Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH:25]2[CH2:27][CH2:26]2)[OH:24])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[C:28]([O:24][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:25]1[CH2:27][CH2:26]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 72 %

Procedure:
To a solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](cyclopropyl)methanol (120.0 mg, 0.284 mmol) in pyridine (0.5 mL) was added acetic anhydride (0.3 mL) at 0° C. The reaction mixture was stirred at room temperature for 7 hrs. The mixture was concentrated. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified, by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from diisopropyl ether/n-hexane to give the title compound as a colorless powder (94.5 mg, 0.203 mmol, 72%).
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:31])[N:18]([CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:19]=[N:20]2)=[C:15]([O:32][CH2:33][C@H:34]2[CH2:38][CH2:37][CH2:36][N:35]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:14]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[CH3:27][C:26]([CH3:29])([CH3:28])[C:25]([O:24][CH2:23][N:18]1[C:17](=[O:31])[C:16]2[C:21](=[CH:22][C:13]([OH:12])=[CH:14][C:15]=2[O:32][CH2:33][C@H:34]2[CH2:38][CH2:37][CH2:36][N:35]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:20]=[CH:19]1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(OCc2ccccc2)cc2ncn(COC(=O)C(C)(C)C)c(=O)c12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cc(O)cc2ncn(COC(=O)C(C)(C)C)c(=O)c12
Temperature: 70 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
Ammonium formate (1.80 g, 28 mmol) and 10% palladium on carbon (0.180 g) were added to a solution of tert-butyl (2R)-2-{[(7-(benzyloxy)-3-{[(2,2-dimethylpropanoyl)oxy]methyl}-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (1.58 g, 2.8 mmol) in ethyl acetate (30 ml) and the mixture stirred at 70° C. for 24 hours. The mixture was filtered through Celite and then evaporated under reduced pressure. The residue was purified by silica gel chromatography eluting with a 0 to 10% mixture methanol in dichloromethane to give tert-butyl (2R)-2-{[(3-{[(2,2-dimethylpropanoyl)oxy]methyl}-7-hydroxy-4-oxo-3,4-dihydroquinazolin-5-yl)oxy]methyl}pyrrolidine-1-carboxylate (0.750 g, 52% yield):
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12](SC)[O:13][CH3:14])(=[O:10])=[O:9].S(Cl)([Cl:20])(=O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12]([Cl:20])[O:13][CH3:14])(=[O:10])=[O:9]
Reactant: COC(=NS(=O)(=O)c1ccccc1C)SC
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COC(Cl)=NS(=O)(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To 6.8 g of O-methyl S-methyl N-(2-methylphenylsulfonyl)carbonimidothioate in 20 ml of methylene chloride is added 6.8 g of sulfuryl chloride. The reaction mixture is stirred under a nitrogen atmosphere at ambient temperature for 2 hours, and then refluxed for an additional 2 hours. Removal of the solvent under reduced pressure gives 5.0 g of methyl N-(2-methylphenylsulfonyl)carbonimidochloridate as a light yellow oil. This product is used without further purification in the reaction described in Example 3.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1)[C:6]([O:8]CC1C=CC=CC=1)=[O:7].[H][H]>CO.[C].[Pd]>[CH3:1][O:2][CH2:3][O:4][C@H:5]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:21][CH:22]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: COCO[C@H](Cc1ccc(N2CCOCC2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCO[C@H](Cc1ccc(N2CCOCC2)cc1)C(=O)O
Yield: 113.2 %

Procedure:
To a solution of benzyl (R)-2-methoxymethoxy-3-(4-morpholinophenyl)propionate (1.66 g) in methanol (8.6 ml) was added 10% palladium-carbon (0.2 g), and hydrogenation was carried out in a hydrogen atmosphere at atmospheric pressure and room temperature for 100 minutes. After the catalyst was filtered off, the solvent was distilled off under reduced pressure. The residue was further subjected to azeotropic distillation with isopropyl ether-hexane to provide 1.44 g of (R)-2-methoxymethoxy-3-(4-morpholino-phenyl)propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([N:29]3[CH2:30][CH2:31][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28]3)[CH:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCN1CCNCC1
Reactant: COc1ccc(Nc2nc(Cl)cc(-c3ccccc3)n2)cc1Cl
Solvent: CCCCO
Product: CCN1CCN(c2cc(-c3ccccc3)nc(Nc3ccc(OC)c(Cl)c3)n2)CC1

