Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[N:9][N:10]([C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[CH:11]=2)[CH:2]=1.Br[C:20]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[C:22]=2[CH:21]=1.N1C=CC=CC=1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[N:23]1[C:22]2[CH:21]=[C:20]([O:18][C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([N:10]4[CH:11]=[C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH:8]=[N:9]4)[CH:13]=3)[CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2
Reactant: Brc1ccc2c3ccccc3n(-c3ccccn3)c2c1
Reactant: Oc1cccc(-n2cc(-c3cccnc3)cn2)c1
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: c1ccc(-n2c3ccccc3c3ccc(Oc4cccc(-n5cc(-c6cccnc6)cn5)c4)cc32)nc1
Temperature: 95 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
To a dry Shlenck tube equipped with a magnetic stir bar was added 3-(4-(pyridin-3-yl)-1H-pyrazol-1-yl)phenol 5 (475 mg, 2.0 mmol, 1.0 eq), 2-bromo-9-(pyridin-2-yl)-9H-carbazole (776 mg, 2.4 mmol, 1.2 eq), Cut (38 mg, 0.2 mmol, 0.1 eq), picolinic acid (49 mg, 0.4 mmol, 0.2 eq) and K3PO4 (819 mg, 4.0 mmol, 2.0 eq). The tube was evacuated and backfilled with nitrogen. The evacuation and backfill procedure was repeated another two times. Then solvent DMSO (10 mL) was added under nitrogen. The mixture was stirred in an oil bath at a temperature of 90-100° C. for 3 days and then cooled down to ambient temperature. Water was added to dissolve solid. The mixture was extracted with ethyl acetate three times. The combined organic layer was washed with water three times, dried over sodium sulfate, and then filtered. The solvent was removed under reduced pressure, and the residue was purified through column chromatography on silica gel using dichloromethane/methanol (50:1) as eluent to obtain the desired product Ligand ON13 as a brown-red solid 656 mg in 68% yield. 1H NMR (DMSO-d6, 400 MHz): δ 6.92 (dd, J=8.0, 2.4 Hz, 1H), 7.04 (dd, J=8.0, 1.6 Hz, 1H), 7.28 (t, J=7.6 Hz, 1H), 7.33-7.40 (m, 3H), 7.45 (t, J=8.0 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.55 (t, J=2.0 Hz, 1H), 7.60 (dd, J=7.6, 1.6 Hz, 1H), 7.71 (s, 1H), 7.73 (s, 1H), 7.98-8.03 (m, 2H), 8.16 (d, J=7.6 Hz, 1H), 8.21 (d, J=7.2 Hz, 1H), 8.22 (s, 1H), 8.38 (dd, J=4.4, 1.6 Hz, 1H), 8.62 (dd, J=4.4, 1.6 Hz, 1H), 8.91 (d, J=2.4 Hz, 1H), 9.08 (s, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 102.54, 107.98, 111.12, 112.68, 113.27, 115.75, 119.02, 120.11, 120.19, 121.01, 121.27, 121.79, 122.11, 123.28, 123.87, 125.32, 125.99, 127.66, 131.06, 132.41, 138.90, 139.36, 139.49, 139.97, 140.78, 146.54, 147.62, 149.52, 150.48, 154.81, 158.56.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][NH2:14])[CH3:10]>C1(C)C=CC=CC=1>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[CH2:13][N:14]=[CH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH3:10]
Reactant: CCOC(CN)OCC
Reactant: O=Cc1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(CN=Cc1ccncc1)OCC
Yield: 100 %

