Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:5]=1[NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1cccc(O)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1NS(=O)(=O)c1ccc(OC)cc1
Yield: 96.2 %

Procedure:
To a solution of 0.139 g (0.412 mmol) of the product of Example 31 in 2.0 mL of DMF was added 0.70 g (1.03 mmol) of imidazole and 0.075 g (0.495 mmol) of t-butyldimethylsilyl chloride. The reaction mixture was then srtied at room temperature for 3h and then diluted with 75 mL of ether. The resulting mixture was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 0.179 g (96%) of the desired product as a white solid. Electrospray Mass Spec: 452.2 (M+H)+
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[CH:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:15]1([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]1
Reactant: O=C1C=CC(c2ccc(OCc3ccccc3)cc2)(c2ccccc2F)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccc(O)cc2)(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
Compound 5 (300 mg, 8.05 mmol) was dissolved in EtOAc (15 mL). Pd/C (100 mg, 10%) was added. The flask was charged with hydrogen gas (vacuum, H2, vacuum, H2) and the mixture was stirred overnight at room temperature. The crude mixture was filtered through a pad of celite (eluated with 40 mL of EtOAc) and the solvent was evaporated under reduced pressure to yield 230 mg, 99% of 6. 1H-NMR (CDCl3) δ 7.37 (td, 1H, J=8.0 Hz and 1.7 Hz), 7.25-7.17 (m, 1H), 7.19 (d, 2H, J=8.7 Hz), 7.16-7.11 (m, 1H), 7.00-6.93 (m, 1H), 6.78 (d, 2H, J=8.2 Hz), 2.82-2.72 (m, 2H), 2.67-2.56 (m, 2H), 2.51-2.37 (m, 4H), 1.43 (s, H2O/OH); 13C-NMR (CDCl3) δ 211.9, 161.4 (d, J=248 Hz), 154.2, 136.7, 132.9 (d, J=10.8 Hz), 128.7 (d, J=8.8 Hz), 128.3 (d, J=5.0 Hz), 127.9 (d, 2C, J=1.1 Hz), 124.1 (d, J=3.5 Hz), 117.0 (d, J=24.2 Hz), 115.3 (2C), 44.2 (d, J=2.7 Hz), 38.5 (2C), 35.5 (d, 2C, J=4.6 Hz); 19F-NMR (CDCl3) δ−108.6 (m).
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][C:20]#N)=[CH:17][CH:16]=1>Cl>[Cl:9][C:7]1[C:6]([S:10](=[O:12])(=[O:13])[NH2:11])=[CH:5][C:3]2[NH:4][C:20]([CH2:19][C:18]3[CH:22]=[CH:23][C:15]([CH3:14])=[CH:16][CH:17]=3)=[N:1][C:2]=2[CH:8]=1
Reactant: Cc1ccc(CC#N)cc1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Agent: Cl
Product: Cc1ccc(Cc2nc3cc(Cl)c(S(N)(=O)=O)cc3[nH]2)cc1
Temperature: 25 °C
Yield: 11.2 %

Procedure:
To 150 ml of 6 N hydrochloric acid was added 17.7 g of 2-amino-4-chloro-5-sulfamylaniline followed by the addition of 15.7 g of 4-methylbenzyl cyanide; the mixture was then refluxed for 9 hours. The precipitate was collected by filtration and added to 300 ml of concentration ammonium hydroxide. After stirring for ten minutes at ambient temperature, the solid was collected and then added to 300 ml of water and stirred at 40° C. for ten minutes. The crude product was collected and dissolved in 1 liter of methanol which was brought to a boil; after stirring for five minutes, charcoal was added, and stirring continued for ten more minutes. The mixture was then filtered through two sheets of filter paper and then through Celite. Concentration in vacuo provided a solid which upon recrystallization from acetonitrile provided 3.0 g of pink crystals, m.p. 214°-217°.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5][C:4]=2[C:3]1=O.[CH2:15]([C:17]([NH:22][C:23]([NH2:25])=[S:24])([CH2:20][OH:21])[CH2:18][CH3:19])[CH3:16]>C(O)C.C(OCC)(=O)C>[CH2:15]([C:17]([NH:22][C:23]1[S:24][C:2]2[CH2:11][CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:12]#[N:13])[CH:8]=3)[C:3]=2[N:25]=1)([CH2:20][OH:21])[CH2:18][CH3:19])[CH3:16]
Reactant: N#Cc1ccc2c(c1)CCC(Br)C2=O
Reactant: CCC(CC)(CO)NC(N)=S
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(CC)(CO)Nc1nc2c(s1)CCc1cc(C#N)ccc1-2
Yield: 54.3 %

