Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: O=S(=O)(NCC(Cc1cccnc1)c1ccc(OCc2ccccc2)cc1)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCO
Product: O=S(=O)(NCC(Cc1cccnc1)c1ccc(O)cc1)c1ccc(Cl)cc1
Yield: 59 %

Procedure:
The N-[2-(4-benzyloxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide (170 mg) was dissolved in 10 ml of ethanol, followed by addition of 0.2 g of 10% palladium carbon, and stirred for catalytic reduction via hydrogen at 55° C. overnight, to obtain 82 mg of N-[2-(4-hydroxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.F[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>CS(C)=O>[CH3:8][CH:4]1[NH:3][CH:2]([CH3:1])[CH2:7][N:6]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:5]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC1CNCC(C)N1
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CC(C)NC(C)C2)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 75.7 %

Procedure:
2,6-Dimethylpiperazine(3.43 g, 30.00 mmol) was added to ethyl 4-fluorobenzoate (1.101 mL, 7.5 mmol), in DMSO (10 mL) warmed to 120° C. under nitrogen. The resulting solution was stirred at 120° C. for 20 h. The reaction mixture was cooled and the solvent was evaporated. The crude product was purified by silica column chromatography, eluting with 10% methanol in dichloromethane containing 1% 0.880 ammonia. Pure fractions were evaporated to dryness to afford ethyl 4-(3,5-dimethylpiperazin-1-yl)benzoate (1.490 g, 76%) as a colourless solid. 1H NMR (399.9 MHz, CDCl3) δ 1.15 (6H, d), 1.37 (3H, t), 2.39 (1H, d), 2.42 (1H, d), 2.97-3.05 (2H, m), 3.65-3.69 (2H, m), 4.33 (2H, q), 6.84-6.87 (2H, m), 7.90-7.93 (2H, m)—NH not seen. MS: m/z=264 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH:18]2[CH2:24][CH:23]3[N:25]([CH3:26])[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)=[C:13]([OH:27])[CH:12]=1.F[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N+]([O-])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:8][O:9][C:10]([C:11]1[CH:16]=[CH:15][C:14]2[N:17]([CH:18]3[CH2:19][CH:20]4[N:25]([CH3:26])[CH:23]([CH2:22][CH2:21]4)[CH2:24]3)[C:30]3[C:35]([O:27][C:13]=2[CH:12]=1)=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28]
Reactant: COC(=O)c1ccc(NC2CC3CCC(C2)N3C)c(O)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)Oc1ccccc1N2C1CC2CCC(C1)N2C
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixture of the TFA salt of 3-hydroxy-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylamino)-benzoic acid methyl ester, 1a (0.424 g, 0.734 mmol), 2-fluoronitrobenzene (95 μL, 0.9 mmol) and potassium carbonate (564 mg, 4 mmol) in DMF was heated to reflux for 70 min. The mixture was allowed to cool to rt, filtered, and purified via reverse phase HPLC to yield 440 mg (88%) of 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid methyl ester, 2a, as TFA salt. MS m/z (MH+) 365.1.
Reaction SMILES: [CH2:1]([CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[O:10][CH:9]1[C@H:20]([N:24]1[CH:28]=[C:27]([CH2:29][N:30]2C(=O)C3=CC=CC=C3C2=O)[N:26]=[C:25]1[C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:30][CH2:29][C:27]1[N:26]=[C:25]([C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[N:24]([C@@H:20]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:18])[C:8]=2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:15][CH:14]=[C:13]([Cl:19])[CH:12]=3)[CH:21]([CH3:23])[CH3:22])[CH:28]=1
Reactant: Cc1ccc(-c2nc(CN3C(=O)c4ccccc4C3=O)cn2[C@H](C(C)C)C2Oc3cc(Cl)ccc3C(=O)C2Cc2ccccc2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc(CN)cn2[C@@H](c2oc3cc(Cl)ccc3c(=O)c2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.1 %

Procedure:
To N-{1-[(R)-1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-chromen-2-yl)-2-methyl-propyl]-2-p-tolyl-1H-imidazol-4-ylmethyl}-phthalimide (0.50 g, 0.78 mMol) in EtOH (15 mL) was added hydrazine monohydrate (0.12 mL, 2.5 mMol). The reaction was stirred at RT for 72 h, filtered through a pad of Celite® to remove the insoluble precipitate, rinsed with EtOH and evaporated to dryness. Purification by flash chromatography on silica gel [5-10% (5% NH4OH in MeOH)/CH2Cl2] gave the title compound (364 mg, 91%) as a white solid foam: 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8.6 Hz, 1H), 7.63 (d. J=1.8 Hz, 1H), 7.37 (m, 6H), 7.15 (m, 3H), 6.71 (d, J=1.7 Hz, 1H), 6.69 (s, 1H), 5.00 (d, 0.1=10.9 Hz, 1H), 4.07 (d, J=15.5 Hz, 1H), 3.92 (d, 1H), 3.88 (d, 1H), 2.72 (br s, 2H), 2.65 (m, 1H), 2.49 (s, 3H), 2.48 (d, J=15.5 Hz, 1H), 0.93 (d, J=6.6 Hz, 3H), 0.30 (d, J=6.7 Hz, 3H); MS (ES) m/e 512.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([OH:10])=[O:9])[N:3]=1.Cl.[CH3:12]O>>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:12])=[O:9])[N:3]=1
Reactant: Cn1nc(C(=O)O)nc1N
Reactant: CO
Agent: Cl
Product: COC(=O)c1nc(N)n(C)n1