Procedure:
300 g pyridine-4-carbaldehyde and 372 g 2,2-diethoxy-ethylamine were refluxed in 2 L toluol over night. The mixture was evaporated to give 621 g of the desired product. The residue was purified by chromatographie on silica to give 100 g desired product.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:20]([O:22][CH3:23])=O.[BH4-].[Na+].Cl>C1COCC1>[CH2:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:11]([OH:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:20][O:22][CH2:23][C:19]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCCCCCCCCOCc1ccccc1
Reactant: COC=O
Agent: Cl
Agent: II
Agent: [BH4-]
Solvent: C1CCOC1
Product: OC(CCCCCCCCOCc1ccccc1)CCCCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To freshly activated Mg turnings (24.08 g, 1.003 mol) was added 200 mL anhydrous THF, followed by the addition of pinch of iodine into the mixture under inert atmosphere. After initiation of the Grignard formation a solution of Compound 3 (150 g, 0.5016 mol) in 1 L of dry THF was added slowly controlling the exothermic reaction. After complete addition, the reaction was heated to reflux for 1 hour, then cooled to room temperature. Methyl formate (60.24 g, 1.0033 mol) was then added slowly and reaction was continued for 2 hours. After completion, the reaction was quenched by slow addition of 10% HCl followed by water (1 L) and extracted with ethyl acetate (3×1 L). The organic layer was taken in 5 liter beaker, diluted with 500 mL of methanol and cooled to 0° C. To this solution excess of NaBH4 (˜5 eq) was added in portions to ensure the hydrolysis of formate ester which was not cleaved by addition of HCl. The resulting solution was stirred for an hour and then volatilites were removed under vacuum. The residue was taken in water (1 L) and acidified by 10% HCl solution (PH 4). The product was then extracted with ethyl acetate (3×1 L). The organic phase was then dried and concentrated on rotary evaporator to afford compound 4 (57 g, 24%) as solid. 1H NMR (400 MHz, CDCl3): δ=7.35-7.32 (m, 8H), 7.29-7.24 (m, 2H), 4.49 (s, 4H), 3.56 (m, 1H), 3.46-3.43 (m, 4H), 1.63-1.56 (m, 4H), 1.44-1.34 (m, 28H). C13 NMR (100 MHz, CDCl3): δ=138.56, 128.21, 127.49, 127.34, 72.72, 71.76, 70.37, 37.37, 29.64, 29.56, 29.47, 29.33, 26.07, 25.54.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:18])([CH3:17])[O:11][SiH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:6]([F:19])[CH:5]=1.[OH-].[Na+]>CCO>[C:13]([SiH2:12][O:11][C:10]([CH3:18])([CH3:17])[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][C:6]=1[F:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1ccc(C(C)(C)O[SiH2]C(C)(C)C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2.20 g (7.37 mmol) 4-(tert-butyl-dimethyl-silanyloxymethyl)-3-fluoro-benzoic acid methyl ester (preparation 16c) in 30 mL EtOH is added 12 mL 1 M aqueous NaOH-solution. The mixture is stirred 1 h at RT, additional 4 mL 1 M aqueous NaOH-solution are added and the reaction mixture is stirred an additional hour. The solvent is evaporated, the residue is acidified with 1 M aqueous HCl-solution. The precipitate is collected and dried.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH2:50][OH:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]=[O:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C=O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 45 °C
Yield: 58 %

Procedure:
To a solution of [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 1j (8.53 g, 12.08 mmol) in dichloromethane (350 mL) was added 2-iodoxybenzoicacid (6.77 g, 24.2 mmol) at room temperature. The mixture was refluxed at 45° C. for 36 hours and quenched with 150 mL of water. The mixture was partitioned between dichloromethane and water. The organic layer was washed with saturated aqueous sodium chloride (150 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 1k as pale yellow oil (4.94 g, 60.0%).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH:20][CH2:21][C@H:22]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:23]([OH:25])=[O:24])=[O:19])[CH:16]=2)[CH2:11][N:10]1[CH2:36][CH2:37][NH:38][C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1>[Pd].CC(O)=O>[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH:20][CH2:21][C@H:22]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:23]([OH:25])=[O:24])=[O:19])[CH:16]=2)[CH2:11][N:10]1[CH2:36][CH2:37][NH:38][C:39]1[NH:44][CH2:43][CH2:42][CH2:41][N:40]=1
Reactant: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1ccc2c(c1)C(=O)N(CCNc1ncccn1)C2
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1ccc2c(c1)C(=O)N(CCNC1=NCCCN1)C2
Reaction time: 2.5 h

Procedure:
10% Pd/C (101 mg) was added to HOAc/12 0 N HCl solution (19:1, 31 ml) containing 6-6 (649 mg, 1.01 mmol) and the mixture hydrogenated at 60 PSI for 2.5 hr. Filtration and concentration gave a gum which was purified by flash chromatography (silica, 7:1.5:1.5 EtOH/NH4OH/H2O) to provide 6-7 as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15](C3C=CC(CNC)=CC=3)[CH2:14][CH2:13]2)[CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH2:32][OH:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:4]3[CH:3]=[CH:2][C:28]([CH2:30][CH2:31][CH2:32][OH:33])=[CH:27][C:5]=3[CH2:6][NH:8][CH3:9])[CH2:14][CH2:13]2)[CH:9]2[CH2:10][CH2:11]2)=[O:7])=[CH:27][CH:28]=1
Reactant: OCCCBr
Reactant: CNCc1ccc([C@H]2CC[C@H](N(C(=O)c3ccc(Cl)cc3)C3CC3)CC2)cc1
Product: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(C(=O)c2ccc(Cl)cc2)C2CC2)CC1

