Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][CH:10]([C:14]#[N:15])[C:11]([NH2:13])=[O:12])=[CH:4][C:3]=1[O:16][CH3:17].Cl>C1(C)C=CC=CC=1.Cl[Ti](Cl)(Cl)Cl>[NH2:15][C:14]1[C:6]2[C:5](=[CH:4][C:3]([O:16][CH3:17])=[C:2]([Br:1])[CH:7]=2)[N:8]=[N:9][C:10]=1[C:11]([NH2:13])=[O:12]
Reactant: COc1cc(N=NC(C#N)C(N)=O)ccc1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc2nnc(C(N)=O)c(N)c2cc1Br
Temperature: 25 °C

Procedure:
To a mixture of 2-((4-bromo-3-methoxyphenyl)diazenyl)-2-cyanoacetamide (Method 12) (34.4 g, 115.8 mmol) in toluene (250 ml) under N2 was added TiCl4 (51.1 ml, 463 mmol). The reaction mixture was stirred at reflux for 4 hours before being allowed to cool to room temperature. The reaction mixture was carefully poured over an ice cold solution of 3N HCl (˜600 ml), the mixture was then allowed to warm to rt, and was then stirred at 90° C. for 10 minutes. A precipitate formed which was collected via vacuum filtration, washed with water (˜200 mL), ethanol (˜200 mL), ether (˜200 mL), and dried in vacuo to yield the title compound as a brown solid which was used without further purification (30.0 g, 87%). 1H NMR: 10.30 (s, br, 1H), 9.95 (s, br, 1H), 9.15 (s, 1H), 8.55 (s, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 4.15 (s, 3H); m/z 298.
Reaction SMILES: [SH:1][CH2:2][C@H:3]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([C:13]([OH:15])=[O:14])[NH:5][C:4]1=[O:16].[C:17](Cl)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([S:1][CH2:2][C@H:3]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([C:13]([OH:15])=[O:14])[NH:5][C:4]1=[O:16])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: O=C1N[C@@H](C(=O)O)CCCCCC[C@@H]1CS
Solvent: c1ccncc1
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans 3-mercaptomethyl-2-oxo-1-azacyclodecane-10-carboxylic acid (0.75 g, 3.06 mmol) is dissolved in pyridine (20 mL). Acetyl chloride (0.26 g, 3.37 mmol) is added, and the reaction is stirred at room temperature overnight. The reaction is quenched by cooling to 0° C., adding concentrated hydrochloric acid (20 mL), diluting with water, and extracting several times with ethyl acetate. The combined organic layers are dried (MgSO4), and the solvent is evaporated to give trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid, MS:M+1=288.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH:8]1([CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.I[CH2:28][CH2:29][CH3:30]>CC(C)=O>[CH:8]1([CH2:14][CH2:15][N:16]([CH2:28][CH2:29][CH3:30])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COc1cccc(CCNCCC2CCCCC2)c1
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCN(CCc1cccc(OC)c1)CCC1CCCCC1

Procedure:
48 g of potassium carbonate were added to a solution of 17.8 g of the product of Step B in 180 ml of acetone and after the addition of 17.5 ml of 1-iodopropane, the mixture was refluxed under an inert atmosphere for 41/2 hours and was filtered. The filtrate was evaporated to dryness and the residue was taken up in ether. 100 ml of 2 N sodium hydroxide solution was added to the mixture and the decanted organic phase was washed with water, dried and evaporated to dryness to obtain 19.25 g of N-(2-cyclohexylethyl)-3-methoxy-N-propyl-benzeneethanamine in the form of a yellow oil which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([CH2:8][C:9](OC)=[O:10])[CH:7]=1.COCCOC.C(O)C.[OH-].[Na+]>Cl.[Pd]>[NH2:16][C:3]1[CH:4]=[C:5]2[C:6]([CH2:8][C:9](=[O:10])[NH:13]2)=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Nc1cc2c(cc1F)CC(=O)N2
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A mixture of 10% Pd on carbon (2.44 g, 10% by weight), methyl (5-fluoro-2,4-dinitrophenyl)acetate (24.4 g, 93.8 mmol), ethylene glycol dimethyl ether (100 mL) and ethanol (100 mL) is hydrogenated on a Parr hydrogenator for 11/2 hours. After the uptake of 47-48 psi, the reaction mixture is removed from the hydrogenator. The catalyst is filtered and the filtrate is concentrated in vacuo to give a dark oil. The oil is diluted with 1M hydrochloric acid, heated at reflux for 20 minutes, cooled to room temperature and the pH is adjusted to 8 with 3N sodium hydroxide solution. The pH adjusted solution is extracted with ethyl acetate and the combined organic extracts are dried and concentrated in vacuo to give the title product as a light brown solid (13.2 g, mp 185°-187° C. dec) which is identified by 1H NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([O:26]CC)=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([F:22])([F:23])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(F)c(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(-c2ccc(F)c(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1