Procedure:
A stirred suspension of 5-amino-1-methyl-1H-1,2,4-triazole-3-carboxylic acid (9.10 g) in methanol (100 ml) was saturated with dry hydrogen chloride, and heated under reflux for 4.5 h. The cooled solution was partially evaporated, diluted with water (100 ml) and the pH was adjusted to pH 7 with potassium carbonate. The solution was filtered, and the filtrate partially evaporated to give the title compound as a white solid (4.60 g) m.p. 190-1; tlc System B, Rf 0.6.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4]([O:6][CH3:7])=[O:5].[CH:10]1(O)[CH2:15][CH2:14]C[CH2:12][CH2:11]1.S(=O)(=O)(O)O>CO>[CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4]([O:6][CH:7]1[CH2:14][CH2:15][CH2:10][CH2:11][CH2:12]1)=[O:5]
Reactant: COC(=O)C(=O)N(C)C
Reactant: OC1CCCCC1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CN(C)C(=O)C(=O)OC1CCCCC1
Temperature: 80 °C

Procedure:
In a 1,000 mL reactor, are mixed at 20-25° C., methyl 2-(dimethylamino)-2-oxoacetate) (compound 1) (393 g, 3 mol), cyclohexanol (360 g, 3.6 mol) and 98% sulfuric acid (66 g, 0.67 mol). The temperature of the mixture is brought to and maintained at 80° C. for 36 hours. Progression of the reaction is followed by gas chromatography analysis. At the end of the reaction, the methanol formed is removed from the reaction medium by distillation under reduced vacuum (P min=150 mbars) and an aqueous solution of sodium hydrogen carbonate is then added to the reaction medium so that the final pH is 7. The organic phase is separated from the aqueous phase. The latter is counter-extracted with 500 mL of dichloromethane. The organic phases are collected and the reaction medium is then concentrated for removing the dichloromethane. To the residue are added 5 g of potassium carbonate and the thereby obtained medium is then distilled under partial vacuum (Tbp 115-120° C., P<1 mbar). The expected product is obtained with a purity of more than 98.2% (466 g).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](ON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added tert-butyl (3R)-3-(aminooxy)piperidine-1-carboxylate 11 (0.19 g, 0.86 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.14 g, 1.03 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.03 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl (3R)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 12 (0.28 g, 82° A) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:28]1[S:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[S:29][C:30]6[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=6[N:32]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Clc1nc2ccccc2s1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5nc6ccccc6s5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-chloro-benzothiazole following a procedure analogous to that described for Intermediate 12; K2CO3 and acetonitrile are used as base and solvent, respectively, at 90° C. LC (method 3): tR=0.78 min; Mass spectrum (ESI+): m/z=492 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Ni]>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CON(C)C(=O)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1

