Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[N:14][NH2:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[C@@H]1(N)CCCC[C@H]1N.CCCCCCCCCCCC.I[C:43]1[CH:44]=[C:45]([CH3:50])[CH:46]=[C:47]([CH3:49])[CH:48]=1>[Cu]I.O1CCOCC1>[CH3:50][C:45]1[CH:44]=[C:43]([NH:15][N:14]=[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:48]=[C:47]([CH3:49])[CH:46]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: N[C@@H]1CCCC[C@H]1N
Solvent: C1COCCO1
Solvent: CCCCCCCCCCCC
Product: Cc1cc(C)cc(NN=C(c2ccccc2)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 23 h
Yield: 80.3 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (2.0 mg, 0.0105 mmol, 1.0 mol %), benzophenone hydrazone (245 mg, 1.25 mmol), sodium tert-butoxide (145 mg, 1.51 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (13 μL, 0.108 mmol, 11 mol %), dodecane (235 μL), 5-iodo-m-xylene (150 μL, 1.04 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 23 h. The resulting dark brown suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of hexane-ethyl acetate 5:1. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; hexane-ethyl acetate 40:1; 15 mL fractions). Fractions 10-12 provided 251 mg (80% yield) of the product as a bright yellow solid. The 1H NMR spectrum was in accord with that reported by Buchwald et al. Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 44, 10251.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:23])=[CH:5][N:6]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(OCc2c(N3CCCC3)noc2C)nc1
Product: Cc1onc(N2CCCC2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 49 %

Procedure:
As described for example 40f, 6-(5-methyl-3-pyrrolidin-1-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.28 mmol), was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (30 mg, 49%) which was obtained as a white solid after purification by chromatography (silica, 40 to 90% ethyl acetate in heptane). MS: m/e=387.2 [M+H]+.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]1([CH2:19][O:20][C:21]([NH:23][C:24]2([C:30]([OH:32])=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.[NH2:43][C@H:44]([CH2:48][OH:49])[CH:45]([CH3:47])[CH3:46]>C(Cl)Cl>[C:13]1([CH2:19][O:20][C:21]([NH:23][C:24]2([C:30]([NH:43][C@H:44]([CH2:48][OH:49])[CH:45]([CH3:47])[CH3:46])=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:22])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)[C@H](N)CO
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)[C@@H](CO)NC(=O)C1(NC(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
After 422 mg (2.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 555 mg (2 mmol) of 1-[[(phenylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid, 322 mg (2.1 mmol) of 1-hydroxybenzotriazole and 206 mg (2 mmol) of L-valinol in 20 ml of methylene chloride under ice-cooling, the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution, and then saturated brine. The organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 662 mg (91%) of the title compound.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]1([CH:16](O)[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl.[Br:27][C:28]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:29]=1[CH2:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:6]1([CH2:16][CH2:17][N:34]2[CH2:33][CH2:32][CH:31]([CH2:30][C:29]3[CH:37]=[C:38]([O:41][CH3:42])[CH:39]=[CH:40][C:28]=3[Br:27])[CH2:36][CH2:35]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(O)c1cccc2ccccc12
Reactant: COc1ccc(Br)c(CC2CCNCC2)c1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Br)c(CC2CCN(CCc3cccc4ccccc34)CC2)c1
Reaction time: 3 h
Yield: 80.8 %

Procedure:
Methanesulfonyl chloride (100 μl, 1.26 mmol) was added dropwise to a solution of 1-naphthylethanol (206 mg, 1.20 mmol) and triethylamine (350 μl, 2.40 mmol) in dichloromethane (2 ml) under ice-cooling and stirred for 3 hours. The solvent was distilled off and the resulting residue was dissolved in acetonitrile (3 ml) together with a base converted from 4-(2-bromo-5-methoxybenzyl)piperidine hydrochloride (384 mg, 1.20 mmol) according to the method described in Example 11, potassium iodide (199 mg, 1.20 mmol) and potassium carbonate (332 mg, 2.40 mmol). The resulting solution was heated under reflux for 3.5 hours and then allowed to cool. The precipitate was filtered off and the filtrate was concentrated, and then the residue was purified by a silica gel column chromatography (chloroform:methanol=20:1) to obtain the title compound (425 mg, 81%) as a light-brown solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.S(Cl)(Cl)=O.[NH2:17][C:18]1[CH:22]=[CH:21][S:20][C:19]=1[C:23]([NH2:25])=[O:24].C(N(CC)C(C)C)(C)C>C1COCC1>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:17][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([NH2:25])=[O:24])=[O:8])=[C:4]([F:12])[CH:3]=1
Reactant: NC(=O)c1sccc1N
Reactant: O=C(O)c1cc(F)c(Br)cc1F
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1sccc1NC(=O)c1cc(F)c(Br)cc1F

