Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH2:17]=[C:18]([CH3:20])[CH3:19].C([O-])(O)=O.[Na+]>O1CCOCC1>[C:18]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=1[OH:1])([CH3:20])([CH3:19])[CH3:17]
Reactant: C=C(C)C
Reactant: O=C(O)c1ccc(O)cc1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(O)cc1O
Temperature: -50 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-dihydroxy benzoic acid (3.08 g; 20 mmol) in dioxane (50 mL) was added conc. H2SO4 (3 mL) and the solution was cooled to −50° C. Isobutene (40 g) was added, the reaction flask sealed and allowed to warm to room temperature. The reaction mixture was stirred overnight, cooled to −30° C. and pH adjusted to 8 using saturated NaHCO3 (aq). The organic phase was Isolated, dried, evaporated to dryness and purified by column chromatography (SiO2-heptane/EtOAc=4:1) to yield 2.3 g (54%). MS (LC-MS): 209 (MH−).
Reaction SMILES: C([O-])(C)(C)C.[K+].[C:7]([NH:9][CH:10]=[N:11][CH:12]1[C:19]2[CH:18]=[CH:17][S:16][C:15]=2[CH2:14][C:13]1([CH3:21])[CH3:20])#[N:8].[CH3:22][O:23][C:24](=[O:27])[CH2:25]Br>CS(C)=O>[CH3:22][O:23][C:24]([C:25]1[N:11]([CH:12]2[C:19]3[CH:18]=[CH:17][S:16][C:15]=3[CH2:14][C:13]2([CH3:21])[CH3:20])[CH:10]=[N:9][C:7]=1[NH2:8])=[O:27]
Reactant: COC(=O)CBr
Reactant: CC1(C)Cc2sccc2C1N=CNC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1c(N)ncn1C1c2ccsc2CC1(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3.3 g of potassium tert.-butanolate are added to a mixture of 6.2 g of N-cyano-N'-(5,6-dihydro-5,5-dimethyl-4H-cyclopenta[b]thiophen-4-yl)-formamidine and 5 ml of dimethyl sulfoxide. After the mixture has been stirred for 15 hours at room temperature, 3.1 ml of bromoacetic acid methyl ester are added dropwise thereto. After 2 hours, ice-water is added to the reaction mixture. Extraction with ether, drying of the organic phase with sodium sulfate and evaporation of the solvent yield 8.4 g of N-cyano-N'-(5,6-dihydro-5,5-dimethyl-4H-cyclopenta[b]thiophen-4-yl)-N'-methoxycarbonylmethylformamidine in the form of a yellowish-brown oil. The oil is placed in 8 ml of methanol and, after the addition of 2.6 ml of 30% methanolic sodium methanolate solution, is heated at boiling for 16 hours. After cooling, the reaction solution is poured onto an ice-water/ether mixture. The organic phase is separated off, extracted with water and dried over sodium sulfate. Filtration and evaporation yield 5.1 g of brown crystals which are purified by chromatography on silica gel (eluant: ethyl acetate/hexane 1:1). 3.7 g of 4-amino-1-(5,6-dihydro-5,5-dimethyl-4H-cyclopenta[b]thiophen-4-yl)-5-imidazolecarboxylic acid methyl ester are obtained in the form of beige crystals having a melting point of 161°-162° C.