Procedure:
6-Bromo-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (0.23 g, 0.90 mmol) was dissolved in 10 mL of ethanol and N-[1-ethyl-1-(hydroxymethyl)propyl]thiourea (133 mg, 1.32 mmol), prepared in step 5 of example 2, was added and the mixture was heated to reflux for 1 h. The mixture was cooled, diluted with ethyl acetate and washed with H2O, NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (3% acetone/hexane) afforded 2-{[1-ethyl-1-(hydroxymethyl)propyl]amino}-4,5-dihydronaphtho[1,2-d][1,3]thiazole-7-carbonitrile (160 mg, 55%) as a white solid. HRMS: calcd for C18H21N3OS+H+, 328.14781. found (ESI-FTMS, [M+H]1+), 328.14836; Analytical HPLC: purity 93.3% at 210-370 nm, 10.3 min.; 96.4% at 254 nm, 10.3 min.; the Xterra® RP18 column, 3.5μ, 150 ×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:50])[N:7]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:28][CH2:29][CH2:30][N:31]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][C:32]1=[O:42])[CH2:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:22])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>C(#N)C>[C:46]([O:45][C:43](=[O:44])[N:27]([CH2:26][CH2:25][CH2:24][CH2:23][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:50])[CH2:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:18][CH2:19][CH2:14][CH2:15][CH2:16][CH3:17])[C:12]1=[O:22])[CH2:28][CH2:29][CH2:30][N:31]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C:32]1=[O:42])([CH3:49])([CH3:48])[CH3:47]
Reactant: CCCCCCBr
Reactant: CC(C)(C)OC(=O)N(CCCCN(CCCn1c(=O)[nH]c2ccccc2c1=O)C(=O)OC(C)(C)C)CCCn1c(=O)[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCn1c(=O)n(CCCN(CCCCN(CCCn2c(=O)c3ccccc3n(CCCCCC)c2=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(=O)c2ccccc21
Reaction time: 3 h

Procedure:
(4-{tert-butoxycarbonyl-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]amino}butyl)-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]carbamic acid tert-butyl ester (3 g, 4.3 mmol) was dissolved in 120 mL acetonitrile. Potassium carbonate (3.45 g, 25.0 mmol) and 1-bromohexane (3.5 g, 21.1 mmol) were added thereto and stirred for 3 hours under reflux. The solvent was concentrated under reduced pressure, and silica gel column-chromatography of the remaining residue was performed to give the title compound of colorless oil form (3.7 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[O:6][CH:5]=[C:4]([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:3]=1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[CH3:1][C:2]1[O:6][CH:5]=[C:4]([C:7]2[C:17]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:3]=1
Reactant: Cc1cc(-c2cccc3c2OCCN(C(=O)OC(C)(C)C)C3)co1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cccc3c2OCCNC3)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A mixture of tert-Butyl 9-(5-methyl-3-furyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (92.0 mg, 0.279 mmol), ethyl acetate (2 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (60.0 mg, 81.0%) as a solid.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([S:21]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.8 %

Procedure:
A solution of triethylamine (0.27 mL, 1.94 mmol) and morpholine (0.085 mL, 0.97 mmol) in dry dichloromethane (2 mL) was added to a stirred suspension of 6-chloropyridine-3-sulfonyl chloride (0.204 g, 0.96 mmol; described in: Naegeli, C. et al. Helv. Chim. Acta. 1938, 21, 1746-1750) in dry dichloromethane (1 mL). The resulting clear solution was stirred at room temperature for 20 min. The solvent was evaporated and the residue was purified on a silica gel column using dichloromethane/methanol, (97:3), as the eluent to give 0.176 g (70% yield) of the title compound: 1H NMR (DMSO-d6, 400 MHz) δ 8.75 (dd, J=3, 1 Hz, 1H), 8.18 (dd, J=8, 3 Hz, 1H), 7.82 (dd, J=8, 1 Hz, 1H), 3.63 (m, 4H), 2.96 (m, 4H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2N=N[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1)[CH3:2].[CH:26](N1CCCC1)=[CH2:27]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:26]=[CH:27][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1nnc(-c2ccc(CC)cc2)c(-c2ccccc2)n1
Reactant: C=CN1CCCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccc(CC)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure D, ethyl 6-(4-ethyl-phenyl)-5-phenyl-1,2,4-triazine-3-carboxylate (Compound 13, 105 mg, 0.30 mmol) and crude 1-vinylpyrrolidine (Compound 38, 2 g) in CHCl3 (10 ml) were reacted to produce the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][N+:3]=1[O-].[OH-].[Na+]>C(O)(=O)C.[Fe]>[NH2:8][C:6]1[C:5]([CH3:11])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1c[n+]([O-])c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cnc(Cl)cc1N
Temperature: 100 °C

