Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1>CO.C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)n1
Solvent: CCO
Solvent: CO
Product: COc1ccc(N)c(N)n1

Procedure:
2-Amino-6-methoxy-3-nitropyridine (2.8 g, 16.5 mmol) was dissolved in warm 1:1 methanol/ethanol (200 mL). The solution was cooled, purged with argon, and 10% palladium on carbon was added (0.45 g). Hydrogen was introduced (1 atm) and the reaction stirred until complete. The catalyst was filtered and the solvent evaporated from the filtrate to give the title compound. MS 140 (M+1) 1H NMR (500 MHz, CDCl3) δ 6.93 (d, J=8 Hz, 1H), 6.04 (d, J=8 Hz, 1H), 4.15 (br s, 2H), 3.80 (s, 3H), 3.0 (br s, 2H).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12]([NH:15][NH2:16])([CH3:14])[CH3:13]>C(O)(=O)C>[CH:12]([N:15]1[C:9]([CH3:10])=[CH:8][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:16]1)([CH3:14])[CH3:13]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: CC(C)NN
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(C(C)C)n1
Reaction time: 2 h
Yield: 31 %

Procedure:
To ethyl 2,4-dioxopentanoate (20.1 g, 127 mmol) in acetic acid (100 mL) at 0° C. was added drop-wise isopropylhydrazine (9.42 g, 127 mmol). The cold bath was removed and the reaction mixture was stirred for 2 hours. The reaction mixture was then diluted with EtOAc/H2O (300 mL/100 mL). The organic layer was washed with saturated NaHCO3 aqueous solution (100 mL), H2O (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by silica gel flash chromatography (1:2 EtOAc/hexane) to give the desired product (31%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([O:15][C:16]3[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.C1C=C(O[C:30](OC2N=CC=CC=2)=[S:31])N=CC=1>C(Cl)Cl>[N:22]([C:19]1[N:20]=[CH:21][C:16]([O:15][C:10]2[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:17][CH:18]=1)=[C:30]=[S:31]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: CSc1nccc(-c2cccnc2Oc2ccc(N)nc2)n1
Solvent: ClCCl
Product: CSc1nccc(-c2cccnc2Oc2ccc(N=C=S)nc2)n1
Reaction time: 8 h

Procedure:
To a mixture of 5-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy)pyridin-2-amine (0.170 g, 0.546 mmol) in DCM was added di-2-pyridyl thionocarbonate (0.133 g, 0.573 mmol). The reaction was allowed to stir overnight. After 16 h, the reaction was washed 4× with water, then transferred to a separatory funnel and diluted with DCM. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-(2-(6-isothiocyanatopyridin-3-yloxy)pyridin-3-yl)-2-(methylthio)pyrimidine. MS m/z=354 [M+H]+. Calc'd for C16H11N5OS2: 353.4.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:33][CH2:34][CH3:35])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=3)[C:19](=O)[C:18]3[C:17]([C:28]([O:30]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:2].O.[NH2:37][NH2:38]>CO>[CH2:34]([O:33][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:37][NH:38][C:28](=[O:30])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=2)=[CH:9][CH:10]=1)[CH3:35]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(C(OCC)OCC)cc1)N2
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2nccn2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of ethyl 2-(4-(diethoxymethyl)phenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (490 mg, 1.03 mmol), methanol (20 mL) and hydrazine monohydrate (2 mL) was stirred under 25° C. for 3 hr. The resulting mixture was evaporated under reduced pressure to 10 ml and then filtered, 250 mg of 8-(4-(diethoxymethyl)phenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a solid was obtained, yield 55%. LC-MS (ESI) m/z: 446 (M+1)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)OCC1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>CO.[Pd]>[OH:25][C@H:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[CH2:23][NH:22][CH:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C(O)/C=C/c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(CCC(=O)O)cc3)CC2)ccc1O
Reaction time: 24 h
Yield: 94.2 %