Reaction SMILES: [CH2:1]([C:6]1[CH2:20][C@@H:19]([OH:21])[C@H:18](/[CH:22]=[CH:23]/[C@@H:24]([OH:32])[CH2:25][C@H:26]([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C:7]=1[S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[CH2:2][CH2:3][CH2:4][CH3:5].P([O-])([O-])([O-])=O.Cl.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>CC(C)=O>[CH2:1]([C:6]1[CH2:20][C@@H:19]([OH:21])[C@H:18](/[CH:22]=[CH:23]/[C@@H:24]([OH:32])[CH2:25][C@H:26]([CH3:31])[CH2:27][CH2:28][CH2:29][CH3:30])[C:7]=1[S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1=C(SCCCCCC(=O)OC)[C@@H](/C=C/[C@@H](O)C[C@H](C)CCCC)[C@H](O)C1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)=O
Product: CCCCCC1=C(SCCCCCC(=O)O)[C@@H](/C=C/[C@@H](O)C[C@H](C)CCCC)[C@H](O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.3 %

Procedure:
To methyl (11R,12S,13E,15S,17R)-9-pentyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (20 mg, 0.042 mmol) in acetone (1 mL) was added pH 8 phosphate buffer (5 mL). To this was further added esterase containing solution (derived from pig's liver, made by Sigma Co., 50 μl). The solution was agitated at room temperature for 24 hours. Dilute hydrochloric acid was added to the reaction solution to make the solution pH 4. Further, the solution was made saturated by ammonium sulfate, then the desired product was extracted with ethyl acetate. The extract was washed with brine, then was dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then subjected to thin layer chromotography for separation (development solution: ethyl acetate) to obtain (11R,12S,13E,15S,17R)-9-pentyl-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoic acid (5.4 mg, 14%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C[C:12]1C=C(C)[N:14](C(N)=N)[N:13]=1.[N+]([O-])(O)=O.CCN(C(C)C)C(C)C.O>O1CCOCC1>[NH2:14][N:13]=[CH:12][NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: C1COCCO1
Solvent: O
Solvent: O=[N+]([O-])O
Product: NN=CNc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A solution of 3-aminobenzoic acid (41.1 g) in dioxane (300 ml) was treated with 3,5-dimethyl(pyrazole-1-carboxamidine) HNO3 (100 g), DIEA (90 ml) and H2O (100 ml). The reaction was refluxed for 3 hours and stirred overnight at room temperature. The solid was filtered and washed with dioxane (150 ml) and 1:1 dioxane:H2O (250 ml). The solid was then suspended in diethyl ether (400 ml) and CH3CN (100 ml) and treated with 4N HCl/dioxane (100 ml) and 20% HCl (1 ml). After 48 hours, the reaction was filtered and dried to give 3-[(aminoiminomethyl)amino]benzoic acid (34.1 g) as a lavender solid. MS was consistent with the desired product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([Li])=[CH:2]1.BrC1C=CSC=1.C([Li])CCC.[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22]I.C(=O)=O.CC(C)=O>>[S:1]1[CH:5]=[CH:4][C:3]([CH2:22][CH2:21][CH2:20][CH2:19][Cl:18])=[CH:2]1
Reactant: ClCCCCI
Reactant: [Li]c1ccsc1
Agent: Brc1ccsc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Product: ClCCCCc1ccsc1
Temperature: 25 °C

Procedure:
3-Thienyl lithium was generated from 3-bromothiophene and n-butyl lithium at -70° C. To the 3-thienyl lithium was then added an excess of 1-chloro-4-iodobutane at dry ice-acetone temperature. Upon slow warm up to room temperature a mixture of 2 and 3-thienyl butylchloride were obtained. The mixture was converted to the 2- and 3-thienyl butyl amines via the azide intermediates (Scheme 9) as described for the synthesis of 2-thienyl butyl amine, then reacted with thiophosgene to give the desired product, 3-TBITC, in low yield. The 2 isomers were separated by preparative liquid chromatography using a recycling mode. The 3-TBITC was obtained in 97% purity.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[Cl:48])[C:40]2=[O:49])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[CH:56]=[N:55][CH:54]=[CH:53][N:52]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[Cl:48])[C:40]2=[O:49])[C:36]([NH:50][C:51]2[CH:56]=[N:55][CH:54]=[CH:53][N:52]=2)=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Nc1cnccn1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2c(Cl)cccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1cnccn1)[C@H](CC1CCCCC1)N1Cc2c(Cl)cccc2C1=O
Yield: 17.5 %

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(4-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (ca. 1:1 mixture of regioisomers, prepared in Example 36, Step C; 243 mg; 0.76 mmol) and 2-aminopyrazine(1 70 mg; 1.77 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as outlined in Example 9, Step B) provided after chromatography (Biotage 40M column, eluent: 20% ethyl acetate/hexanes) 53 mg of (S)-3-Cyclohexyl-2-(4-Chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide: EI-HRMS m/e calcd for C21H23ClN4O2 (M+) 398.1510, found 398.1520; and 41 mg of regioisomeric (S)-3-Cyclohexyl-2-(7-Chloro-1-oxo-1,3dihydro-isoindol-2-yl)-N-pyrazin-2-yl-propionamide: EI-HRMS m/e calcd for C21H23ClN4O2 (M+) 398.1510, found 398.1507.