Procedure:
Iron (1.0 g) was added to a solution of 10 (500 mg, 2.6 mmol) in glacial acetic acid (10 mL). The reaction mixture was then heated at 100° C. for 20 minutes. The suspension was poured on aqueous NaOH 1M and extracted with ethyl acetate. After drying over Na2SO4, the solvent was then evaporated and 11 was isolated as a colorless solid (370 mg, 2.6 mmol, HPLC Rt 1.3 min, FIA ES+ 143.0).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23].Cl>ClCCl>[CH:21]([S:22]([NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])(=[O:24])=[O:23])=[CH2:20]
Reactant: O=S(=O)(Cl)CCCl
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.9 %

Procedure:
2-Aminoacetophenone hydrochloride (1.00 g, 5.85 mmol) was dissolved in dichloromethane (50 mL). To the solution was added triethylamine (2.50 mL, 17.9 mmol), and the mixture was stirred at room temperature for 10 minutes. After the reaction mixture wascooled to 0° C., chloroethanesulfonyl chloride (0.92 mL, 8.80 mmol) was added, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture was added 2 mol/L hydrochloric acid and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added a mixed solvent of ethyl acetate and n-hexane for crystallization to obtain 2-(vinylsulfonylamino)acetophenone (0.42 g, 32%).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:17])=[C:6]([O:15][CH3:16])[CH:7]=[C:8]2[CH:13]=[O:14])[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22]Cl.O>CN(C=O)C>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:17][CH2:20][O:21][CH3:22])=[C:6]([O:15][CH3:16])[CH:7]=[C:8]2[CH:13]=[O:14])[CH3:2]
Reactant: CCc1cccc2c(C=O)cc(OC)c(O)c12
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Reaction time: 0.17 h

Procedure:
324 g of 5-ethyl-4-hydroxy-3-methoxy-1-naphthalenecarbaldehyde was dissolved in 1 liter of N,N-dimethylformaldehyde, to which 68 g of 60% sodium hydride was gently added under ice-cooling conditions. After agitation for 10 minutes, 128 ml of chloromethyl methyl ether was gradually added so that the reaction temperature did not exceed 15° C. After agitation at room temperature for 20 minutes, the reaction solution was poured into iced water and extracted with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate. The solvent was distilled off and the resultant residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to obtain 288 g of the captioned compound as a brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:24])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.[Cl:25][C:26]([Cl:30])=[CH:27][CH2:28]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH2:28][CH:27]=[C:26]([Cl:30])[Cl:25])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][N:14]=1
Reactant: ClCC=C(Cl)Cl
Reactant: Oc1cc(Cl)c(OCCCOc2ccc(C(F)(F)F)cn2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
A mixture of 0.5 g of 3,5-dichloro-4-[3-(5-trifluoromethylpyridin-2-yloxy)propyloxy]phenol, 0.25 g of 1,1,3-trichloropropene, 0.2.g of potassium carbonate and 3 ml of N,N-dimethylformamide was stirred at room temperature overnight. The reaction mixture was subjected to silica gel chromatography, which afforded 0.3 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-[3-(5-trifluoromethylpyridin-2-yloxy)propyloxy]benzene (47% yield), nD20.5 1.5377.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:5][CH:4]=1.[CH3:17][O:18][C:19](=[O:25])[NH:20][C:21](=[NH:24])SC>C(N(CC)CC)C>[NH2:15][C:14](=[N:13][C:10]1[S:11][CH:12]=[C:8]([C:6]2[O:7][C:3]([CH2:2][NH:1][C:21]([NH2:24])=[N:20][C:19]([O:18][CH3:17])=[O:25])=[CH:4][CH:5]=2)[N:9]=1)[NH2:16]
Reactant: COC(=O)NC(=N)SC
Reactant: NCc1ccc(-c2csc(N=C(N)N)n2)o1
Solvent: CCN(CC)CC
Product: COC(=O)N=C(N)NCc1ccc(-c2csc(N=C(N)N)n2)o1
Temperature: 25 °C
Reaction time: 26 h
Yield: 23.3 %