Procedure:
After stirring a mixture of 4-bromo-2,5-difluorobenzoic acid and thionyl chloride for one hour at 80° C., the solution was removed and an oily substance was obtained. A mixture of the obtained oily substance, 3-aminothiophene-2-carboxamide, N,N-diisopropylethylamine and THF was stirred for two hours under ice cooling to give 3-[(4-bromo-2,5-difluorobenzoyl)amino]thiophene-2-carboxamide.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[OH:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[O:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[O:4][CH2:3][CH2:2][O:11][N:12]1[C:13](=[O:22])[C:14]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]2[C:16]1=[O:17]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1OCCOC1CCCCO1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
A suspension of 10.8 g of 2-(2-bromoethoxy) tetrahydropyran, 7.0 g of N-hydroxyphthalimide and 11.1 g of potassium carbonate in 100 ml of dimethylformamide was stirred at 80° C. for 2.5 hours. Ethyl acetate and water were then added to the reaction mixture to make a solution. The ethyl acetate layer was then separated and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, after which the resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 8.62 g of the title compound as a syrup.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CC(C)=O.O>[N:12]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[N+:13]=[N-:14]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirred solution of p-bromomethylbenzoic acid (13.607 g, 63.3 mmol) in acetone (300 ml) and H2O (15ml) was added dropwise at room temperature a solution of NaN3 (4.123 g, 63.4mmol) in H2O (40 ml). The reaction mixture was stirred at room temperature overnight (ca 20 h). After evaporation of the acetone, the residual solid was suspended in water and filtered, yielding 10.13 g (57.2 mmol, 90.3%) of p-azidomethylbenzoic acid as a white powder: 1Hmr (DMSO-d6 δ: 4.57 (2H, s, --CH3N3), 7.43-7.55-7.93-8.07 (4H, A2'B2', aromatic Hs) and 12.7 ppm (br, s, --CO2H): ir (nujol) νmax : (--N3) and 1670 cm-1 (--CO2H).
Reaction SMILES: O.NN.[C:4]([NH:7][C:8]1[CH:29]=[CH:28][C:11]([O:12][CH2:13][CH:14]([OH:27])[CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)=[CH:10][CH:9]=1)(=[O:6])[CH3:5].[ClH:30]>C(O)C>[ClH:30].[NH2:16][CH2:15][CH:14]([OH:27])[CH2:13][O:12][C:11]1[CH:28]=[CH:29][C:8]([NH:7][C:4](=[O:6])[CH3:5])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(OCC(O)CN2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(OCC(O)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydrazine hydrate (3.6 g, 0.071 mol) was dissolved in 50 ml ethanol and added slowly to a suspension of Compound XVII (25 g, 0.071 mol) in 300 ml boiling ethanol. After 30 min., all the material dissolved. The temperature of the reaction mixture was reduced to 75° C. and maintained for an additional 1.5 hr. At the end of this time, the mixture was cooled to room temperature and concentrated hydrochloric acid added dropwise to pH 1 (pH paper) to destroy the hydrazide intermediate. Since not all of the material dissolved, the mixture was filtered to remove undissolved phthalhydrazide and the filtrate stored at 4° C. overnight. Filtration of the newly precipitated material gave 10.6 g of the title compound m.p. 192°-197° C. Recrystallization from ethanol/ether yielded 9.0 g of small white cluster crystals which were homogenous by thin layer chromatography (30:10:3:12 butanol/pyridine/acetic acid/water, Rf =0.46) m.p. 198.5°-200° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:6][C:7]([C:10]([O:12]C)=[O:11])=[N:8][N:9]=1)(=[O:3])[CH3:2].[Li+].[OH-]>C1COCC1.CO.O>[C:1]([NH:4][C:5]1[NH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1nnc(NC(C)=O)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1nnc(C(=O)O)[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
A mixture of methyl 5-acetamido-4H-1,2,4-triazole-3-carboxylate (500 mg, 2.72 mmol) and LiOH (2.1 eq) in THF/MeOH/H2O (8/4/2 mL) was stirred at 50° C. for 1 h (precipitates formed). All the volatiles were removed and the white solid residue was acidified with 7 mL of HCl (1 N), filtered and washed with H2O to afford the titled compound as a white solid (413 mg), which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][S:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=2[O-:22])=[O:15])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].C(OO)(=[O:25])C>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][S:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=2[O-:22])(=[O:25])=[O:15])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(CS(=O)c2cccc[n+]2[O-])cc([N+](=O)[O-])c1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(CS(=O)(=O)c2cccc[n+]2[O-])cc([N+](=O)[O-])c1
Temperature: 70 °C

