Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[I:14]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(Cl)(Cl)Cl.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([I:14])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(I)c(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
Methyl 3-cyano-4-hydroxybenzoate (6.47 g) was dissolved in chloroform (80 mL) and methanol (10 mL), and N-iodosuccinimide (8.63 g) and trifluoromethanesulfonic acid (2.5 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and the obtained residue was washed with water to obtain the title compound (11.29 g) as a pale yellow crystal.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:3][C:2]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: OB(O)c1cncnc1
Product: CN1CCN(Cc2cc3nc(-c4cncnc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 164. (400 MHz CDCl3): 2.31 (3H, s, CH3), 2.50 (4H, b, CH2), 2.61 (4H, b, CH2), 3.85 (2H, s, CH2), 3.88-3.91 (4H, m, CH2), 4.06-4.08 (4H, m, CH2), 7.33 (1H, s, ar), 9.27 (1H, s, ar), 9.67 (2H, s, ar). MH+=412.27
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][NH2:26])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].N1C=CC=CC=1.O>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:25][NH:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CNS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
Methanesulfonyl chloride (0.186 mL, 275 mg, 2.4 mmol) was added dropwise to a stirred, cooled (0° C.) solution of 2-(4-t-butoxycarbonylpiperazin-1-yl)phenylmethylamine (0.58 g, 2 mmol) and pyridine (0.32 mL, 0.32 g, 4 mmol) in dichloromethane (10 mL) and the mixture was stirred at room temperature for 3 h. Further methanesulfonyl chloride (0.046 mL, 69 mg, 0.6 mmol) was added and the mixture was stirred at room temperature for 3 h. Water (1 mL) was added and the solvent was evaporated under reduced pressure. Aqueous sodium hydrogen carbonate (saturated, 20 mL) and water were added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic fractions were washed with aqueous citric acid (10%, 2×20 mL), aqueous sodium hydrogen carbonate (saturated, 2×20 mL) and brine (20 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with CH2Cl2 /MeOH/NH3 (Aq.) (99:1:0.1) to give the title compound as a colorless solid (344 mg, 47%), δH (250 MHz, CDCl3) 7.33 (2H, m), 7.15 (2H, m), 5.80 (1H, br t, J 4.0 Hz), 4.40 (2H, d, J 4.0 Hz), 3.60 (4H, br t, J 3.4 Hz), 2.88 (4H, t, J 3.4 Hz), 2.82 (3H, s), and 1.49 (9H, s). m/e (ES+) 370 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][N:6]=[C:7]([NH2:19])[C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=2[F:18])[CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1.C(OCC)(=O)C>C1C=CC=CC=1>[CH:1]1([CH2:4][O:5][N:6]=[C:7]([NH:19][C:29](=[O:30])[CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[C:8]2[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=2[F:18])[CH2:3][CH2:2]1
Reactant: NC(=NOCC1CC1)c1c(F)cccc1C(F)(F)F
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1ccc(CC(=O)NC(=NOCC2CC2)c2c(F)cccc2C(F)(F)F)cc1

