Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1I)=[O:4].[F:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([S:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1.[Na+]>>[F:12][C:13]1[CH:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([S:27]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:3](=[O:4])[CH2:2][OH:1])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1
Reactant: O=S([O-])c1ccc(/C=C/c2ccc(F)cc2)cc1
Reactant: O=C(CO)c1ccccc1I
Agent: [Na+]
Product: O=C(CO)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from 2-hydroxy-1-(2-iodophenyl)ethanone (Step 1) and sodium 4-[(E)-2-(4-fluorophenyl)vinyl]benzenesulfinate according to the method of Example 135 Step 2. δH (500 MHz, d6 DMSO): 8.07 (1H, d, J=7.8 Hz), 7.88 (2H, d, J=8.4 Hz), 7.80 (2H, d, J=8.4 Hz), 7.76-7.66 (4H, m), 7.54 (1H, d, J=7.4 Hz), 7.45 (1H, d, J=16.4 Hz), 7.28 (1H, d, J=16.4 Hz), 7.23 (2H, t, J=8.7 Hz), 5.47 (1H, t, J=5.9 Hz), 4.54 (2H, d, J=5.9 Hz).
Reaction SMILES: [N:1]([CH2:4][C:5]1([OH:13])[CH2:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6]1)=[N+:2]=[N-:3].[H-].[Na+].[CH3:16]I>O1CCCC1>[N:1]([CH2:4][C:5]1([O:13][CH3:16])[CH2:10][CH2:9][CH2:8][C:7]([CH3:11])([CH3:12])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC1(C)CCCC(O)(CN=[N+]=[N-])C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(CN=[N+]=[N-])CCCC(C)(C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of EXAMPLE 166B (1.33 g) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 435 mg) in tetrahydrofuran (15 mL) at 0° C. The mixture was stirred for 10 minutes at 0° C. and for 30 minutes at room temperature. CH3I (1.55 g) was added dropwise. The resulting reaction mixture was stirred overnight at room temperature, and then quenched with water (100 mL) and extracted with ethyl acetate (3×50 mL). The extracts were washed with brine, dried (Na2SO4), and filtered. After concentration, the crude material was purified by flash chromatography on silica gel using 0 to 7% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(O)(=O)[C:13]1[CH:21]=[CH:20][C:18](O)=[C:15]([O:16]C)[CH:14]=1.C(O)CCCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:2]([O:16][CH2:15][CH2:14][CH2:13][CH2:21][CH2:20][CH3:18])(=[O:1])[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: COc1cc(C(=O)O)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCO
Product: CCCCCCOC(=O)c1ccc(O)c(OC)c1
Yield: 86 %

Procedure:
Hexyl vanillate was synthesized according to the method of Pearl, I.A., and McCoy, J. F. "Reaction of Vanillin and its Derived Compounds. Some Esters of Vanillic Acid." J. AM. CHEM. SOC. 69: 3071 (1947). Vanillic acid (20.2 g, 0.12 mol) was refluxed with n-hexanol (29.9 ml, 0.24 mol) in the presence of p-toluenesulfonic acid (0.2 g) for 26 hours. After the unreacted alcohol was removed by distillation in a vacuum, the hexyl vanillate was distilled and obtained in 86% yield.
Reaction SMILES: [Cl-].[NH4+:2].C([Al](CC)CC)C.[CH2:10]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])[CH2:11][CH3:12].C(Cl)(Cl)[Cl:23]>C1(C)C=CC=CC=1.CCCCCC>[ClH:23].[CH2:10]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]([NH2:2])=[NH:17])[CH2:11][CH3:12]
Reactant: ClC(Cl)Cl
Reactant: [NH4+]
Reactant: CCCOc1ccccc1C#N
Agent: CC[Al](CC)CC
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCOc1ccccc1C(=N)N
Product: Cl
Temperature: 2.5 °C