Procedure:
The title compound was prepared by treating (3-chloro-4-methoxy-phenyl)-(4-chloro-6-phenyl-pyrimidin-2-yl)-amine (0.5 g, 1.4 mmol) with N-ethyl piperazine (0.16 g, 1.4 mmol) in n-butanol at refluxing temperature.
Reaction SMILES: C([O:5][C:6](=[O:21])[C@H:7]([CH:18]([CH3:20])[CH3:19])[NH:8][C:9](=[O:17])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][C:9]([NH:8][C@H:7]([C:6]([OH:21])=[O:5])[CH:18]([CH3:20])[CH3:19])=[O:17])[CH:12]=1
Reactant: CC(C)[C@H](NC(=O)Cc1cccnc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NC(=O)Cc1cccnc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.4 g of N-(3-pyridylacetyl)-(L)-valine-tert-butyl ester are dissolved in 20 ml of trifluoroacetic acid/methylene chloride (1:1) and the solution is stirred at RT for 16 h. The reaction solution is fully concentrated by evaporation and the residue is digested with DIPE. The title compound is obtained in the form of a white amorphous solid. 1H-NMR (200 MHz, CD3OD): 8.9-8.6 (m, broad, 1H), 8.5 (m, 1H), 7.95 (m, 1H), 4.33 (m, 1H), 3.93 (s, 2H), 2.2 (m, 1H), 0.98 (2d, 6H).
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[CH2:7]=[CH:8][CH:9]=[CH:10][CH3:11]>>[Cl:1][C:2]1([F:6])[C:3]([F:5])([F:4])[CH2:7][CH:8]=[CH:9][CH:10]1[CH3:11]
Reactant: FC(F)=C(F)Cl
Reactant: C=CC=CC
Product: CC1C=CCC(F)(F)C1(F)Cl
Reaction time: 1 h
Yield: 52 %

Procedure:
A flow reactor equipped with dual tubes having 20 mm of inner diameter of the outer tube, 16 mm of outer diameter of the inner tube, and 60 cm of length of the tubes was employed. The temperature in the reactor was kept at 520° C. Chlorotrifluoroethylene (CTFE), 1,3-pentadiene and nitrogen gas were continuously injected into the flow reactor at the rates of 36.1 g/hr, 20.4 g/hr, and 0.4 mol/hr, respectively, and the vapor phase condensation was carried out for 1 hour. Then, 4.7 g of unreacted chlorotrifluoroethylene (CTFE) was recovered. The resultant was purified by steam distillation, and then the water layer was removed to give 32.1 g of the mixture (GC%=52%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)=[O:9]
Reactant: Clc1ccccc1
Reactant: O=C(Cl)CCCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(CCCCCCBr)c1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
7-Bromoheptanoyl chloride (3.2 g) was added to chlorobenzene (30 ml), and aluminum chloride (1.6 g) was added under ice-cooling, which was followed by stirring for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 2.2 g of 7-bromo-1-(4-chlorophenyl)-1-heptanone.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:28])[CH3:27].[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>C(Cl)Cl>[C:26]([C:3]1[O:4][C:5]2=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=[C:10]2[C:2]=1[N:1]([S:30]([CH3:29])(=[O:32])=[O:31])[S:30]([CH3:29])(=[O:32])=[O:31])(=[O:28])[CH3:27]
Reactant: CC(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N(S(C)(=O)=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.030 g (0.0696 mmol)of the product from Example 5 in CH2Cl2 (1 mL) cooled to 0° C. was treated with methanesulfonyl chloride (5 μL; 0.0696 mmol), followed by triethylamine (30 μL; 0.209 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with saturated NaHCO3 solution. The reaction mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 586.9 (M+1), 588.9 (M+3); Rt=4.16 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]([CH3:21])[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[CH3:21])=[CH:19][CH:18]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC1CNCCN1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-Chloro-phenyl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.83 g, 0.68 mmol) was dissolved in HCl/dioxane (4M, 8 mL) and stirred for 2 hr at rt. The mixture was then evaporated in vacuo, basified with aqueous sodium hydroxide (1M, 50 mL), and extracted with ethyl acetate (3×100 mL). The organic layers were evaporated and the crude residue used in the next step, (0.56 g, brown oil)
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH:11]([C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1)[C:10]([O:18][CH2:19][CH3:20])=[O:17])[CH3:16]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cnc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncc(F)cc1F
Temperature: 110 °C
Yield: 85 %