Procedure:
In 200 ml of benzene was dissolved 20.0 g of N'-cyclopropylmethyloxy-2-fluoro-6-trifluoromethylbenzamidine, and to the solution was added 16. 0 g of 4-methoxyphenylacetylchloride. The solution was heated under refluxing for 10 hours. After cooling, ethyl acetate was added to the solution, followed by washing with water and drying over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography to obtain 23.6 g of the objective compound.m.p. 75-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:12]([CH3:24])[C:11]([CH2:25][OH:26])=[N:10]1.[H-].[Na+].C[O:30][C:31](=[O:44])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:43])[CH:40](Br)[CH3:41])=[CH:34][CH:33]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[C:12]([CH3:24])[C:11]([CH2:25][O:26][CH:40]([CH3:41])[C:39]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([C:31]([OH:44])=[O:30])=[CH:33][CH:34]=2)=[O:43])=[N:10]1
Reactant: Cc1c(CO)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(NC(=O)C(C)Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1c(COC(C)C(=O)Nc2ccc(C(=O)O)cc2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of 100 mg of [1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-yl]-methanol in 3 ml of DMF were added 54 mg of sodium hydride (60% in mineral oil) at room temperature. After 15 min, 100 mg of tetrabutylammonium iodide and 117 mg of 4-(2-Bromo-propionylamino)-benzoic acid methyl ester were added and the reaction mixture was heated to 80° C. for 8 h. After cooling to room temperature and dilution with 1 M aqueous hydrochloric acid the reaction mixture was filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 24 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:24]>CN(C=O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]([N:28]2[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]2)=[O:9])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)([O-:3])=[O:2]
Reactant: CCN1CCNCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN1CCN(C(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In an ice bath under N2-atmosphere, 3-nitro-5-trifluoromethyl-benzoic acid (Lancaster; 11.8 g, 50 mmol), CH2Cl2 (150 ml), a few drops of DMF and oxalylchloride ( 7.0 ml, 81 mmol) are mixed and then stirred for 3 h at rt. The resulting solution is concentrated in vacuo. The residue is dissolved in CH2Cl2 (170 ml) and added dropwise to an ice cooled solution of N-ethyl-piperazine (12.7 ml, 0.10 mol) in CH2Cl2 (100 ml). After stirring for 1 h at rt, the mixture is washed with a diluted solution of Na2CO3, 2 portions of water and finally brine. The aqueous layers are re-extracted twice with AcOEt, the combined organic phases dried (Na2SO4) and concentrated giving the title compound as an oil: MS: [M+1]+=332; 1H-NMR (CDCl3): 8.53 (s, 1H), 8.44 (s, 1H), 8.00 (s, 1H), 3.84 (m, 2H), 3.43 (m, 2H), 2.57 (m, 2H), 2.48 (q, 2H), 2.44 (m, 2H), 1.12 (t, 3H).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[NH2:18][OH:19].Cl.NO.C[O-].[Na+]>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[N:18][OH:19])[NH2:17])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: NO
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(N)Nc1nc(CSCCC(N)=NO)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 35 ml of methanol was dissolved 4.72 g of methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate and then 25 ml of a methanol solution of free hydroxylamine prepared by treating 1.2 g of hydroxylamine hydrochloride with 0.93 g of sodium methoxide was added to the solution. After stirring the mixture for 2 hours at room temperature, the solvent was distilled off under reduced pressure and the residue formed was purified by a column chromatography using a mixed solvent of chloroform and methanol as a developing solvent and recrystallized from methanol-acetone to provide 1.3 g of 3-[(2-guanidinothiazol-4-yl)methylthio]propionamidoxime. The product has the following physicochemical properties:
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([O:14]CC)=O.P(Cl)(Cl)(Cl)=O.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][NH2:30].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[C:12](=[O:14])[C:3]2=[CH:4][NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]2=[N:30]1
Reactant: NNc1ccccc1F
Reactant: CCOC(=O)c1c[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (3.8 g, 17 mmol) was dissolved in phosphorus oxychloride (25 mL, 0.26 mol, 15 equiv) and stirred at ambient temperature for 14 hours. The mixture was concentrated in vacuo and the residue was concentrated from toluene (3×25 mL). The resulting residue was dissolved in 1,2-dimethoxyethane (60 mL) and degassed N,N-dimethylformamide (10 mL) and treated with 2-fluorophenylhydrazine (4.4 g, 35 mmol, 2 equiv) and potassium carbonate (12 g, 87 mmol, 5 equiv). The mixture was placed into a preheated oil bath at 80° C. for 14 hours. The mixture was cooled to ambient temperature, diluted with water (100 mL) and ethyl acetate (100 mL) and filtered. The solid was collected and dried in vacuo, providing the titled compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25]O)=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C-:33]#[N:34].[Na+].C(=O)(O)[O-].[Na+]>ClCCl.CS(C)=O>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][C:33]#[N:34])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: C[C@@H](Cn1ncc2ccc3oc(CO)cc3c21)NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[C@@H](Cn1ncc2ccc3oc(CC#N)cc3c21)NC(=O)OCc1ccccc1

Procedure:
A solution of the product from Example 2, Step B (0.55 g, 1.45 mmol) in dichloromethane (20 mL) was cooled (ice bath), thionyl chloride (0.16 mL, 2.18 mmol) was added, and the mixture was stirred for thirty minutes. The reaction mixture was evaporated to a residue which was dissolved in dichloromethane (20 mL) and evaporated. A solution of sodium cyanide (0.29 g, 5.8 mmol) in DMSO (10 mL) was added to this residue and the mixture was stirred at room temperature for one hour. Saturated aqueous sodium bicarbonate (100 mL) was added and the mixture was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with saturated aqueous sodium bicarbonate (2×150 mL), dried (MgSO4) and evaporated to a tan solid (0.49 g, 87%): LC/MS m/z 389 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[C:23]([CH:33]=1)[CH2:24][NH:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C@H:9]1[C:10]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[C:26]([NH:25][CH2:24][C:23]1[CH:33]=[C:19]([Cl:18])[CH:20]=[CH:21][C:22]=1[N:34]1[CH:38]=[N:37][N:36]=[N:35]1)=[O:32])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C)C1C(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(C)(C)[C@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1