Procedure:
21.41 g (400 mmol) of ammonium chloride are suspended in 400 ml of toluene and cooled to 0-5° C. 200 ml of a 2M solution of triethylaluminium in hexane are added dropwise, and the mixture is stirred at room temperature until the evolution of gas has ceased. After addition of 32.2 g (200 mmol) of 2-propoxybenzonitrile, the reaction mixture is stirred at 80° C. (bath) overnight. With ice-cooling, the cooled reaction mixture is added to a suspension of 300 g of silica gel and 2.85 of ice-cooled chloroform, and the mixture is stirred for 30 minutes. The mixture is filtered off with suction and the filter residue is washed with the same amount of methanol. The solvent is distilled off under reduced pressure, the residue is stirred with 500 ml of a mixture of dichloromethane and methanol (9:1), the solid is filtered off and the mother liquor is concentrated. The residue is stirred with petroleum ether and filtered off with suction. This gives 22.3 g (52%) of product.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4](/[CH:5]=[CH:6]\[C:7]#[N:8])[C@H:3]1[C:9](Cl)=[O:10].[CH3:13][OH:14].C1C=CC=CC=1.N1C=CC=CC=1>O>[CH3:1][C:2]1([CH3:12])[C@@H:4](/[CH:5]=[CH:6]\[C:7]#[N:8])[C@H:3]1[C:9]([O:14][CH3:13])=[O:10]
Reactant: CO
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1/C=C\C#N
Solvent: O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COC(=O)[C@@H]1[C@H](/C=C\C#N)C1(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
1.85 g of (1R,cis) 2,2-dimethyl-3-[(Z)-cyanoethenyl]-cyclopropane-1-carboxylic acid chloride were added at 0° to solution of 2 ml of methanol, 10 ml of benzene and 1 ml of pyridine and the reaction solution was stirred at 20° C. for 16 hours and was poured into water. The mixture was extracted with benzene and the organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with benzene to obtain 0.511 g of methyl (1R,cis) 2,2-dimethyl-3[(Z)-2-cyanoethenyl]cyclopropane-1-carboxylate.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:17]([O:19][C:20](=[O:33])[CH:21]([N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[C:26]1=[O:32])[O:22][CH2:23][CH3:24])[CH3:18].CC1(C)N([O])C(C)(C)CCC1>C(Cl)Cl>[CH2:17]([O:19][C:20](=[O:33])[CH:21]([O:22][CH2:23][CH3:24])[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:26]1=[O:32])[CH3:18]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)C(OCC)n1cccc(N)c1=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(OCC)n1cccc(Nc2ccccc2)c1=O
Reaction time: 72 h
Yield: 47.6 %

Procedure:
To a 100 ml flask was added in sequence molecular sieves 4Å(200 mg), phenylboronic acid (418 mg), CH2Cl2 (10 ml), triethylamine (0.48 ml), a solution of (RS)-(3-amino-2-oxo-2H-pyridin-1-yl)-ethoxy-acetic acid ethyl ester (412 mg, example 19.2) in CH2Cl2 (10 ml), cupric acetate (31 mg) and TEMPO (295 mg). A CaCl2 trap was placed over the flask. The reaction was then stirred under air for 3 days. The solids were filtered off and washed with CH2Cl2. The filtrate was concentrated. The crude product was purified by chromatography (silica gel, gradient cyclohexane/EtOAc) to give (RS)-ethoxy-(2-oxo-3-phenylamino-2H-pyridin-1-yl)-acetic acid ethyl ester (258 mg) as green oil. MS 317.2 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:4]=[C:5]([O:9]CC2C=CC=CC=2)[C:6](=[O:8])[CH:7]=1>CCO.[Pd]>[NH2:1][C:2]1[N:3]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH:4]=[C:5]([OH:9])[C:6](=[O:8])[CH:7]=1
Reactant: Nc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(=O)c(O)cn1-c1cccc(-c2ccccc2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 2-amino-5-(benzyloxy)-1-(biphenyl-3-yl)pyridin-4(1H)-one (2.65 g, 7.19 mmol) and 10% Pd/C (230 mg) in EtOH (300 mL) was stirred under an H2 balloon for 2 h. After this time, LCMS indicated that the reaction was complete. After evacuation and purge with N2 (3×), the EtOH solution was warmed to 50° C. and stirred 1 h at 50° C. The warmed EtOH solution was filtered and the catalyst was washed with warmed EtOH (4×50 mL). The combined EtOH solution was concentrated to give 2-amino-1-(biphenyl-3-yl)-5-hydroxypyridin-4(1H)-one as slightly yellow solid. 1H NMR (500 MHz, DMSO): δ 7.81 (d, J=7.9 Hz, 1 H); 7.76 (d, J=7.7 Hz, 2 H); 7.71-7.59 (m, 2 H); 7.49 (t, J=7.6 Hz, 2 H); 7.43-7.37 (m, 2 H); 6.91 (s, 1 H); 5.66 (s, 2 H); 5.54 (s, 1 H). HRMS Calcd for (C17H14N2O2+H)+ 279.1128. Found 279.1128.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[Br:12]N1C(=O)CCC1=O.O>CC#N>[Br:12][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([NH2:9])[C:5]=1[NH2:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Solvent: O
Solvent: CC#N
Product: Nc1cccc(Br)c1N
Temperature: 70 °C
Reaction time: 14 h
Yield: 119.9 %

