Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:2]
Reactant: CCOC(=O)CCCCCCCCCC=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCCCCCCc1cccc(N)c1
Reaction time: 4 h
Yield: 97.5 %

Procedure:
Ethyl-12-(m-nitrophenyl)-11-dodecenoate (9.76 g, 28.1 mmol was dissolved in ethyl acetate (55 ml). The solution was hydrogenated over 5% Pd/C (0.346 g) at room temperature and at an initial pressure of 45 psi for four hours. The reaction mixture was filtered through Celite and the solvent was removed under reduced pressure to yield an oily residue. The crude product was purified by column chromatography (80 g silica gel, hexanes:ethyl acetate, discontinuous gradient 10:1-2:1) to yield the reduced compound 5, ethyl-12-(m-aminophenyl)-dodecanoate (8.75 g, 97.5% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[ClH:11].[CH2:12]([OH:14])[CH3:13]>>[ClH:11].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[NH:10])[O:14][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)Cc1ccc(F)cc1

Procedure:
A solution of 4-fluorophenylacetonitrile (50 g, 0.37 mol) in absolute ethanol (300 ml) was treated with dry HCl gas with ice cooling for 1 hour. The solvent was evaporated in vacuo, and the residual oil triturated with ether. The solid was filtered off, washed with ether and dried (67 g, 83%), then used in subsequent steps without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CC[O:11][C:12]([CH:14]1[C:18](=O)[CH2:17][CH2:16][CH2:15]1)=O>COCCO>[CH3:8][C:7]1[C:2]2=[N:1][C:15]3[CH2:16][CH2:17][CH2:18][C:14]=3[C:12](=[O:11])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1N
Reactant: CCOC(=O)C1CCCC1=O
Solvent: COCCO
Product: Cc1cccn2c(=O)c3c(nc12)CCC3
Yield: 70.8 %

Procedure:
A mixture of 10.8 g of 2-amino-3-picoline, 31.2 g of ethyl cyclopentanone-2-carboxylate, and 250 ml of ethylene glycol monomethyl ether is stirred and heated under reflux for 40 hours. The solution is concentrated as far as possible on a rotary evaporator. The residual oil crystallizes and is filtered with suction to give 14.15 g of air-dried solid. This is recrystallized from 425 ml of cyclohexane to give 11.3 g of product, after drying at 78°. The melting point is 100°-102°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]=1[F:17].[NH3:18].CO>ClCCl>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH2:18])=[C:4]([F:17])[C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Fc1c(CBr)ccc(Cl)c1Oc1ccccc1
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: NCc1ccc(Cl)c(Oc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
A mixture of 1-(bromomethyl)-4-chloro-2-fluoro-3-(phenyloxy)benzene (0.058 g, 0.184 mmol) and 7M ammonia in methanol (3 mL, 21.00 mmol) in dichloromethane (1 mL) was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated with dichloromethane to give the desired product (0.023 g, 47% yield). 1H NMR (400 MHz, DMSO-d5) δ ppm 7.93 (br. s., 2H), 7.52-7.60 (m, 1H), 7.46 (t, 1H), 7.26-7.38 (m, 2H), 7.01-7.12 (m, 1H), 6.86 (d, 2H), 4.07 (s, 2 H). ES MS: m/z 252 (M+1).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].COCCOCCOC.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.B(O)O>C(O)C.C(OCC)(=O)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: COCCOCCOC
Product: Nc1ccccc1-c1ccc(F)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 2-bromoaniline (1.72 g, 10.0 mmol) in diglyme (30 mL) tetrakis(triphenylphosphine)-palladium(0) (0.13 g, 0.3 mmol) and 2.0 M aqueous sodium carbonate solution (15 mL, 30.0 mmol) were added. In a separate flask, 4-fluorophenylboronic acid (2.23 g 16.0 mmol) was dissolved in ethanol (8 mL) and the mixture containing 2-bromoaniline was added to this boronic acid solution. The obtained brown reaction mixture was heated at 80° C. for 6 hours, then cooled, diluted with ethyl acetate and washed with saturated ammonium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography using Kieselgel 60 (0.015-0.040 mm) as adsorbent (Merck) and n-hexane:ethyl-acetate=2:1 as eluent to yield after recrystallization from ethanol 1.8 g (60%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[C:6]#[N:7]>C(O)C.[Pt]>[NH2:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C#N)ccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: COc1cc(C#N)ccc1N
Yield: 60.1 %