Procedure:
The title compound was prepared as a mixture of diastereomers from 1-(tert-butoxycarbonyl)-3,3-dimethyl-dl-proline (61 mg, 0.25 mmol) and N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 95 mg, 0.25 mmol) essentially according to the EDC coupling procedure described in Example 39, Step D. The diastereomeric products were separated by reverse phase HPLC and were carried on directly to deprotection.
Reaction SMILES: C([CH:5]([C@H:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[C:41]4[C:36](=[N:37][CH:38]=[C:39]([Cl:42])[CH:40]=4)[CH:35]([OH:43])[C:34]([CH2:45][CH2:46][OH:47])([OH:44])[C:33]3=[O:48])[CH2:28][CH2:27]2)=[O:25])=[C:20]([F:49])[CH:19]=1)[CH3:10])[C:6]([OH:8])=[O:7])(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:42][C:39]1[CH:40]=[C:41]2[C:36]([CH:35]([OH:43])[C:34]([CH2:45][CH2:46][OH:47])([OH:44])[C:33](=[O:48])[N:32]2[CH:29]2[CH2:30][CH2:31][N:26]([C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][C@H:9]([CH3:10])[CH2:5][C:6]([OH:8])=[O:7])=[CH:19][C:20]=3[F:49])=[O:25])[CH2:27][CH2:28]2)=[N:37][CH:38]=1
Reactant: C[C@@H](Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(O)(CCO)C(O)c4ncc(Cl)cc43)CC2)c(F)c1)C(C(=O)O)C(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](CC(=O)O)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(O)(CCO)C(O)c4ncc(Cl)cc43)CC2)c(F)c1
Reaction time: 6 h
Yield: 96.1 %

Procedure:
To a dichloromethane solution (1 ml) of tert-butyl (3R)-3-{[4′-({4-[7-chloro-3-(2-hydroxyethyl)-2-oxo-3,4-dihydroxy-1,5-naphthyridin-1(2H)-yl]piperidin-1-yl}carbonyl)-3′-fluorobiphenyl-2-yl]oxy}butanoic acid (28.3 mg) were added at room temperature triethylsilane (20.2 mg) and trifluoroacetic acid (0.5 ml). The reaction solution was stirred for 6 hours, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin layer chromatography to afford (3R)-3-{[4′-({4-[7-chloro-3-(2-hydroxyethyl)-2-oxo-3,4-dihydroxy-1,5-naphthyridin-1(2H)-yl]piperidin-1-yl}carbonyl)-3′-fluorobiphenyl-2-yl]oxy}butanoic acid (25.0 mg).
Reaction SMILES: [O:1]([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1)=O)C1C=CC=CC=1.O.[NH2:29][NH2:30].O>O1CCOCC1>[NH:29]([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:15][CH:16]=1)=[O:1])[NH2:30]
Reactant: CCOC(=O)N1CCN(c2ccc(NC(=O)Oc3ccccc3)cn2)CC1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)N1CCN(c2ccc(NC(=O)NN)cn2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67 %

Procedure:
A mixture of ethyl 4-[5-[(phenoxycarbonyl)amino]-2-pyridinyl]-1-piperazinecarboxylate (0.3 mol crude residue) and hydrazine hydrate (1.5 mol) in 1,4-dioxane (1100 ml) was stirred for 6 hours at room temperature. The reaction mixture was poured into water (4000 ml) and the resulting precipitate was filtered. The filtrate was extracted three times with CH2Cl2 (700 ml each time). The separated organic layer was washed with water, dried, filtered and the solvent was evaporated. The residue was stirred in DIPE. The precipitate was filtered and dried (25° C.; 20 hours), yielding 62 g (67%) of ethyl 4-[5-[(hydrazinocarbonyl)amino]-2-pyridinyl]-1-piperazinecarboxylate (interm. 9).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:3][CH:4]=1
Reactant: Oc1ccnc2ccccc12
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ccnc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.8 %