Procedure:
A mixture of 4-chloro-2-nitrobenzenamine (2.0 g, 11.59 mmol) and 1-bromopyrrolidine-2,5-dione (2.3 g, 12.75 mmol) in MeCN (30 mL) was stirred at 70° C. for 14 h. The reaction mixture was poured into water (100 mL) and stirred at RT for 1 h. The precipitate was filtered and washed with water. The solid was dried under vacuum to afford 3-bromobenzene-1,2-diamine as a yellow solid (2.6 g, 86.7%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:16][O:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[N:6]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13].[NH3:27]>C1COCC1.CS(C)=O>[CH2:22]([O:21][P:19]([CH2:18][O:17][CH2:16][C:5]1[N:6]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:7]2[C:3]([N:4]=1)=[C:2]([NH2:27])[N:10]=[CH:9][N:8]=2)([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: CCOP(=O)(COCc1nc2c(Cl)ncnc2n1CC(C)(C)C)OCC
Reactant: N
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOP(=O)(COCc1nc2c(N)ncnc2n1CC(C)(C)C)OCC

Procedure:
A solution of 6-chloro-8-diethylphosphonomethoxymethyl-N9-neopentylpurine (1 mmol) in THF-DMSO was treated with liquid ammonia (10 mmol) at 25° C. for 6 h. Extraction and chromatography afforded 8-diethylphosphonomethoxymethyl-N9-neopentyladenine as a white solid. TLC: Rf=0.44,25% MeOH-EtOAc.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH2:4].C[C:14]([CH3:27])([C:25]#[CH:26])[C:15]([O:17][C:18](=[O:24])[C:19]([CH3:23])([CH3:22])[C:20]#[CH:21])=O.[CH3:28][CH2:29]N(CC)CC>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:4][C:3]1[CH:5]=[C:6]([F:12])[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[C:21]#[C:20][C:19]([CH3:22])([CH3:23])[C:18]([O:17][CH2:15][C:14]1[CH:25]=[CH:26][CH:29]=[CH:28][CH:27]=1)=[O:24]
Reactant: CCN(CC)CC
Reactant: C#CC(C)(C)C(=O)OC(=O)C(C)(C)C#C
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(C)(C#Cc1cc([N+](=O)[O-])c(F)cc1N)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 2-bromo-5-fluoro-4-nitroaniline (23.0 g, 0.1 mol) in Et3N (250 mL) was added benzoic 2,2-dimethylbut-3-ynoic anhydride (59.0 g, 0.29 mol), CuI (1.85 g) and Pd(PPh3)2Cl2 (2.3 g) at room temperature. The mixture was stirred at 80° C. overnight. After cooling to room temperature, the reaction was quenched with water and the aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layer was dried over anhydrous Na2SO4, the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (10% ethyl acetate in petroleum ether) to give benzyl 4-(2-amino-4-fluoro-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (20.0 g, 56%). 1H NMR (400 MHz, CDCl3) 8.05 (d, J=8.4 Hz, 1H), 7.39-7.38 (m, 5H), 6.33 (d, J=13.2 Hz, 1H), 5.20 (s, 2H), 4.89 (br s, 2H), 1.61 (s, 6H).
Reaction SMILES: CS[C:3]([S:9][CH3:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6].[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>CCO>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:3](=[C:4]([C:7]#[N:8])[C:5]#[N:6])[S:9][CH3:10])=[CH:20][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CSC(SC)=C(C#N)C#N
Solvent: CCO
Product: CSC(Nc1ccc(C(C)(C)C)cc1)=C(C#N)C#N
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A mixture of 2-(di(methylthio)methylene)malononitrile I-7 (300 mg, 1.76 mmol) and 4-tert-butylaniline (263 mg, 1.76 mmol) in EtOH (5 mL) was refluxed for 3 days. After the reaction mixture was allowed to cool to room temperature, the resulting solid was filtered, washed with minimal EtOH, and dried to give compound 5 (255 mg, 53.5% yield, 98.9% purity) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][CH2:22][CH:23]([C:25]([O:27][CH3:28])=[O:26])[N:24]=4)=[CH:16][C:15]=3[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:12])=[O:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.BrC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>ClCCl>[F:1][C:2]1[CH:34]=[CH:33][C:5]2[S:6][C:7]([S:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][CH:22]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[N:24]=4)=[CH:16][C:15]=3[S:29]([CH3:32])(=[O:31])=[O:30])(=[O:11])=[O:12])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: COC(=O)C1COC(c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)=N1
Solvent: ClC(Cl)(Cl)Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1coc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
Into 40 mL of dichloromethane was dissolved 1.10 g of Compound 22, followed by addition of 498 mg of bromotrichloromethane at −20° C. Further, 700 mg of DBU was added dropwise at the same temperature and the whole was stirred at the same temperature for 5 minutes and then warmed to 0° C., followed by 3.5 hours of stirring. After confirmation of disappearance of the starting material, the reaction was terminated by adding saturated aqueous sodium hydrogen carbonate solution at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=20/1) to obtain 597 mg of the title compound as colorless powder.
Reaction SMILES: ClC(OCC(C)C)=O.O.[C:10]([NH:17][C@H:18]([C:23]([OH:25])=O)[CH2:19][CH:20]([CH3:22])[CH3:21])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN1CCOCC1.[CH3:33][O:34][CH2:35][CH2:36][CH2:37][NH2:38]>C1COCC1>[CH3:33][O:34][CH2:35][CH2:36][CH2:37][NH:38][C:23](=[O:25])[C@H:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[NH:17][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: COCCCN
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: COCCCNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 90.9 %