Procedure:
A suspension of 4-(5-aminomethylfuran-2-yl)-2-(diaminomethyleneamino)thiazole (1.6 g), imino(methylthio)methylcarbamic acid methylester (1.2 g) and triethylamine (1.5 g) was stirred at room temperature for 26 hours and then refluxed for 2.5 hours. Imino(methylthio)methylcarbamic acid methylester (1.0 g) was added to the reaction mixture and the mixture was refluxed for 10 hours. The solvent was removed under reduced pressure. The residue was chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (10:1, V/V). Recrystallization from a mixture of methanol and diisopropyl ether afforded 2-(diaminomethyleneamino)-4-[5-(2-methoxycarbonylguanidino)methylfuran-2-yl]thiazole (530 mg).
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][CH2:3][NH:2]1.CN(C)CCCN=C=NCC.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36](O)=[O:37])=[CH:30][CH:29]=1.Cl>ClCCl>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]([N:2]2[CH2:3][CH2:4][CH:5]3[CH:10]([CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][CH2:6]3)[CH2:1]2)=[O:37])=[CH:32][CH:33]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: CCOC(=O)C1CCCC2CCNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C1CCCC2CCN(C(=O)CCc3ccc(F)cc3)CC21
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.6 %

Procedure:
A solution of ethyl (4aSR,8SR,8aSR)-decahydroisoquinoline-8-carboxylate (273 mg, 1.29 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (309 mg, 1.61 mmol) in dichloromethane (10 mL) was treated with 3-(4-fluorophenyl)propanoic acid (271 m, 1.61 mmol). The mixture was stirred at room temperature for 4 hours, and then treated with 1.0 N aqueous hydrochloric acid. The mixture was extracted with dichloromethane (3×5 mL), and the combined organic phases were washed with 1.0 N aqueous sodium hydroxide, dried over magnesium sulfate and concentrated to provide a residue. The residue was purified by radial thin layer chromatography, eluting with 33% ethyl acetate/hexane, to provide a colorless oil (385 mg, 82%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][NH:5][C:4](=[S:7])[CH:3]1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].C([O-])(=O)C.[Na+].Br[CH2:20][C:21](=O)[CH2:22][C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24].C(Cl)(Cl)Cl>C1C=CC=CC=1>[CH:11]([O:10][C:8]([C:3]1[CH:2]([CH3:1])[CH2:6][N:5]2[C:21](=[CH:22][C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:24])[CH2:20][S:7][C:4]=12)=[O:9])([CH3:13])[CH3:12]
Reactant: O=C(CBr)CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)OC(=O)C1C(=S)NCC1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)OC(=O)C1=C2SCC(=CC(=O)Oc3ccc([N+](=O)[O-])cc3)N2CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
8.9 g of isopropyl 4-methyl-2-thioxopyrrolidine-3-carboxylate was dissolved in 200 ml of benzene and 5.1 g of anhydrous sodium acetate and 16.7 g of 4-nitrophenyl 4-bromoacetoacetate were added thereto. The obtained mixture was stirred at room temperature for 8 hours. Then 500 ml of chloroform was added and the mixture was washed with water and a saturated aqueous solution of sodium chloride. After drying and distilling off the solvent, the obtained residue was purified by silica gel column chromatography. A fraction eluted with dichloromethane was crystallized from a mixture of ether and n-hexane. Thus 11.9 g of the title compound was obtained.
Reaction SMILES: FC1C=CC([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]3)=[CH:10][CH:9]=2)=CC=1.BrC1C=CC([Cl:28])=CC=1>>[Cl:28][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([CH3:20])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2ccc(-c3ccc(F)cc3)cc2)CCN1
Reactant: Clc1ccc(Br)cc1
Product: C[C@@H]1CN(c2ccc(Cl)cc2)CCN1

Procedure:
The title compound was prepared following the procedure of Intermediate 22 but starting from 1-bromo-4-chlorobenzene. Purification by flash chromatography (CHCl3/MeOH) gave the title compound as a beige solid. M+(ESI): 211.2. HPLC purity: >96%).
Reaction SMILES: [C:1]([NH:3][C:4]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)#[N:2].[SH2:12].C(Cl)Cl>N1C=CC=CC=1>[CH3:10][C:8]1[CH:7]=[C:6]([CH3:11])[N:5]=[C:4]([NH:3][C:1]([NH2:2])=[S:12])[N:9]=1
Reactant: Cc1cc(C)nc(NC#N)n1
Reactant: S
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)nc(NC(N)=S)n1
Reaction time: 1 h