Procedure:
To a stirred solution of 2,3,5-trifluoro-pyridine (2 g, 15.02 mmol) in dimethyl sulfoxide (20 mL) was added diethyl malonate (4.60 g, 28.72 mmol). Then cesium carbonate (9.35 g, 28.72 mmol) was added and the reaction mixture was heated to 110° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with water (2×25 mL), brine (25 mL), dried over sodium sulphate and evaporated in vacuo to afford the title compound as oil in 85% yield, 3.5 g.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[N:4]=[C:3]1[C:18]([F:21])([F:20])[F:19].[CH2:22](I)[CH3:23].[O-]CC.[Na+]>CO>[CH2:22]([O:1][N:2]1[C:6]2[CH:7]=[C:8]([C:14]([F:15])([F:16])[F:17])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:5]=2[N:4]=[C:3]1[C:18]([F:19])([F:21])[F:20])[CH3:23]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc2c1nc(C(F)(F)F)n2O
Reactant: CCI
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Product: CCOn1c(C(F)(F)F)nc2c([N+](=O)[O-])cc(C(F)(F)F)cc21

Procedure:
A 6 g. portion of 1-hydroxy-4-nitro-2,6-bis(trifluoromethyl)benzimidazole was mixed with 50 ml. of methanol, 10 ml. of ethyl iodide, and 2.5 g. of sodium ethoxide. The mixture was heated at reflux temperature overnight with stirring, and was then cooled and evaporated to dryness. The residue was taken up in ether, and the ether solution was washed with water. The ether layer was then evaporated to dryness, and the residue was recrystallized from petroleum ether to produce the desired 1-ethoxy-4-nitro-2,6-bis(trifluoromethyl)benzimidazole, m.p. 94°-96°C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[O:11]=[C:12]1[NH:17][CH2:16][C@@H:15]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@@H:14]2[CH2:13]1>>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:17]2[C:12](=[O:11])[CH2:13][C@H:14]3[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:15]3[CH2:16]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC(=O)C[C@H]2C1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CC(=O)N(c3ccc([N+](=O)[O-])nc3)C[C@@H]2C1
Yield: 85 %

Procedure:
Following general N—C coupling procedure 1, 5-bromo-2-nitropyridine and cis-tert-butyl 6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate were combined and gave after purification cis-tert-butyl 5-(6-nitropyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (1.0 g) in 85% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.58 (d, J=2.53 Hz, 1H), 8.28 (d, J=8.59 Hz, 1H), 8.07 (dd, J1=8.84, J2=2.27 Hz, 1H), 4.18-3.61 (m, 4H), 3.29 (m, 2H), 2.85 (m, 3H), 2.55 (m, 1H), 1.47 (s, 9H)
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[N:15]=[N:16][NH:17][CH:18]=3)=[C:9]([O:19][CH3:20])[C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[N:15]=[N:16][NH:17][CH:18]=3)=[C:9]([O:19][CH3:20])[C:8]2=[S:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1c(Cc2c[nH]nn2)ccn(-c2ccccc2)c1=O
Solvent: Cc1ccccc1
Product: COc1c(Cc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 156.3 %