Procedure:
3.60 g (8.72 mmol) of the compound of Example 27A are provided in 50 ml of 1,4-dioxane, 50 ml (50 mmol) of a 1N solution of lithium hydroxide in water are added, and the mixture is heated under reflux for 1 h. The mixture is concentrated, the residue is diluted with water, a conc. aqueous hydrogen chloride solution is subsequently added until the pH is acidic, the mixture is extracted with ethyl acetate, and the organic phase is dried over magnesium sulfate, filtered and concentrated. 3.30 g (98% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:27])([CH3:26])[C:3]1[S:4][C:5]([C:8]23[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:13][C@@H:12]2[CH2:11][O:10][NH:9]3)=[CH:6][N:7]=1.[C:28]([N:36]=[C:37]=[S:38])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[C:28]([NH:36][C:37]([N:9]1[C:8]2([C:5]3[S:4][C:3]([Si:2]([CH3:27])([CH3:26])[CH3:1])=[N:7][CH:6]=3)[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:13][CH:12]2[CH2:11][O:10]1)=[S:38])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: C[Si](C)(C)c1ncc(C23CN(C(=O)OCc4ccccc4)C[C@@H]2CON3)s1
Solvent: C1CCOC1
Product: C[Si](C)(C)c1ncc(C23CN(C(=O)OCc4ccccc4)CC2CON3C(=S)NC(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a mixture of benzyl (3aS)-6a-(2-trimethylsilylthiazol-5-yl)-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (0.218 g, 0.54 mmol) in THF (3.60 mL) is added benzoyl isothiocyanate (0.088 g, 0.54 mmol). The mixture is stirred for 1 hour at room temperature and more benzoyl isothiocyanate (0.044 g, 0.27 mmol) is added. The reaction is stirred for 3 hours at room temperature, concentrated under reduced pressure, and purified by silica gel chromatography eluting with a gradient of 5% to 100% ethyl acetate in hexanes to give title compound (0.204 g, 67%). ES/MS (m/e): 404 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=2[C:5]([CH:21]=O)=[C:4]([CH3:23])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:43](Br)(Br)([Br:45])[Br:44]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([CH:21]=[C:43]([Br:45])[Br:44])=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(Cl)c32)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=C(Br)Br)c(C)cc(Cl)c32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-chloro-5-methyl-1-tosyl-1H-indole-4-carbaldehyde (48 mg, 0.138 mmol) and PPh3 (109 mg, 0.414 mmol) in DCM (1.4 mL) at 0° C., was added CBr4 (68.6 mg, 0.207 mmol) and the reaction was warmed to room temperature. After 10 minutes the reaction mixture was loaded onto silica gel and was purified by flash chromatography (0-50% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.00 (d, J=3.79 Hz, 1H) 7.88 (s, 1H) 7.73 (m, J=8.59 Hz, 2H) 7.42 (m, J=7.83 Hz, 2H) 7.23 (s, 1H) 6.71 (d, J=3.79 Hz, 1H) 2.37 (s, 3H) 2.23 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[O:12][CH3:13]>[C].[Pd].CO>[F:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[NH2:9]
Reactant: COc1c(F)cc(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1c(N)cc(C)cc1F
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
5% Palladium-carbon (wet, 100 mg) was added to a methanol (5 ml) solution of 1-fluoro-2-methoxy-5-methyl-3-nitrobenzene (I-25) (250 mg, 1.35 mmol), followed by stirring under hydrogen atmosphere for 30 minutes. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (9:1) was concentrated under reduced pressure to obtain the entitled compound (170 mg, 81%) as a yellow oily substance.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[PH:7](=[O:32])([O-:31])[O:8][CH2:9][C:10](CC1C=CC=CC=1)(CC1C=CC=CC=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-]>C1C=CC=CC=1>[Cl-:2].[PH:7](=[O:32])([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:31][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[PH]([O-])OCC(Cc1ccccc1)(Cc1ccccc1)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=[PH](OCCc1ccccc1)OCc1ccccc1