Procedure:
A solution of (E)-3-[4-(4-oxo-piperidin-1-yl)-phenyl]-acrylic acid (which was obtained in Example 170) (0.10 g, 0.40 mmol) and N-[5-((1R)-2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methane-sulfonamide (which was obtained in Example 10) (0.12 g, 0.48 mmol) in methanol (15 mL) was treated with avetic acid (0.03 g, 0.5 mmol), and 0.05 g of 10% Pd/C. The mixture was hydrogenated at 25 psi for 24 h, and then filtered through Celite and evaporated. The residue was triturated with ether to give 0.18 g of an off-white solid; m.p. 130–133° C.; 1H NMR (DMSO-d6) δ 1.30–1.46 (m, 2 H), 1.84–1.95 (m, 2 H), 2.37–2.50 (m, 4 H), 2.60–2.78 (m, 4 H), 2.92 (s, 3 H), 3.53–3.62 (m, 3 H), 4.46–4.55 (m, 1 H), 6.85 (d, 2 H), 6.92–7.10 (m, 4 H), 7.18 (dd, 1 H); MS (ES) m/z: 478.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[N:4]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.C1C=C(Cl)C=C(C(OO)=[O:43])C=1.OS([O-])=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:34])[N:4]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([CH3:30])[CH3:31])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33])[CH2:5][C:6]1[CH:7]=[N+:8]([O-:43])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)N(Cc1cccnc1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N(Cc1ccc[n+]([O-])c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}(pyridin-3-ylmethyl)carbamate (12 mg, 0.025 mmol) (Example 123) in CH2Cl2 (400 μL) was added m-CPBA (28 mg, 0.13 mmol). The reaction was stirred at room temperature for two hours and then was poured into NaHSO3 (10 mL). The mixture was extracted with EtOAc (50 mL), and the organic extracts were washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 10 to 20% MeOH/EtOAc afforded methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[(1-oxidopyridin-3-yl)methyl]carbamate. Rf=0.36 (20% MeOH/EtOAc). LCMS=489.2 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 6.21-8.22 (m, aromatics, 10H), 4.32 (s, 2H), 3.77 (s, 2H), 3.37 (s, 3H), 3.17 (s, 3H), 2.89 (m, 1H), 1.19 (d, J=7.0 Hz, 6H).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:27][CH:26]2[NH:28][CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH2:17]([CH:21]1[CH2:22][CH:23]2[N:28]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][CH2:7][C:6]3=[O:15])[CH:26]([CH2:25][CH2:24]2)[CH2:27]1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC1CC2CCC(C1)N2
Reactant: C[C@H](CI)CN1C(=O)CCc2ccccc21
Solvent: CC#N
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)CCc2ccccc21
Reaction time: 20 h
Yield: 30.5 %

Procedure:
A 4 mL vial was charged with (S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.185 g, 0.56 mmol) and 3-butyl-8-azabicyclo[3.2.1]octane (0.100 g, 0.60 mmol) in MeCN (0.5 mL) and shaken at 40° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; n-heptane/EtOAc 4:1) to give the title compound (107LH54) (0.063 g, 30%). 1H NMR (CD3OD) d 7.29-7.19 (m, 3H), 7.03-6.99 (m, 1H), 4.03-4.00 (m, 2H), 3.14-3.13 (m, 1H), 3.07-3.05 (m, 1H), 2.90-2.86 (m, 2H), 2.62-2.57 (m, 2H), 2.28-2.19 (m, 2H), 1.97-1.82 (m, 3), 1.58-1.42 (m, 5H), 1.34-1.15 (m, 8H), 0.90-0.87 (m, 6H); 13C NMR (CD3OD) d 173.1, 140.3, 129.1, 128.4, 128.3, 124.3, 117.2, 62.2, 61.2, 58.2, 46.5, 39.0, 38.0, 32.9, 32.1, 30.3, 29.1, 27.8, 27.3, 26.3, 24.0, 17.1, 14.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:10])[CH:9]=1)[CH:5]=O.[CH3:11][C:12](C)([O-:14])C.[Br-].O1CCOC1CP(CCCC)(CCCC)CCCC.Cl>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][CH:12]=[O:14])[CH:7]=[C:8]([Br:10])[CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: CCCC[PH](CCCC)(CCCC)CC1OCCO1
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Product: O=CC=Cc1cc(Br)cc(Br)c1
Temperature: 1 °C
Reaction time: 2 h