Procedure:
To a cooled solution of 3-methoxybenzonitrile (10 g, 75 mmol) in acetic anhydride (150 ml) was added 70% nitric acid (60 mL) at a rate that kept the reaction mixture below 50° C. After 1 h the reaction mixture was poured onto ice (400 cc) and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried (Na2SO4). Concentration under reduced pressure and chromatography with ethyl acetate/hexanes gave 2.69 g (20%) of 3-methoxy-4-nitrobenzonitrile: 1H NMR (DMSO-d6): δ 8.04 (d, 1H), 7.93 (d, 1H), 7.61 (dd, 1H), 3.97 (s, 3H). 3-Methoxy-4-nitrobenzonitrile (2.6 g, 14.6 mmol) was suspended in ethanol(100 mL) and added to a mixture of 5% platinum on carbon (250 mg) in ethanol (150 mL). The reaction mixture was stirred under a hydrogen gas atmosphere. After 24 h the reaction was filtered, concentrated, and chromatographed (ethyl acetate/hexanes, 25/75) to yield 1.3 g (60%) of 4-amino-3-methoxybenzonitrile: 1H NMR (DMSO-d6): δ 7.1 (m, 2H), 6.65 (d, 1H), 5.77 (br s, 2H), 3.79 (s, 3H). 4-Amino-3-methoxybenzonitrile (1.3 g, 8.77 mmol) and 3,4-diethoxy-3-cyclobutene-1,2-dione (1.5 g, 8.82 mmol) in ethanol (50 mL) was heated in an oil bath at 110°-115° C. for 3 days. The reaction mixture was filtered hot, and the filtrate was reduced to half its volume. Filtration gave 0.58 g (24%) of a yellow solid: mp 159°-161° C.; 1H NMR (DMSO-d6): δ 10.42 (br s, 1H), 7.54 (d, 1H), 7.44 (dd, 1H), 7.39 (d, 1H), 4.70 (q, 2H), 3.86 (s, 3H), 1.36 (t, 3H). IR (KBr): 3413, 3026, 2650, 2576, 2439, 1719, 1630, 1548 cm-1 ; MS (m/z) 272 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4cccc(F)c4F)cc3c2C1
Yield: 78.9 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.6 μL (0.051 mMol) 2,3-difluorobenzoyl chloride, 13.4 mg (79%) of the title compound were recovered as a beige solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][NH:8][CH3:9].[CH2:10]([O:12][C:13]([C:15]1[C:16]([S:27][CH2:28][CH3:29])=[N:17][C:18]2[C:23]([C:24]=1[CH3:25])=[CH:22][CH:21]=[C:20](F)[CH:19]=2)=[O:14])[CH3:11].CCCCCC>CCO>[CH2:10]([O:12][C:13]([C:15]1[C:16]([S:27][CH2:28][CH3:29])=[N:17][C:18]2[C:23]([C:24]=1[CH3:25])=[CH:22][CH:21]=[C:20]([N:8]([CH3:9])[CH3:7])[CH:19]=2)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1c(SCC)nc2cc(F)ccc2c1C
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1c(SCC)nc2cc(N(C)C)ccc2c1C
Temperature: 90 °C
Yield: 38 %