Procedure:
1 mmole of phosphorus pentachloride in benzene is added to a solution in benzene of 1 mmole of dibenzylphenylethyl phosphonate, which has been previously obtained. The mixture is refluxed at 70° C. for 3 to 4h under an anhydrous atmosphere until the chloride is completely obtained. The benzene of said mixture is then evaporated and is taken up in dichloromethane. This solution is used immediately for carrying out coupling with the peptide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:31]1[CH2:32][CH2:33][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH2:30]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: Cc1ccc(C2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(C2CCN(C(=O)c3cnoc3-c3ccccc3Cl)C2)cc1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-methylphenyl)pyrrolidine oxalate (15.1 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (7.2 mg). Calcd for C21H19ClN2O2: 366.1135, found 366.1133.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH:13]=[C:12]([OH:16])[CH:11]2[CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C.[BH4-].[Na+].O>C(#N)C.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:14](=[O:15])[CH2:13][C@H:12]([OH:16])[C@@H:11]2[CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCCC1C(O)=CC(=O)N1c1ccc(C#N)c(Cl)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CCC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a mixture of 2-chloro-4-(3-hydroxy-5-oxo-2-propyl-2,5-dihydro-1H-pyrrol-1-yl)benzonitrile (800 mg) and acetic acid (1.82 mL) in acetonitrile (25 mL) was added sodium borohydride (273 mg) at 0° C. in small portions. The mixture was warmed to room temperature and stirred for 1 hr. Water and saturated brine were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1→ethyl acetate), and recrystallized from tetrahydrofuran-hexane to give the title compound as colorless crystals (yield: 578 mg, 72%).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][C@H:40]([C:44]([NH:46][C@H:47]([C:53]([OH:55])=[O:54])[CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[O:45])[C@@H:41]([CH3:43])[OH:42].C(N(CC)CC)C.Cl>O1CCCC1.O>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][C@H:40]([C:44]([NH:46][C@H:47]([C:53]([OH:55])=[O:54])[CH2:48][CH2:49][C:50]([OH:52])=[O:51])=[O:45])[C@@H:41]([CH3:43])[OH:42])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)O)C(=O)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a solution of N-hydroxysuccinimide ester of 3-hexadecanoyloxyoctadecanoic acid (1.5 g) in tetrahydrofuran (100 ml) were added a solution of N-(L-threonyl)-L-glutamic acid (0.79 g) and triethylamine (0.88 ml) in water (220 ml). The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was acidified with 1N hydrochloric acid, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. Ethyl acetate was distilled off to give a residue which was purified by silica gel column chromatography. Elution with chloroform-methanol (20:1) afforded powder of N-[N-(3-hexadecanoyloxyoctadecanoyl)-L-threonyl]-L-glutamic acid (1.0 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([NH2:25])[NH:19][C:18]3=[O:26])[CH2:11][C:12]#[CH:13])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:27][N:28]([CH3:30])[NH2:29]>CO>[NH2:25][C:20]1[NH:19][C:18](=[O:26])[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([CH2:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:1](=[N:29][N:28]([CH3:30])[CH3:27])[CH3:2])=[CH:9][CH:8]=3)[CH2:11][C:12]#[CH:13])[CH:16]=2)[N:21]=1
Reactant: C#CCN(Cc1ccc2nc(N)[nH]c(=O)c2c1)c1ccc(C(C)=O)cc1
Reactant: CN(C)N
Solvent: CO
Product: C#CCN(Cc1ccc2nc(N)[nH]c(=O)c2c1)c1ccc(C(C)=NN(C)C)cc1