Procedure:
The 3-(2-benzyloxy-4-nitro-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester was dissolved in 1:1 THF/MeOH, and Raney Ni added. The solution was hydrogenated at 30 psi. When the reaction was complete, the solvent was removed to give the crude give 3-(4-amino-2-benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester. The product can be used crude, or chromatographed with 7.5% methanol/ethyl acetate. 1H NMR (CDCl3) 7.65-7.3 (8H, m), 6.2 (2H, m), 5.78 (2H, d, J=9.76 Hz), 5.2-5.1 (2H, m), 4.8-4.7 (1H, m), 4.2-4.0 (2H, br), 3.59 (3H, s), 2.56 (3H, s), 2.6-2.4 (2H, m), 1.41 (9H, s). MS (m/z) (M+1)=494.
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4]1.[C:19]([O-:22])(=[O:21])[CH3:20].[Na+]>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:9][C:7]1([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4][C@@H:3]([CH2:2][O:22][C:19]([CH3:20])=[O:21])[O:8]1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
In 10 mL of N,N-dimethylformamide were suspended 1.00 g (3.60 mmol) of tert-butyl 2-[(4R,6S)-6-(chloromethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate [synthesized by the process described in Example 6], 0.5 g (1.80 mmol) of tetra-n-butylammonium chloride and 0.89 g (10.8 mmol) of sodium acetate, and the suspension was stirred at 100° C. for 20 hours. After cooling to room temperature, the reaction mixture was diluted with 20 mL of water and extracted 3 times with n-hexane.
Reaction SMILES: [C:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=O)[CH3:2].CO.C[O-].[Na+].I[CH2:26]CC>C1COCC1.CO>[CH2:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:26]
Reactant: CCCI
Reactant: CC(=O)SC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCSC1CCN(c2ccc(N)cc2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-acetylthiopiperidin-1-yl)nitrobenzene (3.34 g) in a mixture of THF (30 ml) and methanol (30 ml) was added 28% sodium methoxide methanol solution (2.67 ml) at 0-5° C. and stirred at the same temperature for 30 minutes. To the mixture was added iodopropane (1.51 ml) at the same temperature and stirred at ambient temperature for 2 hours. The reaction mixture was evaporated in vacuo and dissolved in ethyl acetate (100 ml). The solution was washed three times with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. A solution of the resulting residue, ammonium chloride (1.0 g) and iron powder (4.0 g) in a mixture of ethanol (60 ml) and water (30 ml) was refluxed for 2 hours. The reaction mixture was evaporated in vacuo. The resulting residue was chromatographed on silica gel (300 ml) eluting with ethyl acetate. The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(4-propylthiopiperidin-1-yl)aniline (2.47 g).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([Cl:27])=[CH:22][C:21]=1[SH:28].[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[S:28][C:21]1[CH:22]=[C:23]([Cl:27])[C:24]([CH3:26])=[CH:25][C:20]=1[Cl:19]
Reactant: Cc1cc(Cl)c(S)cc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc(Cl)c(Sc2ccc([N+](=O)[O-])c(Oc3ccccc3)c2Cl)cc1Cl
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 14.2 gm of 2,3-dichloro-6-nitro-1-phenoxy-benzene, 10.2 gm of 2,5-dichloro-4-methylthiophenol, 5.0 ml of 10 N sodium hydroxide and 40 ml of dimethylsulfoxide was stirred for 5 hours at 100° C. and then allowed to stand overnight at room temperature. Thereafter, the reaction mixture was admixed with 400 ml of 1 N sodium hydroxide, and the product precipitated thereby was collected and recrystallized from 150 ml of ethanol. 20.5 gm (90% of theory) of the light yellow crystalline title compound, m.p. 138°-144° C., were obtained.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][OH:30].[H-].[Na+]>CN(C)C=O.O>[F:11][C:8]1[CH:9]=[CH:10][C:2]2[O:30][CH2:29][C@H:25]3[CH2:26][CH2:27][CH2:28][N:24]3[C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(O)c1cc(F)ccc1F
Reactant: OC[C@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2cc(F)ccc2OC[C@H]2CCCN12
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.7 %

Procedure:
To a solution of 2,5-difluorobenzoic acid (1.0 g; 6.325 mmol) in dimethylformamide (5 ml) was added 1,1′- carbonyldiimidazole (1.07 g; 6.64 mmol) and the solution stirred at room temperature for 1 h, followed by the addition of (R)-(−)-2-pyrrolidinemethanol (0.655 ml; 6.64 mmol). The reaction was stirred at room temperature overnight whereupon 60% sodium hydride in mineral oil (0.507 g; 12.7 mmol) was carefully added and the mixture was heated to 120° C. for 2 h. The reaction was cautiously diluted with water and extracted with ethyl acetate and the organic layer washed with water then dried (Na2SO4) and evaporated to give the crude product. Trituration with ether and filtration afforded the title compound (0.29 g). M.p.: 85-86° C.; EIMS: m/z=222.2 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2.Cl.[NH2:36][OH:37].[OH-].[Na+].O>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](/[C:12](=[N:36]/[OH:37])/[NH2:13])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[CH3:15])=[CH:7]2
Reactant: NO
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C#N)n4)ncnc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(/C(N)=N/O)n4)ncnc32)cc1
Temperature: 25 °C

Procedure:
A mixture of (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl) isoquinoline-1-carbonitrile 29 (600 mg, 1.28 mmol, 1.0 eq), hydroxylamine hydrochloride (269 mg, 3.84 mmol, 3 eq) and NaOH (154 mg, 3.84 mmol, 3 eq) in EtOH (15 mL) was stirred at reflux 4 h. The mixture was cooled to RT, poured into water (100 mL) and then extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-10% MeOH-DCM) to afford the product (S,Z)-8-chloro-N′-hydroxy-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carboximidamide 30.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[C:5]([CH3:18])[CH:4]=1.[C:19]([N:22]1[CH2:26][CH:25]=[N:24][C:23]1=O)(=[O:21])[CH3:20]>>[C:19]([N:22]1[CH2:26][CH2:25][N:24]=[C:23]1[NH:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[C:5]([CH3:18])[CH:4]=1)(=[O:21])[CH3:20]
Reactant: Cc1cc(N)n(-c2cccc(C(F)(F)F)c2)n1
Reactant: CC(=O)N1CC=NC1=O
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1cccc(C(F)(F)F)c1