Procedure:
2.8 g (20.5 mmol) K2CO3 and a 40% aq. dimethylamine solution (20.5 ml) were added to a solution of 2.0 g (6.8 mmol) 2-ethylsulfanyl-7-fluoro-4-methyl-quinoline-3-carboxylic acid ethyl ester in EtOH (20 ml) and the mixture was heated for 16 h at 90° C. in a closed vessel. Then the reaction solution was concentrated to small volume under vacuum and the residue was taken up with water. It was then extracted with EE. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 25:1) of the residue yielded 810 mg (2.55 mmol, 38%) 7-dimethylamino-2-ethylsulfanyl-4-methyl-quinoline-3-carboxylic acid ethyl ester.
Reaction SMILES: [O:1]1[CH2:14][CH:2]1[CH2:3][O:4][C:5]1[C:13]2[C:9](=[N:10][S:11][N:12]=2)[CH:8]=[CH:7][CH:6]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>O1CCOCC1>[CH:15]([NH:18][CH2:14][CH:2]([OH:1])[CH2:3][O:4][C:5]1[C:13]2[C:9](=[N:10][S:11][N:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: c1cc(OCC2CO2)c2nsnc2c1
Solvent: C1COCCO1
Product: CC(C)NCC(O)COc1cccc2nsnc12
Yield: 62 %

Procedure:
5.2 g (25 mM) 4-(2,3-epoxypropyloxy)-2,1,3-benzthiadiazole in 60 ml. dioxan were heated under reflux for 4 hours with 30 ml. isopropylamine. The reaction mixture was then evaporated and the residue was chromatographed on a silica gel column (silica gel particle size 0.063-0.200 mm., elution agent methanol with a small addition of glacial acetic acid). The residue obtained after evaporation of the eluted fractions was recrystallized from diisopropyl ether. There were obtained 4.1 g (62% of theory) 4-(3-isopropylamino-2-hydroxy-propyloxy)-2,1,3-benzthiadiazole, which had a melting point of 100°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]=[CH:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19].O1CCCC1.[H][H]>[Rh].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:19]
Reactant: COC(=O)C=Cc1cc(Cl)ccc1OCCCCCBr
Reactant: [H][H]
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCc1cc(Cl)ccc1OCCCCCBr
Yield: 100.8 %

Procedure:
A mixture of 2.02 g (5.59 mmol) of 3-[2-[(5-bromopentyl)oxy]-5-chlorophenyl]-2-propenoic acid methyl ester (mixture of E/Z-isomers), 90 mL of tetrahydrofuran, 190 mL of toluene, and 1.26 g of 5% rhodium on alumina was stirred at room temperature, in an atmosphere of hydrogen, until reduction was complete. The catalyst was removed by suction filtration and the filtrate was concentrated in vacuo giving 2.05 g (ca. 100%) of 2-[(5-bromopentyl)oxy]-5-chlorobenzenepropanoic acid methyl ester as a pale-yellow oil which was used without further purification.
Reaction SMILES: [CH:1]1(/[CH:7]=[CH:8]/[C:9]2[O:13][C:12]([CH:14]([OH:24])[CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd]>[CH:1]1([CH2:7][CH2:8][CH:9]2[O:13][CH:12]([CH:14]([OH:24])[CH2:15][CH2:16][NH:17][C:18](=[O:23])[C:19]([F:21])([F:22])[F:20])[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NCCC(O)c1ccc(/C=C/C2CCCCC2)o1)C(F)(F)F
Agent: [Pd]
Product: O=C(NCCC(O)C1CCC(CCC2CCCCC2)O1)C(F)(F)F
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of (E)-N-(3-(5-(2-cyclohexylvinyl)furan-2-yl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (0.11 g, 0.319 mmol) and Pd/C (10% wt, 0.037 g) in EtOAc (10 mL) was degassed by alternating vacuum/H2 three times and then stirred under H2 atmosphere at room temperature for 40 hrs, filtered through Celite and concentrated under reduced pressure to give N-(3-(5-(2-cyclohexylethyl)tetrahydrofuran-2-yl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide which was used directly in the next step without additional purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][NH:23][NH2:24])=[CH:20][CH:19]=1.C(O)(=O)C>CO>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][NH:23]/[N:24]=[C:8](\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: COc1ccc(CNN)cc1
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(CN/N=C(/c2ccccc2)c2ccc(C)cc2)cc1