Procedure:
A suspension of 3.46 g (10 mmol) of 6-[[(4-acetylphenyl)-2-propynylamino]methyl]-2-amino-4(3H)-quinazolinone (see Example 2j) and 6.01 g (100 mmol) of 1,1-dimethylhydrazine in 250 ml of methanol is heated under reflux for eighteen hours. The solution is concentrated and the residue recrystallized from methanol to give the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[C:7]([O:21][C:22](=O)C)[CH:6]=1)C.CC(C)([O-])C.[K+].C(=O)([O-])[O-].[K+].[K+].IC>CO>[CH3:1][O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[C:7]([O:21][CH3:22])[CH:6]=1
Reactant: CCOC(=O)c1ccc(OCCc2cccc(C)c2)c(OC(C)=O)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CO
Product: COC(=O)c1ccc(OCCc2cccc(C)c2)c(OC)c1
Reaction time: 8 h

Procedure:
The compound of step 2 (150 mg, 0.438 mmol) was dissolved in methanol (3 ml), potassium tert-butoxide (73 mg, 0.657 mmol) was added and the mixture was stirred overnight under reflux. Potassium carbonate (60 mg, 0.44 mmol) and iodomethane (124 mg, 0.876 mmol) were then added repeatedly, at intervals of 1 h, with stirring under reflux until completion of the reaction. The volatiles were evaporated in vacuo, the residue was partitioned between EA and 2 N hydrochloric acid, and the aqueous phase was extracted with EA. The combined organic phases were dried over sodium chloride, decanted and evaporated to dryness to yield the title compound.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12](=[O:25])[O:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[C:16]([O:21]C(=O)C)[CH:15]=3)=[CH:7][CH:6]=1)(=O)C.[OH-].[Li+].O.Cl>CN(C=O)C>[OH:21][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=3)[C:12](=[O:25])[O:13]2)=[CH:18][CH:17]=1
Reactant: CC(=O)Oc1ccc(-c2cc3ccc(OC(C)=O)cc3oc2=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1oc2cc(O)ccc2cc1-c1ccc(O)cc1
Temperature: 65 °C

Procedure:
To a solution of 4-(7-acetoxy-2-oxo-2H-chromen-3-yl)phenyl acetate of formula (3) (80 gm) in DMF (400 mL) an aqueous solution of lithium hydroxide (29.8 g, 0.71 mol) was added at RT and maintained at 60-70° C. for 1-2 hours. After the completion of the reaction, water (800 mL) and dilute hydrochloric acid (112 mL) was added to the reaction mass. The reaction mass was maintained at RT for 1-2 hours. The solid was filtered and dried at 70-75° C. for 6-8 hours to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[I:17])[C:10]([O:12]C)=[O:11])[CH3:3].[OH-].[Na+]>CO>[CH3:3][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[I:17])[C:10]([OH:12])=[O:11])[CH3:1]
Reactant: COC(=O)c1ccc(I)c(OCCN(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCOc1cc(C(=O)O)ccc1I

Procedure:
Methyl 3-[2-(N,N-dimethylamino)ethoxy]-4-iodobenzoate (Intermediate 3) (100 mg) was stirred in methanol (2 ml) and sodium hydroxide solution (2N, 2 ml) for 6 hours at room temperature. The methanol was evaporated under vacuum and the remaining solution neutralised with hydrochloric acid (2M). The mixture was extracted with ethyl acetate/chloroform (1:1) and the organic extracts reduced to dryness under vacuum to give 3-[2-(N,N-Dimethylamino)ethoxy]-4-iodobenzoic acid.
Reaction SMILES: [Cl-].C([Al+]CC)C.Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[CH:32]=[O:33])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.O1CCCC1.[Zn].[Cu]Br>[OH:33][CH:32]([C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1ccccc1CCCCCCCCc1ccccc1
Agent: [Cu]Br
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCCc1ccccc1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of diethylaluminum chloride (0.0082 moles, 8.2 ml) in hexane was added to a slurry of zinc dust (0.0111 mol; 0.7248 g) and a catalytic amount of copper (I) bromide (0.0004 moll; 0.0585 g) in anhydrous tetrahydrofuran (40 ml) while stirring under argon at 20° C. The resulting mixture was then cooled to -20° C. in an ice-methanol bath. A solution of t-butyl bromoacetate (0.0082 mol; 1.32 ml) and 2-(8-henyloctyl)benzaldehyde of Example 5(a) or (b) (0.0082 moles; 2.3969 g) in anhydrous tetrahydrofuran was added slowly over 60 min. The reaction was stirred overnight and was permitted to warm up slowly to room temperature. The mixture was filtered to remove zinc, concentrated, and azeotroped with methylene chloride. The resulting oil was then chromatographed on silica using 5% ethyl acetate in hexane with 0.5% formic acid to yield the desired product.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27].N(C(OCC)=O)=NC(OCC)=O.[OH:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44]O>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:44][C:43]1[CH:42]=[C:41]([OH:40])[CH:48]=[CH:47][CH:46]=1
Reactant: OCc1cccc(O)c1
Reactant: Oc1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Oc1cccc(COc2ccccc2Cl)c1
Reaction time: 1 h
Yield: 50.9 %

