obtain a white solid, which after dried in vacuum at 50° C. afforded the title compound (34.6 mg, yield 15%). LC-MS (ESI) m/z: 362 (M+1)+; 1H-NMR (400 MHz, DMSO-d) δ (ppm): 3.56 (s, 3H), 4.48-4.49 (d, J=6.0 Hz, 1H), 5.01-5.03 (m, 1H), 6.70-6.71 (m, 1H), 6.81-6.84 (m, 1H), 6.98-7.02 (m, 2H), 7.14-7.26 (m, 5H), 7.66-7.67 (m, 1H), 12.33 (s, 1H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[OH:15][NH3+:16]>N1C=CC=CC=1>[C:1]1([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:16][OH:15])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: [NH3+]O
Reactant: O=C(c1ccccc1)C1CCCC1
Agent: [Cl-]
Solvent: c1ccncc1
Product: ON=C(C1=CCCC1)c1ccccc1
Temperature: 25 °C
Yield: 36 %

Procedure:
A mixture of cyclopentylphenylmethanone (15.0 g, 86 mmol), hydroxyl ammonium chloride (12.0 g, 172 mmol) and anhydrous pyridine (90 ml) was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature and the solvent evaporated in vacuo. To the residue was added 10% aqueous citric acid (100 ml) and the mixture was extracted with ethyl acetate (100 ml). The organic phase was washed with 10 % aqueous citric acid (50 ml), brine (25 ml) and dried (Na2SO4). The solvent was evaporated in vacuo. The residue was dissolved in cyclohexane (100 ml) and left for crystallisation. The precipitate was collected and washed with cyclohexane to give 5.8 g of the crude cyclopenten-1-ylphenylmethanone oxime as an amorphous solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>CN(C)C=O.O>[N:20]1([CH2:2][C:3]2[CH:4]=[C:5]([CH:10]=[C:11]([I:13])[CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: c1c[nH]cn1
Reactant: COC(=O)c1cc(I)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(I)cc(Cn2ccnc2)c1
Temperature: 70 °C
Yield: 50.5 %

Procedure:
A mixture of methyl 3-(bromomethyl)-5-iodobenzoate (500 mg, 1.4 mmol), potassium carbonate (388 mg, 2.8 mmol), and imidazole (96 mg, 1.4 mmol) in N,N-dimethylformamide (4 mL) was heated at 70° C. for 3 hours. After cooling, the reaction mixture was diluted with water and then extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography using 100% ethyl acetate afforded 242 mg (51%) of methyl 3-(imidazol-1-ylmethyl)-5-iodobenzoate as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:5]2[CH:20]=[C:21]([O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[C:22]([OH:24])=[CH:23][C:4]=2[N:3]=1.[H-].[Na+].Br[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].C(OCC)(=O)C>CN(C=O)C.O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:5]2[CH:20]=[C:21]([O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[C:22]([O:24][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:23][C:4]=2[N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1nc2cc(O)c(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2n1Cc1ccc(C#N)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2nc(C)n(Cc3ccc(C#N)c4ccccc34)c2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-methyl-5-hydroxy-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole (1.11 g) in DMF (50 mL) was added NaH (0.15 g) at ambient temperature. After stirring at ambient for 30 minutes ethyl bromoacetate (0.4 mL) was added. The reaction was stirred at ambient temperature for 1 hour and was worked up between ethyl acetate and H2O. The organic layer was dried, concentrated and purified by silica gel chromatography (hexane/ethyl acetate/CH2Cl2 /methanol, gradient) to afford 2-methyl-5-(ethoxycarbonylmethoxy)-6-(N-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-cyanonaphth-1-yl)methylbenzimidazole.
Reaction SMILES: [CH3:1][N:2]([C:4](=[Se:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3].[CH3:12][NH:13][N:14]=[C:15]([C:19]([OH:21])=O)[C:16](O)=[O:17].[CH2:22](Cl)[CH2:23]Cl>C(Cl)Cl>[CH3:1][N:2]([C:4]([C:23]1[CH:22]=[CH:7][CH:6]=[CH:5][CH:10]=1)=[Se:11])[NH:3][C:16](=[O:17])[C:15](=[N:14][NH:13][CH3:12])[C:19]([NH:3][N:2]([CH3:1])[C:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[Se:11])=[O:21]
Reactant: ClCCCl
Reactant: CN(N)C(=[Se])c1ccccc1
Reactant: CNN=C(C(=O)O)C(=O)O
Solvent: ClCCl
Product: CNN=C(C(=O)NN(C)C(=[Se])c1ccccc1)C(=O)NN(C)C(=[Se])c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To a solution of N-methylbenzoselenohydrazide, (430 mg, 2.0 mmol) and 2-(2-methylhydrazono)malonic acid (146 mg, 1.0 mmol) in CH2Cl2 (10 mL), was added EDC (480 mg, 2.5 mmol). The mixture was stirred for 1 h at RT. The reaction mixture was diluted with CH2Cl2 (25 mL) and washed with water and brine. The organic layer was dried over MgSO4 and filtered. After removal of the solvent, the product was purified by chromatography column on silica gel (1:1 Hexane:EtOAc and EtOAc) and to give N′1,N′3-dimethyl-2-(2-methylhydrazono)-N′1,N′3-di(phenylcarbonoselenoyl)malonohydrazide; (Compound 13) (330 mg) in 61.5% yield.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH:34]=[N:33][CH:32]=[CH:31]2>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:34]1[C:35]2[C:30](=[CH:29][C:28]([NH:27][C:8](=[O:9])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][O:12][Si:13]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[CH:14]([CH3:15])[CH3:16])=[CH:37][CH:36]=2)[CH:31]=[CH:32][N:33]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: CC(C)[Si](OCC(C(=O)O)c1ccccc1)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)[Si](OCC(C(=O)Nc1ccc2cnccc2c1)c1ccccc1)(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
To 2-phenyl-3-(triisopropylsilyloxy)propanoic acid (E400) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline, and the solution was flushed with N2, capped, and stirred overnight. The mixture was poured into NaHCO3(sat) and extracted with EtOAC. The combined organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (3-4% MeOH/CH2Cl2) gave pure N-(isoquinolin-6-yl)-2-phenyl-3-(triisopropylsilyloxy)propanamide (E401).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14](=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1>[OH:13][CH2:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([CH3:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(CO)c1
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [Cs+]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)cc(CO)c1
Temperature: 25 °C

Procedure:
To a stirred solution of methyl 3-bromo-5-(hydroxymethyl)benzoate (3.0 g, 12.2 mmol) in dioxane (27 mL) is added cesium carbonate (4.0 g, 12.2 mmol), potassium carbonate (34 g, 24.4 mmol), and palladium(0)tetrakis(triphenylphosphine) (704 mg, 0.61 mmol), followed by trimethyl boroxine (1.7 mL, 12.2 mmol). The reaction mixture is refluxed for 5 h, cooled to room temperature, and then partitioned between water and ethyl acetate. The organic layer is washed with water, saturated sodium bicarbonate, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 20% ethyl acetate/hexanes) provides the title compound. ESI MS m/z 181.2 [M+H]+.