Procedure:
To a solution of (4-methylphenyl)(phenyl)methanone (12) (1.9 g, 0.01 mol) in methanol was added 4-methoxybenzyl hydrazine (4.5 g, 0.035 mol) and acetic acid (0.5 mL). The mixture was reflux for 2 h. After cooling, the mixture was concentrated and the residue was extracted with CHCl3, washed with dil. HCl, followed by water, dried over MgSO4 and concentrated in vacuo, to give (Z)-(4-methylphenyl)(phenyl)methanone (4-methoxybenzyl)hydrazone (13). Next, a solution of above benzylhydrazone was dissolved in CH2Cl2 (50 ml) was added dropwise to a solution of Pb(OAC)4 (14.1 g, 0.03 mol) in CH2Cl2 (200 mL). After addition was completed, the mixture was reacted at 30±2° C. for 30 min, the BF3.Et2O (containing 47% of BF3 61 mL) was added. The mixture was reflux for 30 min before quenched into ice water. The organic layer was washed with water, dried over MgSO4 and evaporated. The residue was purified by column chromatography (silica gel-toluene) produce compound 24 (0.6 g). This product was confirmed by comparison of its IR and NMR spectra with that of a sample from the method A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]1[CH2:69][CH2:68][N:67]([CH2:70][CH:71]2[CH2:76][CH2:75][CH2:74][CH2:73][NH:72]2)[CH2:66][CH2:65]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:72]1[CH2:73][CH2:74][CH2:75][CH2:76][CH:71]1[CH2:70][N:67]1[CH2:68][CH2:69][N:64]([CH3:63])[CH2:65][CH2:66]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CN1CCN(CC2CCCCN2)CC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CN3CCN(C)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 1-methyl-4-(piperidin-2-ylmethyl)-piperazine in DMSO at ambient temperature.
Reaction SMILES: [C:1]([Cl:4])(Cl)=O.C1(C)C=CC=CC=1.[CH2:12]([O:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)[CH:28]=2)[NH:23]C(=O)[C:21]1=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:12]([O:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)[CH:28]=2)[N:23]=[C:1]([Cl:4])[C:21]1=[O:36])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)Cl
Reactant: O=c1[nH]c2ccc(-n3ccnc3)cc2n(OCc2ccccc2)c1=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=c1c(Cl)nc2ccc(-n3ccnc3)cc2n1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
A solution of 20% phosgene in toluene (57 ml; 118 mmol) was added to a stirred solution of 4-benzyloxy-6-(1H-imidazol-1-yl)-quinoxaline-2,3(1H,4H)-dione (9.2 g; 27.5 mmol) in 200 ml dry N,N-dimethylformamide at 0° C. The mixture was stirred at 25° C. overnight and then evaporated in vacuo. The residue was stirred with ice-cooled water and 4N sodium hydroxide was added until pH was about 6 which resulted in the title compound (9.5 g; 98%) as a precipitate. M.p. 140° C. (decomp.).
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OCC)=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C.O>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)N1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Yield: 90 %

Procedure:
Ethyl 4-(diphenylmethoxy)piperidine carboxylate (9.7 g) was dissolved in ethanol (85 ml) and water (35 ml), and sodium hydroxide (6.1 g) was added to the mixture, followed by heating the mixture to reflux for 40 hours. Ethanol was removed and water was added to the residue, followed by extraction of the resultant with dichloromethane. Organic layers were combined and dried over anhydrous sodium sulfate. Dichloromethane was removed and the residue was purified with Chromatorex® column chromatography for amines (ethyl acetate:ethanol=5:1) to obtain 7.1 of 4-diphenylmethoxypiperidine. Yield: 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11].[CH:21](=O)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10](=[O:11])[NH:12][N:13]=[CH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: NNC(=O)COc1ccc(C2=NNC(=O)CC2)cc1Cl
Reactant: COc1ccc(C=O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(C=NNC(=O)COc2ccc(C3=NNC(=O)CC3)cc2Cl)cc1
Reaction time: 8 h
Yield: 91.6 %