Procedure:
5-Amino-1-(3-trifluoromethylphenyl)-3-methyl pyrazole HCl (20.0 g.) and 1-acetyl-3-imidazolinone (11.1 g.) were reacted as described in Example I to give 15.0 g. product. mp 173°-175°
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:11]N(C=O)C.C(Cl)(=O)C(Cl)=O.CO>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(O)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(O)cn1
Reaction time: 1 h

Procedure:
To 5-hydroxypyridine-2-carboxylic acid (5.0 g, 36 mmol) suspended in CH2Cl2 (120 mL) was added DMF (1 mL) followed by oxalyl chloride (4.7 g, 37 mmol). After 1 hour, excess MeOH was added. The resulting mixture was stripped of solvent in vacuo yielding a brown solid that was washed with hot EtOAc. Yielded 4.6 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:46][CH2:47][N:48]2[CH:52]=[CH:51][N:50]=[N:49]2)(=O)=O)=CC=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:46][CH2:47][N:48]4[CH:52]=[CH:51][N:50]=[N:49]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCn4ccnn4)c(OC)cc23)cc1Cl
Temperature: 120 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 2-(1H-1,2,3-triazol-1-yl)ethyl 4-methyl-1-benzenesulfonate (59 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 120° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform-methanol to give 92 mg (yield 92%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][O:13][NH:14][C:15](=[O:17])[CH3:16].[C:18](Cl)(=O)/[CH:19]=C/C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][O:13][NH:14][C:15](=[O:17])/[CH:16]=[CH:18]/[CH3:19]
Reactant: C/C=C/C(=O)Cl
Reactant: COc1ccc2[nH]cc(CONC(C)=O)c2c1
Product: C/C=C/C(=O)NOCc1c[nH]c2ccc(OC)cc12

Procedure:
By carrying out the procedure in the same manner as for the synthesis of the compound of Example 13, but replacing the acetic acid chloride with crotonic acid chloride, the title compound is obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)[CH3:2].[CH2:27]([N:29]1[CH:34]=[C:33]([CH:35]=O)[C:32](=[O:37])[NH:31][C:30]1=[O:38])[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.O>[CH2:25]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[C:18]([N:19]4[CH2:20][CH2:21][N:22]([CH2:35][C:33]5[C:32](=[O:37])[NH:31][C:30](=[O:38])[N:29]([CH2:27][CH3:28])[CH:34]=5)[CH2:23][CH2:24]4)[C:12]=3[N:11]=2)=[CH:6][CH:5]=1)[CH3:26]
Reactant: CCN(CC)c1ccc(-c2nc3c(N4CCNCC4)cccc3[nH]2)cc1
Reactant: CCn1cc(C=O)c(=O)[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCN(CC)c1ccc(-c2nc3c(N4CCN(Cc5cn(CC)c(=O)[nH]c5=O)CC4)cccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a solution of Diethyl-[4-(4-piperazin-1-yl-1H-benzoimidazol-2-yl)-phenyl]-amine (1.0 g, 2.0 mMol) in N-methylpyrrolidinone (10 mL) was added 1-Ethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbaldehyde (0.404 g, 2.40 mMol) followed by sodium triacetoxyborohydride (0.849 g, 4.01 mMol) and the mixture stirred at room temperature overnight. Upon arrival the crude reaction mixture was diluted with water (2 mL), filtered, and purified by RP-HPLC (Method E) to yield 168 mg (17% yield) of 5-{4-[2-(4-Diethylamino-phenyl)-1H-benzoimidazol-4-yl]-piperazin-1-ylmethyl}-1-ethyl-1H-pyrimidine-2,4-dione as a very light yellow solid. 1H NMR (DMSO-d6): δ=12.33 (s,1H), 11.25 (s,1H), 7.91 (d, 2H, J=9 Hz), 7.66 (s, 1H), 6.96 (m, 2H), 6.77 (d,2H, J=9 Hz), 6.45 (dd, 1H, J=6.0, 2.8 Hz), 3.74 (q, 2H, J=7.1 Hz), 3.53 (br s, 4 h), 3.40 (q, 4H, J=7.1 Hz), 3.23 (s, 2H), 2.62 (m, 4H), 1.18 (t, 3H, J=7.1 Hz), 1.13 (t, 6H, J=7.1 Hz). LC/MS (Method A), rt=0.85 mins., purity=99.2%, calculated mass=501, [M+H]+=502, [M−H]=500. HPLC (Method D): rt=5.5 mins., purity=99.3% @ 210-370 nm and 98.6% @ 372 nm.