Procedure:
A suspension of 10 g of 2-cyanoamino-4,6-dimethylpyrimidine in 50 ml of pyridine was saturated with hydrogen sulfide and stored for 1 hour at 25°. The H2S treatment was repeated twice more, and the mixture was allowed to stir at 25° for 16 hours. Methylene chloride was added, and the product was filtered and washed with methylene chloride to afford 8 g of 4,6-dimethylpyrimidin-2-yl thiourea, m.p. >260°. IR (Nujol) 3280, 3180, 3120, 1610 cm-1.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:23](I)[CH3:24]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:23][CH3:24])=[O:6]
Reactant: CCI
Reactant: Cc1c(F)cccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(F)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 10 g of 3-fluoro-2-methylbenzoic acid [J. Org. Chem., 26, 3208 (1961)]in 300 ml of dimethylformamide are added 30 g of potassium carbonate and 30 g of ethyl iodide and the mixture is stirred at room temperature for 8 hours. After adding 500 ml of toluene, washing with water and a saturated saline solution and drying over magnesium sulfate, the solvent is distilled off under reduced pressure to give 11 g of ethyl 3-fluoro-2-methylbenzoate (oil). Mass spectrum m/z: 182(M+).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C(O)(=O)C.[C:13]1(C)[CH:18]=CC=C[CH:14]=1>>[N:1]1[C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=2[CH:18]=[CH:13][CH:14]=1
Reactant: Cc1ccccc1
Reactant: NC1=CC(=O)CCC1
Solvent: CC(=O)O
Product: O=C1CCCc2ncccc21

Procedure:
A mixture of 57.93 g of 3-amino-2-cyclohexene-1-one, 76.8 g of 3-(dimethylamino)acrotein, 62.5 ml of glacial acetic acid and 270 ml of toluene is refluxed under argon for 16 hours and concentrated under vacuum to dryness. Toluene (200 ml) is added and the solvent removed under vacuum. To the residue is added one liter of dichloromethane and then 200 ml of saturated NaHCO3 slowly added and solid NaHCO3 added to bring the pH to 8. The mixture is filtered and the CH2Cl2 layer separated. The CH2Cl2 layer is passed through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residual black oil is extracted with hot hexane and the hexane decanted. This process is repeated until no more product extracted into the hexane. The hexane extracts are combined and the solvent removed to give 17.3 g of product as an oil.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19].[CH2:20]([CH:22]1[CH2:25][CH2:24][CH:23]1[NH2:26])[CH3:21]>>[CH2:20]([CH:22]1[CH2:25][CH2:24][CH:23]1[NH:26][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]#[N:19])[CH3:21]
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Reactant: CCC1CCC1N
Product: CCC1CCC1Nc1c(C#N)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-5-cyano-2-trifluoromethylbenzimidazole is reacted with 2-ethylcyclobutylamine to obtain 4-((2-ethylcyclobutyl)amino)-7-nitro-5-cyano-2-trifluoromethylbenzimidazole, m.w., 353.3.
Reaction SMILES: [Br-].[N:2]1([CH2:7][CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C([Li])CCC.[Br:33][C:34]1[C:39]2[O:40][CH2:41][C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=3[C:44](=O)[C:38]=2[CH:37]=[CH:36][CH:35]=1>CCCCCC.O1CCCC1>[Br:33][C:34]1[C:39]2[O:40][CH2:41][C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=3/[C:44](=[CH:8]/[CH2:7][N:2]3[CH2:3][CH2:4][CH2:5][CH2:6]3)/[C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: c1ccc([P+](CCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2COc2c(Br)cccc21
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Brc1cccc2c1OCc1ccccc1/C2=C/CN1CCCC1

Procedure:
Anhydrous 2-(N-pyrrolidinyl)ethyltriphenylphosphonium bromide (20 g, 45 mmole), 45 mmole of n-butyl lithium in hexane (1.6 M), and 4-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one (10 g, 35 mmole) were reacted in 550 mL dry tetrahydrofuran by the procedure in Example 1, Step a. This offered a (Z)/(E) (60:40) isomeric product as a light brown oil. pmr (DMSO-d6)δ: 7.28-7.56 (m, 5H, aromatic H); 7.15-7.26 (2 dd, 1H, H1); 6.88 (t, H3 of 60% Z); 6.84 (t, H3 of 40% E); 6.16 (t, CH= of 40% E): 5.86 (t, CH= of 60% Z); 5.30 (br s, 2H, ArCH2O); 2.28-2.54 (m, 6H, N(CH2)3); 1.66 (m, 4H, 2CH2).