Reaction SMILES: [CH3:1][CH:2]([NH:9][C:10]1[N:15]=[C:14]([C:16]2[N:17]=[N:18][C:19]([CH:32]3[CH2:37][CH2:36][N:35](C(OCC4C=CC=CC=4)=O)[CH2:34][CH2:33]3)=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:13]=[CH:12][N:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>Br.CC(O)=O>[CH3:1][CH:2]([NH:9][C:10]1[N:15]=[C:14]([C:16]2[N:17]=[N:18][C:19]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:20][C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[CH:13]=[CH:12][N:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(Nc1nccc(-c2nnc(C3CCN(C(=O)OCc4ccccc4)CC3)cc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: CC(Nc1nccc(-c2nnc(C3CCNCC3)cc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Yield: 29.5 %

Procedure:
Under Ar, a solution of 29 (0.3 g, 0.47 mmol) in 30% HBr-AcOH (5 mL) was stirred at room temperature for 1 h. The reaction was then treated with 2N HCl and extracted with Et2O (2×). The resulting aqueous was then basified with saturated Na2CO3 and extracted with EtOAc (3×). The organic extracts were dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column (40 mm) and the product eluted with 5% CH3OH CHCl3 saturated with NH3 to yield 70 mg of 30.
Reaction SMILES: [OH:1][C@@H:2]1[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7][S:6](=[O:15])(=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[C@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>C(Cl)Cl.CCCCCCCC(C([NH3+])(C(CCCCCCC)=O)C(CCCCCCC)=O)=O.[Cl-]>[OH:1][C@@H:2]1[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:7][S:6](=[O:15])(=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[C@@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S1(=O)CC2(CCCCC2)[C@@H](O)[C@H](c2ccccc2)c2ccccc21
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S1(=O)CC2(CCCCC2)[C@@H](O)[C@@H](c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.6 %

Procedure:
To a solution of 0.2 g (0.56 mmole) of 59 in 20 ml of CH2Cl2, was added 8 g of 50% NaOH and one drop of Aliquat-336 (methyltricaprylylammonium chloride) phase transfer catalyst. The reaction mixture was stirred for 10 h at room temperature. Twenty g of ice was added to the mixture and the mixture was extracted with CH2Cl2 (3×10 ml) washed with water, brine and dried over MgSO4 and concentrated in vacuo to recover 0.15 g of crude product. This was recrystallized from Hexane/EtOAc to give 125 mg of white crystal, mp 209-210° C. Proton and carbon NMR and mass spectra were consistent with the product.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:12]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Br:12][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc(F)c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 3-fluoro-2-nitroaniline (2.1 g, 13.4 mmol) in DMF (30 mL) at 0° C. was added a solution of N-bromosuccinimide (2.4 g, 13.4 mmol) in DMF (20 mL). The resulting solution was stirred at 0° C. for 30 minutes and then warmed to room temperature over 1 hour. The solution was diluted with EtOAc, washed with H2O and brine, dried over MgSO4, filtered and concentrated to give the title compound (3.1 g, 97%).