Procedure:
To 14.0 g (0.043 mole) of 2-[[(3,5-dinitrophenyl)methyl]sulfinyl]-pyridine-N-oxide in 35 ml of glacial acetic acid was added, dropwise over 0.5 hours with stirring, 8.2 g of 40% peracetic acid in acetic acid. After addition was complete, the mixture was heated to 70° C. for 4.5 hours. The mixture was cooled to room temperature, and then an additional 2.0 g of 40% peracetic acid was added, and the mixture heated to 45-50° C. for three hours while stirring. The mixture became quite thick, so 20 ml of glacial acetic acid was added to enable better stirring and heating was continued at 70° C. for one more hour, followed by stirring at 30° C. overnight. Workup of a small aliquot indicated some sulfoxide to still be present, so heating was continued at 65-70° C. for 4 more hours. The excess peracetic acid was then destroyed by adding 100 ml of water and sodium bisulfite. After neutralizing the mixture to pH 4 with potassium carbonate, the white solid was filtered off, and then dried under vacuum. Yield was 11.5 g or 79%, having a melting point of 198-201° C. This material was recrystallized from ethanol to give a white solid, melting point 202-204° C. Infrared and NMR spectra were consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH2:7][O:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+:12].[C:13]([CH2:16][PH:17](=[O:19])[O-:18])(=O)[CH3:14].[Na+].C(OCC1C=CC=CC=1)C1C=CC=CC=1.Cl.NO>C(O)C>[CH2:7]([O:8][N:9]=[C:13]([CH2:16][PH:17](=[O:18])[O-:19])[CH3:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:12]
Reactant: CC(=O)C[PH](=O)[O-]
Reactant: NOCc1ccccc1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: c1ccc(COCc2ccccc2)cc1
Solvent: CCO
Product: CC(C[PH](=O)[O-])=NOCc1ccccc1