Procedure:
1.00 g of 6-[3-chloro-4-(hydrazinocarbonylmethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (Compound No. 18a, prepared following the procedure described in Example 4) was dissolved in 55 ml of dimethylformamide, and 2.3 g of p-anisaldehyde were added, at room temperature, to the resulting solution. The mixture was then stirred at the same temperature for 8 hours. At the end of this time, the solvent was distilled off in vacuo and chloroform was added to the resulting residue. The resulting precipitate was filtered off to give 1.28 g of the title compound melting at 220°-222° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1Cl)[C:7](=N)[NH:6][C:5]2=N.Cl.C1(CCCCCNC2SCC(=N)N=2)C=CC=CC=1.Cl.N1(C2SCC(=N)N=2)CCCCC1>>[ClH:1].[CH2:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:2][CH:3]=2)[CH2:7][NH:6]1
Reactant: N=C1NC(=N)c2cc(Cl)c(Cl)cc21
Agent: Cl
Agent: N=C1CSC(N2CCCCC2)=N1
Agent: N=C1CSC(NCCCCCc2ccccc2)=N1
Product: c1ccc2c(c1)CNC2

Procedure:
Following the procedure described in Example 9, part B above but using equivalent amount of 5,6-dichloro-1,3-diiminoisoindoline and 2-(5-phenylpentylamino)-4-imino-2-thiazoline hydrochloride in place of the 1,3-diiminosioindoline and 2-piperidino-4-imino-2-thiazoline hydrochloride respctively, there is obtained as the product 1-imino-5,6-dichloro-3-[2-(5-phenylpentylamino)-4-imino-2-thiazolin-5-ylidene[isoindoline hydrochloride.
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>CN(C=O)C>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)=[CH:15][CH:14]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(Cn2cnc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 1.86 g, 46.6 mmol) in dry DMF (5 mL) under nitrogen and cooled to 0° C. was added a solution of benzimidazole (5.0 g, 42.2 mmol) in DMF (15 mL) and the reaction mixture was allowed to stir for 30 min at room temperature. The reaction mixture was cooled to 0° C. and a solution of 4-bromobenzyl bromide (10.6 g, 42.4 mmol) in DMF (10 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature overnight. The solvent was removed under reduced pressure and the residue partitioned between saturated aqueous sodium chloride and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4) and evaporated. The crude product was triturated with ethyl ether and recovered by filtration. Yield: 70%. LCMS (ESI+) 387.2 and 389.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.ClCCCl.N1C=CC=CC=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:37]>>[CH:21]1([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:36](=[O:37])[O:38][C:39]4[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=4)[CH:3]=[CH:4][C:5]=2[CH3:24])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To a suspension of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (196.8 mg, 0.6201 mmol) in 1,2-dichloroethane (6.0 mL, 76 mmol) was added pyridine (0.15 mL, 1.8 mmol) and p-nitrophenyl chloroformate (0.1406 g, 0.6975 mmol). The reaction mixture was stirred at room temperature for 2 hours and then pyridine (0.15 mL, 1.8 mmol) and p-nitrophenyl chloroformate (131.9 mg, 0.6544 mmol) were added. After an additional hour at room temperature, the reaction mixture was evaporated in vacuo and purified via flash chromatography on silica gel (25 g silica, solvent gradient: 0-100% ethyl acetate in heptanes) to yield 114.8 mg (38%) of 4-nitrophenyl 3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenylcarbamate. LCMS (ESI): M+H=483.2; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.16 (s, 1H), 8.47 (s, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.92 (s, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 6.90 (d, J=8.9 Hz, 2H), 6.54 (d, J=5.8 Hz, 2H), 2.14-2.02 (m, 4H), 0.85 (m, 4H).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]>N1C(C)=CC=CC=1C>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: Cc1cccc(C)n1
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a solution of methyl pheophorbide-a (25 g, 42.5 mmol) in 2,6-lutidine (1 L) was added distilled water (10 mL, 556 mmol, 13 equiv., 1% v/v) and the mixture was refluxed under argon with stirring. The reaction was monitored by HPLC (hexane-acetone, 90:10-mobile phase, LiChrospherCN-column, detection at 425 and 410 nm). After 100 min. of reflux, the HPLC of reaction aliquots showed 99.7% of completion. The solution was cooled to room temperature after 120 min of reflux and solvent removed under reduced pressure. Hexane (100 mL) was added and the solid was collected by filtration and rinsed with hexane to remove any traces of 2,6-lutidine. The solid was then precipitated from methylene chloride-methanol to give methyl pyropheophorbide-a (20.3 g, 91%).