Procedure:
Reaction of 151a (0.295 g, 1.04 mmol) and Lawesson's reagent (0.252 g, 0.624 mmol) in toluene (15 mL) within 12 h as described for the synthesis of 147a gave compound 153a (0.291 g, 94%) as yellow solid. 1H NMR (CDCl3, 400 MHz) δ 3.90 (3H, s), 6.04 (2H, s), 6.62-6.68 (2H, m), 7.38-7.42 (1H, m), 7.48 (2H, t, J=7.2), 7.68 (2H, d, J=8.0), 7.82 (1H, d, J=4.8), 8.53 (1H, s); 13C NMR (CDCl3, 100 MHz) δ 50.9, 56.4, 110.0, 112.0, 120.2, 122.4, 128.5, 129.3, 132.2, 136.4, 141.9, 158.7, 171.5 HRMS (EI) calcd for C15H14N4O2 [M]+ 282.1117. found 282.1115. HRMS (EI) calcd for C15H14N4OS [M]+ 298.0888. found 298.0888.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCOC(C)=O>C1COCC1>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=[C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:23])=[CH:8][CH:7]=2)[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCI)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CCN(CCCOc2ccc(NC=C3C(=O)Nc4ccccc43)cc2)CC1
Temperature: 50 °C

Procedure:
A solution of 3-{[4-(3-Iodo-propoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one (66 mg, 0.157 mmol) in 1 mL THF is treated with 1-methylpiperazine (37.2 μL, 2.2 equiv.) and the resulting reaction mixture is heated at 50° C. for 4 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is partitioned between EtOAc and H2O. The organic layer is collected and washed with saturated aqueous NaHCO3, brine, and dried over anhydrous Na2SO4. The yellow solid residue obtained upon evaporation is broken up in 1:9 EtOAc:hexane and collected by filtration to give the named compound as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](O)=O.C=O>>[CH3:21][N:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CO
Reactant: c1ccc(CCCCNCCCc2ccccc2)cc1
Agent: C=O
Product: CN(CCCCc1ccccc1)CCCc1ccccc1

Procedure:
Phenylbutyric acid chloride and 3-phenylpropylamine were reacted to form the amide which next was reduced with diborane to give N-(3-phenylpropyl)-4-phenylbutylamine. The amine was methylated with formic acid/formaldehyde to form the starting material, N-methyl-N-(3-phenylpropyl)-4-phenylbutylamine. 5.3 Grams of N-methyl-N-(3-phenylpropyl)phenylbutylamine was dissolved in 150 ml. of diethyl ether in a 300 ml. round bottom flask. Methyl bromide gas was bubbled through the mixture until it was saturated. The mixture was stirred at room temperature for 3 days. The solid material which had formed was collected by filtration and crystallized from 100 ml. methyl ethyl ketone and ethyl acetate to yield 5.08 g. of N,N-dimethyl-N-phenylpropyl-phenylbutylammonium bromide. M.P. 81°-83° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:12]>>[C:1]1([CH2:7][C:8]([Cl:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: ClC(Cl)Cl
Product: O=C(Cl)Cc1ccccc1