Procedure:
Procedure as for Example 37 using C6H5CH2ONH2HCl (4.797 g), sodium hydroxide (1.2037 g) and sodium acetylmethylphosphinate (4.331 g), except that the benzyl ether is less soluble in ethanol than hydroxylamine hydrochloride and was dissolved in 300 ml solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.CCN(C(C)C)C(C)C.[CH2:38]([N:40]=[C:41]=[O:42])[CH3:39]>ClCCl.O>[CH2:38]([NH:40][C:41]([NH:26][CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])=[O:42])[CH3:39]
Reactant: CCN=C=O
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)NCC(C)(C)c1nc(-c2ccc3cc(OC)ccc3c2)c(-c2ccncc2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A solution of the product of Example 2 (20 mg, 0.05 mmol) in dichloromethane (2 mL) containing Hunig's base (10 μL, 0.07 mmol) was treated with ethyl isocyanate (6 μL, 0.07 mmol) and stirred at room temperature for 8 hours. The mixture was diluted with water and extracted with dichloromethane. The aqueous layer was separated and extracted with additional dichloromethane, the organic layers were combined, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on a Gilson HPLC to give the title compound (12 mg, 50%) as a yellow solid; MS(ES) m/e 444 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][CH2:8][NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:25]([O:27][CH3:28])=[O:26]>C(OCC)C>[CH:10]1([N:9]([CH2:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)[C:25](=[O:26])[O:27][CH3:28])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc(CCNC2CCCC2)cc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)N(CCc1ccc(OC)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of N-(4-methoxyphenethyl)cyclopentanamine (0.827 g, 3.77 mmol) in diethyl ether was added triethylamine (0.83 mL, 5.66 mmol) and methyl chloroformate (0.44 mL, 5.66 mmol) at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 30 min. Filtration and concentration of mixture under reduced pressure gave the crude product which was purified by silica gel column chromatography using hexanes/ethyl acetate to provide the product (0.898 g, 86%) as light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.10 (d, 2H, J=8.6 Hz), 6.81 (d, 211, J=8.6 Hz), 4.32-4.12 (m, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 3.24 (t, 2H, J=7.9 Hz), 2.76 (t, 2H, J=7.9 Hz), 1.79-1.76 (m, 2H), 1.67-1.66 (m, 2H), 1.54-1.47 (m, 4H). LC-MS (ESI) Calcd for C16H23NO3 [M+H]+: 278.17. Found: 278.00.
Reaction SMILES: [S:1]1(=[O:13])(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3][CH2:2]1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C1C=CC=CC=1>O>[N:14]1([C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[S:1](=[O:13])(=[O:12])[CH2:2][CH:3]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: O=C1CCS(=O)(=O)c2ccccc21
Solvent: c1ccccc1
Solvent: O
Product: O=S1(=O)CC=C(N2CCCC2)c2ccccc21

Procedure:
A mixture of 9.8 g. (0.05 mole) of thiochroman-4-one 1,1-dioxide, 5.3 g. (0.075 mole) of pyrrolidine, and 150 ml. of benzene was placed in a flask equipped with a Dean-Stark water separator and was refluxed for 4 hr. The precipitate (4.9 g.) which separated on standing at room temperature was collected. Concentration to one-fourth the original volume gave an additional 5.0 g. These crops were combined and recrystallized from benzene to give 8.0 g. of product, m.p. 154°-157° dec.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[CH3:22])[N:10]=[C:9]2[N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]1[CH3:33].[CH3:34][S:35]([O-:38])(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([OH:38])(=[O:37])=[O:36].[F:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:11]2[N:10]=[C:9]([N:23]3[CH2:32][CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]3[CH3:33])[C:8]3[C:13](=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][CH:7]=3)[N:12]=2)=[C:16]([CH3:22])[CH:17]=1
Reactant: CS(=O)(=O)[O-]
Agent: COc1cccc2c(N3CCc4ccccc4C3C)nc(Nc3ccc(F)cc3C)nc12
Agent: Cl
Solvent: ClCCl
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1.20 g of the compound(2.80 mM) prepared in Example 34 and 50 ml of dichloromethane, 0.2 ml of methane sulfonate(3.08 mM) was dropwise added. The resultant was stirred at room temperature for 30 minutes and Concentrated under a reduced pressure. The residue produced was crystallized by adding ethyl ether to give 1.32 g of the title compound.
Reaction SMILES: [C:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH2:19][CH:20]([OH:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]([CH3:29])([CH3:28])[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N12CCN(CC1)CC2>C1C=CC=CC=1>[C:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH2:19][CH:20]([O:27][C:37](=[O:38])[NH:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:13]([CH3:29])([CH3:28])[CH2:12]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)CC(OC(=O)Nc2ccccc2)CC(C)(C)N1CC(O)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: c1ccccc1
Product: CC1(C)CC(OC(=O)Nc2ccccc2)CC(C)(C)N1CC(OC(=O)Nc1ccccc1)c1ccccc1