Procedure:
3,5-dibromobenzaldehyde (16.1 g, 61.0 mmol) was added to a cold (ice-water bath) solution of tert-butoxide (13.0 g, 116 mmol), (1,3-dioxolan-2-ylmethyl)tri-n-butylphosphine bromide salt (4.5 M, 32 cm3, 144 mmol) in 400 cm3 of ether under argon. The mixture was stirred at 0-2° C. for 2 h. 1.0 M HCl(aq) (300 cm3) was added to the mixture. The reaction was gradually warmed to room temperature and stirred at room temperature for 21 h. The two layers were separated. The aqueous layer was extracted with ether (3×200 cm3). The organic layer and the ether extracts were combined, washed with brine (1×300 cm3) and dried over anhydrous magnesium sulfate. The solvents were completely removed to leave a yellow solid. The solid was purified by column chromatography of silica gel using ethyl acetate-light petroleum (40-60° C.) as eluent to give 3.36 g (19%) of A-1 as a colourless solid; δH(200 MHz; CDCl3) 6.68 (1 H, dd, J 7.4 & 16 Hz, vinylH), 7.33 (1 H, d, J 16 Hz, vinylH), 7.33 (2 H, m, ArH), 7.63 (1 H, m, ArH), and 9.72 (1 H, d, J 7.6 Hz, CHO); m/z [CI(NH3)] 306, 308, 310 (MNH4+), and 288, 290, 292 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:17][C:16]3[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)[CH:9]=[CH:10][C:3]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(Cn2ccc3c(Br)ccnc32)cc1

Procedure:
Reaction of 4-bromo-1H-pyrrolo[2,3-b]pyridine with 4-methoxybenzyl chloride following the method of Example 12 affords the title compound.
Reaction SMILES: [CH2:1]([S:3][C:4](SCC)=[C:5]([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:8])[CH3:2].[O-:26]Cl.[Na+]>C(O)(C(F)(F)F)=O.O>[CH2:1]([S:3][C:4](=[O:26])[CH:5]([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7](=[O:8])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH3:2]
Reactant: [O-]Cl
Reactant: CCSC(SCC)=C(CC(=O)c1ccc(C(F)(F)F)cc1)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCSC(=O)C(CC(=O)c1ccc(C(F)(F)F)cc1)C(F)(F)F

Procedure:
A mixture of 4,4-bis-ethylsulfanyl-3-trifluoromethyl-1-(4-trifluoromethyl-phenyl)-but-3-en-1-one (example C.26 step 3) (36.96 g, 92 mmol) in TFA (54.3 mL) and water (5.8 mL) was refluxed for 18 h under nitrogen atmosphere, the exhaust of the reaction was passed through a NaOCl solution to trap the liberated ethyl mercaptane. The volatiles were evaporated and the mixture was diluted with water and extracted with TBME, the organic layer was washed with sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a brown oil (31.2 g, 95%), which was used without further purification [according to J. Fluorine Chem. 2001, 107, 281.]. MS (EI) 339.0 [(M−F)+].
Reaction SMILES: [Br-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[CH2:34][CH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C@H:42]2[CH2:47][CH2:46][C@H:45]([CH:48]=O)[CH2:44][CH2:43]2)[CH2:38][CH2:37]1.C(OCC)C>COC(C)(C)C>[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[CH2:34][CH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C@H:42]2[CH2:47][CH2:46][C@H:45]([CH:48]=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=3)[CH2:44][CH2:43]2)[CH2:38][CH2:37]1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Agent: [Br-]
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Fc1ccc(C=C[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Reaction time: 1.5 h