Procedure:
Phenylacetyl chloride is prepared according to the method described in Example 8 using phenylacetic acid (2.13 g, 15.6 mmol) to give a pale yellow oil which is dissolved in chloroform (10 mL). This solution is refluxed for 12 hours with a solution of (±)-trans-[2-(4-morpholinyl)]cyclohexanol (2.75 g, 14.9 mmol) in chloroform (10 mL) under nitrogen. The reaction mixture is partitioned between 1M sodium hydroxide solution (100 mL) and dichloromethane (80 mL). The organic layer is separated and the aqueous is washed with more dichloromethane (2×50 mL). The combined dichloromethane extracts are dried over sodium sulfate, and the solvent is removed to leave the crude free ester. This is purified by column chromatography and converted to the hydrochloride salt as described in Example 9. The product is recrystallised from hot methanol to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C1COCC1.CC(OC)(C)C>[CH3:9][C:3]1[CH:4]=[C:5]([O:8][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1cc(O)ccc1N
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1N
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of 4-amino-3-methylphenol (75.0 g, 609 mmol) in THF (1.5 L) was added imidazole (83 g, 1.22 mol). The reaction was cooled to 0° C. and triisopropylsilyl chloride (123 mL, 579 mmol) was added. The reaction mixture was allowed to warm to room temperature, stirred for 3 h, diluted with MTBE (1.5 L) and filtered. The filtrate was washed with water (1.0 L). The aqueous phase was back-extracted with MTBE (500 mL). The organics were combined, washed with 0.5 N NaOH (2×500 mL), brine (500 mL), and dried over MgSO4. The organics were filtered and concentrated to give 2-methyl-4-(triisopropylsilyloxy)aniline (135 g, 482 mmol, 83% yield) as a red oil. Exact mass calculated for C16H29NOSi: 279.2, found: LCMS m/z=280.5, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.09 (d, J=7.0 Hz, 18 H), 1.21 (m, 3 H), 2.12 (s, 3 H), 3.31 (bs, 2 H), 6.53 (d, J=8.4 Hz, 1 H), 6.57 (dd, J1=8.4, J2=2.7 Hz, 1 H), 6.62 (d, J=2.7 Hz, 1 H).
Reaction SMILES: O[CH:2]1[C:6]2[C:7]3[C:12]([CH:13]=[CH:14][C:5]=2[C:4](=[O:18])[O:3]1)=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=[CH:9][CH:8]=3.CC1C=CC(S(O)(=O)=O)=CC=1.[CH:30](OC)([O:33]C)[O:31][CH3:32].CC(O)=O>CO.C([O-])(O)=O.[Na+]>[OH:17][C:15]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[CH:14][C:5]1[C:4](=[O:18])[O:3][CH:2]([C:30]([O:31][CH3:32])=[O:33])[C:6]=12)=[O:16]
Reactant: COC(OC)OC
Reactant: O=C1OC(O)c2c1ccc1c(C(=O)O)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1OC(=O)c2ccc3c(C(=O)O)cccc3c21
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 1-hydroxy-6-hydroxycarbonylnaphtho[1,2-c]furan-3(1H)-one in dry MeOH (15 mL) was added TsOH (150 mg) and CH(OMe)3 (0.5 mL). The mixture was stirred at reflux for 2 h. The mixture was then cooled to rt, diluted with saturated aqueous NaHCO3, acidified with AcOH and extracted with EtOAc. The extract was dried over MgSO4 and concentrated in vacuo. The crude material was chromatographed on silica gel (85:15:1 to 66:33:1 hexanes:EtOAc:AcOH) to give the title compound (120 mg, 79% from 1-hydroxy-6-hydroxycarbonylnaphtho[1,2-c]furan-3(1H)-one).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][C:4]#[C:5][CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C:8]1=[O:13].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:14][N:2]([CH3:1])[CH2:3][C:4]#[C:5][CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([O:12][S:23]([CH3:22])(=[O:25])=[O:24])[C:8]1=[O:13]
Reactant: CN(C)CC#CCN1CC[C@@H](O)C1=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CC#CCN1CC[C@@H](OS(C)(=O)=O)C1=O

Procedure:
A solution of 0.4 g of (R)-1-[4-(dimethylamino)-2-butynyl]-3-hydroxy-2-pyrrolidinone, 0.6 ml of triethylamine and 0.3 ml of methane sulfonyl chloride in 10 ml of dichloromethane was stirred at 0° C. for 1 hour. Saturated aqueous sodium carbonate was added and the mixture separated. The aqueous portion was washed with dichloromethane. The organic layer and wash were combined, washed with sodium chloride solution, dried and evaporated. The residue was evaporated from 10 ml of toluene. The residual oil was purified by chromatography (silica gel), giving 0.4 g of (R)-1-[4-(dimethylamino)-2-butynyl]-3-[(methane sulfonyl)oxy]-2-pyrrolidinone as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:15][C:16]([NH2:18])=[S:17]>>[CH3:1][O:2][C:3]([C:4]1[N:15]=[C:16]([NH2:18])[S:17][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1
Reactant: NC(N)=S
Product: COC(=O)c1nc(N)sc1-c1ccccc1

Procedure:
prepared by reaction of 3-chloro-3-phenyl-2-oxo-propionic acid methyl ester with thiourea. LC-MS: tR=0.77 min; [M+H]+=235.