Procedure:
A mixture of 3.0 parts of the product from Example 81, 0.90 parts of phenyl isocyanate and 0.1 parts of 1,4-diazabicyclo[2,2,2]octane in 25 parts of dry benzene was heated under reflux conditions for 24 hours. The benzene solvent was removed by distillation under reduced pressure and the residue crystallised from petroleum ether (b.p. 60°-80° C.) to give 4-phenylcarbamoyloxy-1-[2'-(phenylcarbamoyloxy)-2'-phenylethyl]-2,2,6,6-tetramethylpiperidine having a melting point of 173° C. and the following elemental analysis by weight:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([Cl:18])[N:3]=1.N[CH2:20][CH2:21][OH:22]>C1COCC1>[Cl:18][C:4]1[C:5]([C:16]#[N:17])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:8]#[N:9])=[C:2]([NH:1][CH2:20][CH2:21][OH:22])[N:3]=1
Reactant: N#Cc1c(N)nc(Cl)c(C#N)c1-c1ccccc1
Reactant: NCCO
Solvent: C1CCOC1
Product: N#Cc1c(Cl)nc(NCCO)c(C#N)c1-c1ccccc1

Procedure:
1 g (3.65 mmol) of 2,6-dichloro-4-phenyl-3,5-pyridinedicarbonitrile [Quintela et al., Heterocycles 38, 1299-1305 (1994)] is, together with 0.33 g (5.47 mmol) of 2-aminoethanol, dissolved in 3 ml of THF, and the mixture is heated under reflux for 8 h. The reaction mixture is purified by preparative HPLC on reversed-phase silica gel (gradient: water+0.1% formic acid/acetonitrile 90:105:95 in 35 minutes).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:37])([F:36])[CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]([C:17]2[N:21]3[N:22]=[CH:23][C:24]([C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([O:31]C)=[O:30])=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:9].C1COCC1.Cl>CO.O>[F:37][C:5]([F:4])([F:36])[CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]([C:17]2[N:21]3[N:22]=[CH:23][C:24]([C:26]4[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=4)[C:29]([OH:31])=[O:30])=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[O:9]
Reactant: COC(=O)c1cccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cccc(C(=O)O)c4)cnn23)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Lithium hydroxide monohydrate (40. mg, 0.96 mmol) was added to a mixture of methyl 3-{3-[3-({[(2,2,2-trifluoro ethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}benzoate (0.090 g, 0.19 mmol) in methanol (2.0 mL)/THF (1.0 mL)/water (0.5 mL) and then the reaction was stirred at r.t. for 4 h. The mixture was adjusted with conc. HCl to PH˜3, and then concentrated under reduced pressure to give the crude product which was directly used in the next reaction without further purification. LCMS (M+H)+: m/z=456.1
Reaction SMILES: C([O:4][C:5]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][C:8]([NH:14][C:15](=[O:36])[NH:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[CH:24][C:23]([CH3:34])=[CH:22][C:21]=3[CH3:35])=[CH:7][C:6]=1[CH:37]([CH3:39])[CH3:38])(=O)C.[OH-].[Na+]>CO>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]1[C:25]2[C:20](=[C:21]([CH3:35])[CH:22]=[C:23]([CH3:34])[CH:24]=2)[N:19]=[CH:18][C:17]=1[NH:16][C:15]([NH:14][C:8]1[CH:9]=[C:10]([CH:11]([CH3:12])[CH3:13])[C:5]([OH:4])=[C:6]([CH:37]([CH3:39])[CH3:38])[CH:7]=1)=[O:36]
Reactant: CC(=O)Oc1c(C(C)C)cc(NC(=O)Nc2cnc3c(C)cc(C)cc3c2-c2ccccc2Cl)cc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)c2ncc(NC(=O)Nc3cc(C(C)C)c(O)c(C(C)C)c3)c(-c3ccccc3Cl)c2c1
Reaction time: 1.5 h

Procedure:
A mixture of 3-[3-(4-acetoxy-3,5-diisopropylphenyl)ureido]-4-(2-chlorophenyl)-6,8-dimethylquinoline (300 mg), methanol (20 ml) and 1N-sodium hydroxide (2 ml) was stirred for 1.5 hrs. at room temperature. After concentrated, the mixture was diluted with water, acidified with 2N-hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then distilled to remove the solvent. The residue was recrystallized from a mixture of acetone and isopropyl ehter to give 4-(2-chlorophenyl)-3-[3-(4-hydroxy-3,5-diisopropylphenyl)ureido]-6,8-dimethylquinoline as colorless prisms. Yield 116 mg (41.9%). m.p. 194°-196° C.