Procedure:
At 0° C. to 616 mg (2.35 mmol) of triphenylphosphine and 400 μL (3.84 mmol) of 2-chlorophenol in 20 mL of methylene chloride was added 370 mL (2.35 mmol) of diethyl azodicarboxylate followed by dropwise addition of a solution of 233 mg (1.9 mmol) 3-hydroxybenzyl alcohol in 2 mL of tetrahydrofaran. The reaction mixture was stirred at 0° C. to ambient temperature for 1 h. The reaction mixture was quenched with water, extracted into diethyl ether, dried (MgSO4), and purified by flash chromatography (methylene chloride/hexane (2:1 to 4:1)) to provided 227 mg (44% yield) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.39 (dd, 1H, J=1.6, 7.8 Hz), 7.25 (t, 1H), 7.15-7.21 (m, 1H), 6.88-7.01 (m, 4H), 6.79 (dd, 1 H, J=2.5, 8.1 Hz), 5.12 (s, 2H), and 4.97 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH:12]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:12][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc([N+](=O)[O-])c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
N-methyl piperazine (2.50 mL, 22.5 mmol) was added dropwise to a solution of 3-chloro-4-nitrobenzaldehyde (2.09 g, 11.3 mmol) and acetic acid (0.29 mL, 5.14 mmol) in toluene (11.7 mL) at room temperature. The reaction mixture was stirred for 1.5 h at room temperature before the addition of further toluene (4.4 mL) and sodium triacetoxyborohydride (3.58 g, 16.9 mmol). The reaction mixture was stirred at room temperature overnight and then quenched by the addition of MeOH (3 mL) and saturated aqueous NaHCO3 (23 mL). The reaction mixture was stirred for 30 min. The phases were separated and the aqueous layer was extracted with toluene (2×30 mL). The combined organic extracts were concentrated under reduced pressure and purified by flash column chromatography (EtOAc:MeOH:NEt3 9:1:0.1) to give the title compound (2.17 g, 71%) as an orange oil.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[CH2:15][CH:16]=1
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Reactant: COc1ccc(CCl)cc1
Agent: Cl
Product: COc1ccc(CN2CC=C(c3cc4ccccc4s3)CC2)cc1
Yield: 4.18 %

Procedure:
4-(Benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (250 mg, 0.99 mmol) was reacted with 4-methoxybenzyl chloride (0.13 ml, 0.99 mmol) as exemplified in Example 1. The crude product was triturated with hot methanol to give the title compound as a pale yellow solid mp 158°-160° C. (Found: C, 75.09; H, 5.05; N, 4.31; C21 H21NOS requires C, 75.19; H, 6.31; N, 4.18%). δH (CDCl3) 2.65 (2H, m, NCH2CH2), 2.74 (2H, m, NCH2 CH2), 3.20 (2H, m, NCH2CH2), 3.61 (2H, s, NCH2Ar), 3.81 (3H, s, OMe), 6.18 (1H, m, NCH2CH), 6.87 (2H, d, J 8.6Hz, ArH), 7.12 (1H, s, ArH), 7.28 (4H, m, ArH), 7.65 (1H, d, J 6.8Hz, ArH), 7.73 (1H, d, J 6.9Hz, ArH). m/z (ES+) 336 (M+1)+.