Procedure:
3 g of p-fluorobenzyl-triphenylphosphonium bromide (preparable from p-fluorobenzyl bromide and triphenylphosphine) are suspended in 50 ml of tert.butyl methyl ether. The suspension is treated at room temperature with 0.75 g of potassium tert.butylate and stirred for 1.5 hours. Subsequently, the mixture is treated dropwise at 0° C. within 5 minutes with a solution of 1.40 g of trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanecarboxaldehyde in 25 ml of tert.butyl methyl ether and stirred at room temperature for a further 24 hours. Thereafter, the reaction mixture is taken up diethyl ether, washed several times with water, dried over magensium sulfate, filtered and concentrated. Chromatographic purification of the resulting crude product on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gives β-[trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]-4-fluorostyrene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:28])[C:11]=1[NH:12][C:13]1[C:22]2[CH:23]=[CH:24][NH:25][C:26](=[O:27])[C:21]=2[C:20]2[C:15](=[CH:16][CH:17]=[N:18][CH:19]=2)[N:14]=1)[C:5]([O:7]C)=O.[CH2:29]([Mg]Br)[CH3:30]>C1COCC1.[Ti+4]>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2([OH:7])[CH2:30][CH2:29]2)[CH:9]=[C:10]([Cl:28])[C:11]=1[NH:12][C:13]1[C:22]2[CH:23]=[CH:24][NH:25][C:26](=[O:27])[C:21]=2[C:20]2[C:15](=[CH:16][CH:17]=[N:18][CH:19]=2)[N:14]=1
Reactant: CC[Mg]Br
Reactant: COC(=O)c1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Agent: [Ti+4]
Solvent: C1CCOC1
Product: O=c1[nH]ccc2c(Nc3c(Cl)cc(C4(O)CC4)cc3Cl)nc3ccncc3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3,5-dichloro-4-[(10-oxo-9,10-dihydropyrido[4,3-c]-1,6-naphthyridin-6-yl)amino]benzoate (67 mg, 0.16 mmol) and titanium (IV) isoproxide (46 mg, 0.16 mmol) in THF (4 mL) was added ethylmagnesium bromide (1.29 mL, 1.29 mmol, 1.0 M in THF) dropwise. The solution was stirred at room temperature overnight and extracted with 3:1 CHCl3/iPrOH. Column chromatography on silica gel (100% CH2Cl2 to 70% CH2Cl2/30% MeOH) afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].[CH3:33][N:34]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41])=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][CH:45]=[C:37]([C:35]([N:34]([CH3:33])[CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)=[O:36])[CH:38]=3)=[C:3]([C:13]3[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=4)[CH:30]=[CH:31][N:32]=3)[CH:4]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: Nc1ccc(OC2CCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A mixture of 26 mg of 2-(2-amino-5-cyclobutoxyphenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide, 21 mg of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid, 27 mg of HATU, and 63 μL of DIEA in 0.2 mL of DMF was stirred at 60° C. for 2 h. The product was isolated by reverse phase chromatography eluting with 0.05% TFA in a water/acetonitrile gradient. This procedure gave 24 mg of a yellow solid. 1H NMR (400 MHz, CD3OD, ppm): δ 9.46 (t, J=5.8 Hz, 1H), 8.85 (d, J=5.3 Hz, 1H), 8.26 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 8.05 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.85-7.80 (m, 1H), 7.80-7.47 (m, 6H), 7.31 (d, J=2.7 Hz, 1H), 7.00 (dd, J=8.9, 2.6 Hz, 1H), 4.83-4.71 (m, 1H), 4.67 (s, 2H), 4.09 (s, 2H), 3.96 (m, 2H), 3.77 (m, 4H), 3.52 (t, J=4.9 Hz, 2H), 3.24 (s, 2H), 3.07 (s, 3H), 2.59-2.39 (m, 2H), 2.25-2.04 (m, 2H), 1.93-1.60 (m, 2H). MS (ESI, m/z) 716.26 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:12]3[CH:21]=[CH:22][C:23]([N+:25]([O-])=O)=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].Br.C(S[C:39]([C:41]1[CH:45]=[CH:44][O:43][CH:42]=1)=[NH:40])C1C=CC=CC=1>>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:13]1[C:12]2[CH:21]=[CH:22][C:23]([NH:25][C:39]([C:41]3[CH:45]=[CH:44][O:43][CH:42]=3)=[NH:40])=[CH:24][C:11]=2[N:10]=[C:9]1[CH2:8][C:7]1[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCN(CC)CC)cc1
Reactant: N=C(SCc1ccccc1)c1ccoc1
Agent: Br
Product: CCOc1ccc(Cc2nc3cc(NC(=N)c4ccoc4)ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
{2-[2-(4-Ethoxy-benzyl)-5-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine 7a (108 mg, 0.273 mmol) was reduced to the amine 8a as outlined above and the resulting ethanolic solution charged to a small, argon purged flask fitted with a magnetic stirbar. Furan-3-carboximidothioic acid benzyl ester hydrobromide 9d (171 mg, 0.574 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 20 hours. The solvent was evaporated and the residue partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 11. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using silica gel column chromatography eluting with 5% 2M NH3 in methanol/95% dichloromethane to afford a pale yellow oil 14 N-(1-(2-(diethylamino)ethyl)-2-(4-ethoxybenzyl)-1H-benzo[d]imidazol-5-yl)furan-3-carboximidamide. Yield: 62.8 mg (50.0%) 1H NMR (DMSO) δ; 0.83 (t, 6H, J=7.0), 1.29 (t, 3H, J=7.0), 2.37-2.50 (2×m, 6H), 3.99 (q, 2H, J=6.9), 4.10 (t, 2H, J=6.8), 4.21 (s, 2H), 5.98-6.09 (br, 1-2H), 6.71 (d, 1H, J=9.6), 6.86 (d, 2H, J=8.7), 6.88-6.92 (m, 1H), 6.96 (br, 1H), 7.18 (d, 2H, J=8.5), 7.33 (d, 1H, J=8.5), 7.68-7.73 (m, 1H), 8.23 (s, 1H). MS (ESI): 460 (MH+, 95%)
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH:7]2[O:8][CH:6]2[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[NH3:27]>C(O)C>[NH2:27][C@@H:6]1[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:15])[CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:1])([CH3:26])[C@H:7]1[OH:8]
Reactant: CC1(C)Oc2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2C2OC21
Reactant: N
Solvent: CCO
Product: CC1(C)Oc2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2[C@@H](N)[C@@H]1O
Temperature: 90 °C