Procedure:
A mixture of 4-hydroxyquinoline (0.44 g, 3.00 mmol)), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (50:50)) yielding the title compound (0.75 g, 90% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:23]([C:21]2[N:22]=[C:18]([CH3:17])[O:19][C:20]=2[C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:13]=[N:12]1
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: CC(=O)CCCCn1cc(NC(=O)c2nc(C)oc2-c2cccc(C)c2)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@H:22]1[O:24][CH2:23]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:21]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:22]1[O:24][CH2:23]1
Reactant: Cc1nnc(-c2cc3c(O)cccc3o2)s1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nnc(-c2cc3c(OC[C@@H]4CO4)cccc3o2)s1
Yield: 74.9 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(4-hydroxybenzo(b)furan-2-yl)-5-methyl-1,3,4-thiadiazole (1.1 g), (S)-glycidyl nosylate (1.2 g) and potassium carbonate (3.0 g), the title compound (1.0 g) was obtained as yellow crystals.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([C:13]2[NH:17][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]4)[CH:19]=3)=[N:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([C:13]2[NH:17][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:29]4)[CH:19]=3)=[N:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(-c2cnc(-c3ccnc(N4CCN(C(C)C)CC4)c3)[nH]2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)N1CCN(c2cc(-c3ncc(-c4cccc(O)c4)[nH]3)ccn2)CC1
Reaction time: 8 h

Procedure:
Boron tribromide (25 mL of a 1 M solution in dichloromethane) was added to a solution of 1-{4-[5-(3-methoxy-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isopropyl-piperazine (1.94 g) in dichloromethane. The resultant yellow suspension was kept at ambient temperature overnight and then quenched by the addition of ice and diluted with water. The resultant mixture was stirred for 30 min and then filtered. The filtrate was extracted with 3N HCl, the solids that had been removed were recombined with the aqueous extracts, and the pH was adjusted to 8 with saturated NaHCO3. The resultant mixture was extracted with 9:1 chloroform/methanol. The combined extracts were concentrated in vacuo, and the residue was concentrated from methanol to provide 1-{4-[5-(3-Hydroxy-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-4-isopropyl-piperazine (quantitative). MS m/z 378 (M++1).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20]([C:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[F:35][C:36]1[CH:52]=[CH:51][C:39]([O:40][C:41]2[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=2)=[CH:38][CH:37]=1.C(OCC)C>O.COCCOC>[CH2:12]([O:19][C:20]([C:22]1([NH:27][S:47]([C:44]2[CH:45]=[CH:46][C:41]([O:40][C:39]3[CH:51]=[CH:52][C:36]([F:35])=[CH:37][CH:38]=3)=[CH:42][CH:43]=2)(=[O:48])=[O:49])[CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1(C(=O)OCc2ccccc2)CCCC1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: COCCOC
Product: O=C(OCc1ccccc1)C1(NS(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2)CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-aminocyclopentanecarboxylic acid benzyl ester p-toluenesulfonic acid salt (200 grams, 0.51 mole) and triethylamine (177 mL, 1.27 mole) in water (1 L) and 1,2-dimethoxyethane (1 L) was added 4-(4-fluorophenoxy)benzenesulfonyl-chloride (161 grams, 0.56 moles). The mixture was stirred at room temperature for 16 hours and then most of the solvent was removed by evaporation under vacuum. The mixture was diluted with ethyl acetate and was washed successively with dilute hydrochloric acid solution, water, and brine. The solution was dried over magnesium sulfate and concentrated to leave a brown solid. Trituration with diethyl ether to afforded 1-[4-(4-fluorophenoxy)benzenesulfonylamino]-cyclopentanecarboxylic acid benzyl ester as a tan solid, 167 grams (70%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[OH:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:15]=[CH:14][C:12]4[N:13]=[C:25]([C:24]5[CH:27]=[CH:28][C:21]([O:20][CH2:19][CH2:18][OH:17])=[CH:22][CH:23]=5)[NH:16][C:11]=4[CH:10]=3)=[CH:3][C:2]=2[N:1]=[C:25]1[C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][OH:17])=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Product: OCCOc1ccc(-c2nc3cc(-c4ccc5nc(-c6ccc(OCCO)cc6)[nH]c5c4)ccc3[nH]2)cc1

Procedure:
Compound 260 was prepared according to the procedure similar to that described in Scheme III from 3,3′-diaminobenzidine and 4-(2-hydroxyethoxy)benzaldehyde. [M+H]+ calcd for C39H26N4O4: 507.20; found: 507.00.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: NC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)Nc1cccc(OCCCCl)c1
Reaction time: 20 h
Yield: 83.1 %

Procedure:
A mixture of 45.6 g (0.3 mole of 1-(3-hydroxyphenyl)urea, 94.5 g (0.6 mole) of 1-bromo-3-chloropropane, 124.4 g (0.9 mole) of anhydrous potassium carbonate and 1 liter of acetone was heated at reflux with mechanical stirring for 20 hr. The mixture was concentrated and the residue was slurried with 1.5 liters of water. The mixture was filtered and the filter cake was recrystallized from 2-propanol to yield 57.0 g (83%) of off-white solid, m.p. 141°-143° C.