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.C(=O)[C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1.C(O)=O>C(N(CC)CC)C>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH2:4][CH2:6][C:7]([OH:9])=[O:8])[CH:21]=[CH:20][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
7.2 g (0.05 mol) of Meldrum's acid and 8.3 g (0.05 mol) of veratraldehyde were weighed to 40 ml of the mixture of formic acid and triethylamine recovered by distillation in Example 3. The reaction was carried out and the final product was separated as described in Example 3. The volume of the mixture of formic acid and triethylamine recovered amounted to 28 ml.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH2:6]([O:11][C:12]1[C@@H:17]([C@H:18]([CH2:20][OH:21])[OH:19])[O:16][C:14](=[O:15])[C:13]=1[OH:22])[CH:7]([CH2:9][OH:10])[OH:8].[CH2:23](Br)[CH:24]=[CH2:25]>O>[CH2:6]([O:11][C:12]1[C@@H:17]([C@H:18]([CH2:20][OH:21])[OH:19])[O:16][C:14](=[O:15])[C:13]=1[O:22][CH2:25][CH:24]=[CH2:23])[CH:7]([CH2:9][OH:10])[OH:8]
Reactant: C=CCBr
Reactant: O=C1O[C@H]([C@@H](O)CO)C(OCC(O)CO)=C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CCOC1=C(OCC(O)CO)[C@@H]([C@@H](O)CO)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 152.4 %

Procedure:
Under an argon atmosphere, water and sodium hydrogen carbonate (1.42 g) were added to 3-O-glyceryl ascorbic acid (1.42 g) obtained in Example 1, and the mixture was stirred at room temperature for 30 minutes. To the mixture, allyl bromide (2.45 g) was added, and the resultant mixture was heated up to 60° C. and stirred for 2 hours. Thereafter, the mixture was concentrated under reduced pressure, then, dissolved in methanol. Then, the resultant solution was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 6.70 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:10/3/0.4), and concentration was performed under reduced pressure to obtain to obtain 3-O-glyceryl-2-O-allyl ascorbic acid (2.51 g).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH:34]([F:36])[F:35])=[N:32][CH:33]=1>C(#N)C.O>[F:35][CH:34]([F:36])[C:31]1[N:32]=[CH:33][C:28]([CH2:27][O:1][C:2]2[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=2[O:17][CH3:18])=[CH:29][CH:30]=1
Reactant: FC(F)c1ccc(CCl)cn1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(CNC(=O)OC(C)(C)C)ccc1OCc1ccc(C(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxy-3-methoxybenzylcarbamate (4.70 g, 18.56 mmol) and potassium carbonate (7.64 g, 55.28 mmol) in acetonitrile (50 mL) was added 5-(chloromethyl)-2-(difluoromethyl)pyridine hydrochloride (4.58 g, 21.40 mmol). The mixture was heated to reflux. After 3 h, the off-white suspension was allowed to cool to room temperature and was diluted with water (200 mL). The mixture was extracted with dichloromethane (3×75 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 7.74 g (>100%) of tert-butyl 4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzylcarbamate as a waxy yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].F[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.O>CN(C=O)C>[CH:23]([C:22]1[CH:25]=[CH:26][C:19]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)=[CH:20][CH:21]=1)=[O:24]
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(CC(=O)O)cc2)cc1
Temperature: 78 °C
Reaction time: 18 h
Yield: 25.5 %

Procedure:
To a suspension of 4-hydroxyphenylacetic acid (5.8 g, 38.2 mmoles) in dry DMF (50 mL) under argon, was added K2CO3 (15.8 g, 114.5 mmoles), and 4-fluorobenzaldehyde (23.7 g, 190.8 mmoles), and the reaction mixture was stirred at 78±2° C. for 18 hours under argon (Note: the reaction mixture becomes very viscous soon after the addition of 4-fluorobenzaldehyde, which slowly liquefies again). Subsequently the reaction mixture was cooled to room temperature, then poured into water (250 mL) and stirred for 15 minutes. The aqueous layer was extracted with ethyl acetate (2×75 mL); the organic layer was discarded and the resulting aqueous layer was acidified with HCl (˜6M) to pH 2.0. The aqueous layer was extracted with ethyl acetate (2×100 mL), the combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate and evaporated under reduced pressure to afford a mixture which was purified by silica gel chromatography using hexane-ethyl acetate (7:3) containing 1% acetic acid as eluent to yield a pale yellow solid (2.5 g, 25.6%). 1H NMR (400 MHz, DMSO-d6): δ ppm: 12.34 (br, 1H), 9.92 (s, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 7.11 (overlapped d, J=8.8 Hz, 2H), 7.10 (overlapped d, J=8.8 Hz, 2H), 3.61 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:12]=[CH:13][CH:14]=2.[N:15]1([CH:20]([CH3:24])[CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][N:17]=[CH:16]1>O1CCOCC1>[Br:1][C:2]1[C:3]2[C:4]3[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([NH:23][CH2:22][CH2:21][CH:20]([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[CH3:24])[C:5]=3[CH:12]=[CH:13][CH:14]=2
Reactant: SC1=Nc2ccc(Br)c3cccc1c23
Reactant: CC(CCN)n1ccnc1
Solvent: C1COCCO1
Product: CC(CCNC1=Nc2ccc(Br)c3cccc1c23)n1ccnc1
Yield: 41.3 %

Procedure:
A mixture of 5.2 g of 6-bromo-benz[cd]indole-2-thiol, 2.8 g of 3-(1H-imidazol-1-yl)butanamine, 6.6 g of mercuric acetate and 100 ml of dry p-dioxane was reacted as described in Example 1, giving 3.0 g of the desired product, mp 240°-241° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][CH2:11][C:12]([O:14]CC2C=CC=CC=2)=[O:13])=[O:9])[CH2:4][CH2:3]1.[H][H].O>[Pd].CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CN1CCN(C(=O)NCC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CN1CCN(C(=O)NCC(=O)O)CC1
Yield: 92 %

Procedure:
2.36 g of benzyl N-(4-methylpiperazin-1-ylcarbonyl)glycinate are added, at 20° C., under an argon atmosphere, to 0.15 g of 5% palladium on carbon in suspension in 100 cm3 of methanol. After stirring for 2.5 hours at 22° C., under 1.6 bar of hydrogen, 50 cm3 of water are added and the mixture is filtered on Clarcel. The cake is washed with three times 70 cm3 of water at 60° C. The filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) at 50° C. The residue is dried under reduced pressure (2.7 kPa) at 50° C. to give 1.5 g of N-(4-methylpiperazin-1-ylcarbonyl)glycine.
Reaction SMILES: [C:1]1(/[CH:11]=[C:12]2/[CH:13]([OH:22])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:38][O:39][C:40]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:41]=1[C:42](O)=[O:43]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]1(/[CH:11]=[C:12]2/[CH:13]([O:22][C:42](=[O:43])[C:41]3[CH:45]=[C:46]([O:49][CH3:50])[CH:47]=[CH:48][C:40]=3[O:39][CH3:38])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(OC)c(C(=O)O)c1
Reactant: OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(OC)c(C(=O)OC2C#CCCCCC#C/C2=C\c2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.1 %

Procedure:
To a solution of Compound 20b (18.6 mg, 6.50×10−2 mmol), DCC (13.4 mg, 6.50×1031 2 mmol), and DMAP (15.8 mg, 0.13 mmol) in dry CH2Cl2 (4 mL) cooled in an ice-water bath was added 2,5-dimethoxybenzoic acid (17.8 mg, 9.76×10−2 mmol) followed by stirring at room temperature for 24 hours. The reaction mixture was filtered through a short plug of Celite with rinsing by EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 20 percent EtOAc in hexane) to give 21.7 mg (74 percent) of Compound 40: pale yellow oil; Rf32 0.33 (20 percent EtOAc in hexane); IR (neat) 2958, 2235, 1721, 1640, 1189, 1064 cm−1; 1H NMR (300 MHz, CDCl3) δ8.32 (d, J=7.26 Hz, 1H), 8.08-8.04 (m, 1H), 7.88-7.78 (m, 2H), 7.60 (s, 1H), 7.54-7.42 (m, 4H), 7.03 (dd, J=9.03 and 3.39 Hz, 1H), 6.92 (d, J=9.03 Hz, 1H), 6.45 (s, 1 H), 3.84 (s, 3H), 3.80 (s, 3H), 2.46-2.25 (m, 4H), 1.95-1.70 (m, 4H); 13C NMR (75 MHz, CDCl3) δ169.9, 154.5, 153.7, 134.2, 133.3, 132.2, 129.5, 129.2, 127.0, 126.9, 126.4, 126.0, 124.3, 123.7, 120.3, 117.1, 114.6, 103.1, 93.5, 81.0, 79.5, 69.6, 57.6, 56.6, 28.3, 28.1, 22.6, 21.5; MS (+CI) m/z (relative intensity) 451 (M+, 3), 164 (100).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][C:5]2[C:7]([Sn](CCCC)(CCCC)CCCC)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:4]=2[O:3]1.Br[C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][C:2]1([CH3:1])[CH2:6][C:5]2[C:7]([C:28]3[CH:37]=[CH:36][CH:35]=[C:30]([C:31]([O:33][CH3:34])=[O:32])[CH:29]=3)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:4]=2[O:3]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)c2c1CC(C)(C)O2
Reactant: COC(=O)c1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-c2ccc(OC)c3c2CC(C)(C)O3)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A solution (30 ml) of Compound 144a obtained in Step A of Example 144 in DMF was added to a mixture of methyl 3-bromobenzoate (1.67 g), palladium acetate (0.18 g), sodium carbonate (2.10 g), and dimethylformamide (DMF) (70 ml), followed by stirring at 80° C. for one hour. A small amount of water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/20) to give Compound 146 (1.69 g, 69.5%) as pale-yellow crystals.
Reaction SMILES: C(C1C=CC([C:10]2[C:29]3[NH:30][C:26](=[CH:27][CH:28]=3)[C:25](C3C=CC(C(O)=O)=CC=3)=[C:24]3[N:40]=[C:21]([CH:22]=[CH:23]3)[C:20](C3C=CC(C(O)=O)=CC=3)=[C:19]3[NH:50][C:16]([CH:17]=[CH:18]3)=[C:15](C3C=CC(C(O)=O)=CC=3)[C:14]3=[N:60][C:11]=2[CH:12]=[CH:13]3)=CC=1)(O)=O.N1C=CC=CC=1.ClC(OCC(C)C)=O>CS(C)=O>[C:26]12[CH:25]=[C:24]3[N:40]=[C:21]([CH:22]=[CH:23]3)[CH:20]=[C:19]3[NH:50][C:16]([CH:17]=[CH:18]3)=[CH:15][C:14]3=[N:60][C:11]([CH:12]=[CH:13]3)=[CH:10][C:29]([NH:30]1)=[CH:28][CH:27]=2
Reactant: O=C(O)c1ccc(-c2c3nc(c(-c4ccc(C(=O)O)cc4)c4ccc([nH]4)c(-c4ccc(C(=O)O)cc4)c4nc(c(-c5ccc(C(=O)O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
The synthesis was performed in a three-necked flask under nitrogen. 50 mg of mezo-tetra(4-carboxyphenyl)porphine (4CP) was dissolved in 5 ml of dry DMSO, the catalysts, i.e. 120 μl of pyridine and 30 μl of isobutyl chloroformate, were added and after 5 minutes a suspension of 0.5 g Cloisite 30 B in 15 ml of dry DMSO was added. The reaction mixture was mixed at 70° C. for 4 hours. The product obtained was filtered on a Buchner funnel with a sintered glass disc and washed with methanol till the transparent filtrate was obtained and then the product was dried in a vacuum dryer. A green powder was obtained.