Procedure:
Intermediate 2a (3.49 g, 9.4 mmol) is treated with a saturated solution of ammonia in ethanol (60 mL) and heated at 90° C. in an autoclave for 15 hours. The solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography on silica gel, eluent 25% aqueous NH3 --MeOH--tBuOMe (1:5:94) to give the title compound as a foam, having the following physical characteristics:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([NH2:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[NH2:15][C:13]([CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.6 %

Procedure:
4-Nitrophenol (10 g), bromoacetamide (10 g) and K2CO3 (15 g) were suspended in acetone (30 mL). The yellow solution was stirred at rt for 3 d. The reaction mixture was diluted with water and acetone was removed under reduced pressure. The light-yellow precipitate was collected by filtration, washed with water and dried to give O-aminocarbonylmethyl-4-nitrophenol (11.5 g) as a beige solid.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH:10]=[C:11]([CH3:22])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][O:17][CH2:18][O:19][CH3:20])C(OC)=O)(=[O:3])[CH3:2].[Cl-].[Na+].O>CS(C)=O>[CH3:22][C:11]([CH2:12][CH2:13][CH:14]=[C:15]([CH3:21])[CH2:16][O:17][CH2:18][O:19][CH3:20])=[CH:10][CH2:9][CH2:4][C:1](=[O:3])[CH3:2]
Reactant: COCOCC(C)=CCCC(C)=CCC(C(C)=O)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCOCC(C)=CCCC(C)=CCCC(C)=O
Temperature: 150 °C
Reaction time: 5 h
Yield: 102.7 %

Procedure:
To a solution of methyl 2-acetyl-5,9-dimethyl-10-(methoxymethyl)oxy-4,8-decadienate (420 mg, 1.37 mmol) in methylsulfoxide (4 ml) were added sodium chloride (160 mg, 2.74 mmol) and water (0.1 ml), and the mixture was stirred at 150° C. After five hours, the reaction mixture was allowed to cool to room temperature, and water (10 ml) was added thereto. The product was extracted with ether (20 m1×2). The extract was dried over Na2SO4, and concentrated to give a residue, which was then purified with silica gel column chromatography to obtain 6,10-dimethyl-11-(methoxymethyl)oxy- 5,9-undecadien-2-one (358 mg, 67%).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]=1>C1CCCC1>[CH2:2]1[CH:1]2[CH:8]3[CH:7]=[CH:6][CH:10]([CH:5]2[CH:4]=[CH:3]1)[CH2:9]3
Reactant: C1=CCC=C1
Reactant: C1=CCCC1
Solvent: C1CCCC1
Product: C1=CC2C3C=CC(C3)C2C1

Procedure:
In a process for the production of cyclopentene from dicyclopentadiene which comprises splitting dicyclopentadiene under heat to form cyclopentadiene; partially hydrogenating the cyclopentadiene to form a crude cyclopentene containing an impurities fraction boiling at a higher boiling point than cyclopentene and containing cyclopentane; purifying the crude cyclopentene by distillation in which said impurities fraction is separated from the crude cyclopentene; the improvement which comprises recycling at least part of the separated impurities fraction as the impurities fraction is produced in said distillation to the dicyclopentadiene splitting stage, said separated impurities fraction comprising predominantly cyclopentane.