Procedure:
Isobutyl chloroformate (520 μL, 4.0 mmol) was added to a solution of N-Boc leucine monohydrate (1.0 g, 4.0 mmol) and N-methyl morpholine (440 μL, 1.73 mmol) in THF at 0° C. After two minutes, 3-methoxypropylamine (410 μL, 4.0 mmol) was added and the mixture was allowed to warm to rt. After thirty minutes, the reaction mixture was filtered through a bed of celite and all volatiles were removed under reduced pressure to yield N-Boc-L-leucine-3-methoxypropyl amide (1.10 g, 92%) as a white solid. 1H NMR: (CDCl3) δ 0.93, 6H, d; 1.42, 9H, s; 3.35, 3H, s; 3.38, 2H, d; 3.43 m 2H, t; 4.03m 1H, m; 4.39, s, 1H; 4.91, 1H, m; 6.60, 1H, m,
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:6]([O:17][CH3:18])=[C:7]([CH:12]=[C:13]([Cl:16])[C:14]=1[NH2:15])[C:8]([O:10][CH3:11])=[O:9].C(N(CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[C:8]([C:7]1[C:6]([O:17][CH3:18])=[C:5]2[C:14](=[C:13]([Cl:16])[CH:12]=1)[NH:15][CH2:2][CH2:3][CH2:4]2)([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Cl)c(N)c(CCCO)c1OC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c2c(c1OC)CCCN2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the compound of step 4 above (1.4 g), triethylamine (1 ml) and TsCl (1.1 g) in CH2Cl2 is stirred at 25° C. for three days. The mixture is washed with saturated aqueous NaHCO3 and evaporated affording a residue which is dissolved in toluene and refluxed for 21/2 hours. The toluene is evaporated and the residue is dissolved in CH2Cl2 and washed with saturated NaHCO3 (25 mls). The organic layer is dried, evaporated and the residue chromatographed on silica gel affording a gum which crystallizes from HexEt2O to give the desired product (M.P. 105°-108° C.).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=[O:4].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH2:25]([O:32][C:33](=[O:44])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:43])[C@H:40]([CH3:42])[NH2:41])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl>[CH2:25]([O:32][C:33](=[O:44])[C@@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39](=[O:43])[C@H:40]([CH3:42])[NH:41][C:3](=[O:4])[C@@H:2]1[CH2:6][CH2:7][CH2:8][NH:1]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 2.5 h

Procedure:
Ac-L-proline (3.05 g, 19.41 mmol) was dissolved in drytetrahydrofuran (100 ml) under an argon atmosphere in a flask fitted with an overhead stirrer and an internal thermometer. The solution was cooled to -15° C. and N-methylmorpholine (2.13 ml, 19.41 mmol) was added followed by isobutylchloroformate (2.51 ml, 19.41 mmol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. Five minutes after the addition was completed, a solution of L-alanyl-L-proline benzyl ester hydrochloride (6.08 g, 19.41 mmol) in chloroform (70 ml) was added followed by a second portion of N-methylmorpholine (2.13 ml, 19.41 mmol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. The reaction mixture was then allowed to slowly warm to room temperatureand stirred at room temperature for 2.5 hours. Thereaction mixture was concentrated to a small residue on a rotary evaporator, diluted with chloroform (500 ml) and poured into a separatory funnel where it was washed with 0.2N hydrochloric acid (3×200 ml) and 5% sodium bicarbonate (200 ml). The organic layer was dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and chromatographed using methylene chloride-methanol as an eluent to give Ac-L-prolyl-L-alanyl-L-proline benzyl ester; Rf: 0.35 (CH3OH/CH2Cl2 --7:93).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]1CCN2C(=NCCC2)CC1>CCOC(C)=O.O>[CH3:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc2ccccc12
Temperature: 90 °C

Procedure:
To a solution of 1-naphthol (1.0 g, 6.94 mmol) in DMC (10 mL), DBU (1.06 g, 6.94 mmol) was added and the resulting mixture was heated to reflux (90° C.) for 16 hours. The reaction was cooled to ambient temperature and diluted with EtOAc (50 mL) and H2O (40 mL). The organic layer was separated and washed in sequence with 2M HCl (2×40 mL), 2M NaOH (2×40 mL) and H2O. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give 1-methoxynaphthalene as an oil. The yield of 1-methoxynaphthalene as determined by HPLC was 99% conversion.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C)C=O.O>[CH2:37]([O:36][C:34](=[O:35])[CH2:33][O:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:4]([CH2:5][N:6]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[CH:8]=[C:7]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:3]=1)[CH3:38]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(Cn2c(-c3ccccc3)cc3cc(OC)ccc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(3-hydroxybenzyl)-5-methoxy-2-phenylindole (108 mg) in N,N-dimethylformamide (1.3 mL) was added potassium carbonate (68.2 mg) at room temperature. Then ethyl bromoacetate (0.047 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (129 mg).
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[NH2:30]>C1(C)C(C)=CC=CC=1>[CH3:35][O:34][C:32]1[CH:31]=[C:29]([NH:30][C:2]2[C:3]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)(=[O:15])=[O:14])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:28]=[C:27]([O:26][CH3:25])[CH:33]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Reactant: COc1cc(N)cc(OC)c1
Solvent: Cc1ccccc1C
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc(OC)c1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A flask was charged with N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide (5 g, 13.7 mmol), prepared using procedures similar to those in Example 1, 3,5-dimethoxyaniline (4.2 g, 27.4 mmol), and 80 mL of xylene. The reaction mixture was stirred under an N2 atmosphere at 150° C. for 3 hours, after which time, solvent was removed on a rotary evaporator, and 10 mL of Dichloromethane and 50 mL of methanol were added. The slurry was heated to reflux and filtered while hot, resulting in 4.6 g (69.7%) of N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-3-nitrobenzenesulfonamide MS (EI) m/z for C22H19N5O6S: 482.2 (MH+).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(OCC)C.[C:17]([CH2:21][CH2:22][CH2:23][C:24]([Cl:26])=[O:25])([O:19][CH3:20])=[O:18]>C(O)(C(F)(F)F)=O>[C:17]([CH2:21][CH2:22][CH2:23][C:24]([C:6]([CH2:7][C:8](=[O:10])[O-:9])([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[OH:11])=[O:25])([O:19][CH3:20])=[O:18].[Cl-:26]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)CCCC(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Product: [Cl-]
Reaction time: 24 h

Procedure:
To a solution of carnitine chloride (2.0 g; 10 m moles) in TFA (5 cc), 4-carbomethoxy butyryl chloride (1.65 cc; 12 m moles) was added and the resulting reaction mixture was kept at room temperature under stirring for 24 hours. To this mixture anhydrous ethyl ether was then added. A solid formed which was filtered off and crystallized from hot isopropanol. M.P. 130°-132° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20](Cl)(=[O:22])[CH3:21].[Cl-].[Al+3].[Cl-].[Cl-].CCOCC>ClCCl>[CH3:10][O:9][C:5]1[C:4]([CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:20](=[O:22])[CH3:21]
Reactant: COc1cccc(OC)c1CCCc1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(C(C)=O)c(OC)c1CCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
A solution of 15.28 g (59.6 mmol) of 1,3-dimethoxy-2-(3-phenylpropyl)benzene from the preceding example, and 4.68 g (59.6 mmol) of acetyl chloride, in 306 mL of dichloromethane was stirred at -5° to 0° C. and 7.95 g (59.6 mmol) of aluminum chloride was added. The resulting mixture was stirred at -5° to 0° C. for 2 hr and then allowed to warm to room temperature before being poured onto ice. Work-up with ether in the usual manner gave a product which was chromatographed on silica gel. Elution with 7:3 hexane-ether afforded 10.0 g (56.3%) of the title compound as a pale-yellow oil.