Procedure:
from trans-N-(4-chlorobenzoyl)-N-cyclopropyl-4-(4-methylaminomethylphenyl)cyclohexylamine and 3-bromo-1-propanol. Melting point: 118°-123° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:41][CH2:42][CH3:43])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([O:38]C)=[O:37])=[CH:32][CH:31]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:40])[CH3:2].[OH-].[K+]>CO>[CH2:1]([O:3][CH:4]([O:41][CH2:42][CH3:43])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:40])[CH3:2]
Reactant: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C(=O)OC)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C(=O)O)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Reaction time: 24 h
Yield: 97.6 %

Procedure:
To a solution of 0.588 g of (RS)-1-(2,2-diethoxyethyl)-3-((4-methoxycarbonylphenyl)aminocarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in 30 ml of methanol was added 5 ml of an aqueous solution of 0.20 g of potassium hydroxide (85%) at room temperature. The mixture was stirred for 1 day, followed by concentration. The concentrate was diluted with water, and washed with chloroform. The aqueous layer was adjusted to pH 2 with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give 0.56 g (98%) of the title compound..
Reaction SMILES: O.[Pd:2].[Pd+2].[C:4]([O-:7])(=O)[CH3:5].[Pd+2].[C:9]([O-:12])(=O)[CH3:10].[CH2:13]([C:17]([CH3:19])=[O:18])C(C)C>>[Pd:2].[CH3:19]/[C:17](/[O-:18])=[CH:13]/[C:4]([CH3:5])=[O:7].[CH3:19]/[C:17](/[O-:18])=[CH:13]/[C:9]([CH3:10])=[O:12].[Pd+2:2]
Reactant: CC(=O)CC(C)C
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: [Pd]
Solvent: O
Product: CC(=O)/C=C(/C)[O-]

Procedure:
In the prior art, preparation of metal colloids has typically been carried out in aqueous solution in the presence of additives such as surfactants, oil microemulsions, nonpolar water-soluble polymers or amphiphilic block or graft copolymers. In addition, preparation of palladium (0) sols with particle diameter ranges between 7 nm and 260 nm has been carried out by thermal decomposition of organopalladium compounds in various organic solvents using refluxing conditions without any additives. This was accomplished by dissolving organopalladium compounds, such as bis(2,4-pentanedionate) palladium (II) [Pd(acac)2] or palladium acetate, in various organic solvents and refluxing the solutions at their boiling point for a period of minutes to several hours. See for example Esumi et al. in Langmuir, 5, 1, 268 (1989) and Tano et al. in J. Colloid Interface Sci., 133, 2, 530 (1989). Stable and relatively monodisperse palladium (0) sols, with particle diameter ranges between 8 nm and 10 nm were only obtained from [Pd(acac)2] in the organic solvent methyl isobutyl ketone which exhibits a high dipole moment of D˜2.7 and a relatively low boiling point of 115.9° C. Bimetallic Pd—Cu colloids, Pd—Cu2O, such as from mixed palladium acetate and copper (II) acetate have similarly been prepared by thermal decomposition in various organic solvents without any additives. See, for example, Esumi et al in Chem. Mater., 2, 5, 564, (1990). The average diameters of the Pd—Cu2O sols ranged between 50 and 130 nm with a decrease of the molar ratio of palladium acetate in the mixed acetates. The prior art of Esumi et al. and Tano et al. describe a critical thermal decomposition temperature for formation of stable metal colloids that ranges between 110° C. and 116° C. in organic solvents of low viscosity, i.e., significantly less than 10 centipoises.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[S:14][C:15]([CH2:18]Cl)=[CH:16][CH:17]=1>>[Cl:12][C:13]1[S:14][C:15]([CH2:18][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: ClCc1ccc(Cl)s1
Product: O=[N+]([O-])c1cc(OCc2ccc(Cl)s2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 2-Chloro-5-chloromethyl-thiophene using the conditions described in Example 10C to provide 2-Chloro-5-(4-chloro-3-nitro-phenoxymethyl)-thiophene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[C:5]2[N:6]([C:8]([C:11]([OH:13])=O)=[CH:9][N:10]=2)[N:7]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[N:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[C:5]2[N:6]([C:8]([C:11]([NH:59][C:56]3[CH:57]=[CH:58][N:53]=[CH:54][CH:55]=3)=[O:13])=[CH:9][N:10]=2)[N:7]=1
Reactant: Nc1ccncc1
Reactant: COc1ccc(CN(c2ccc(C)cn2)c2cc(Cl)nn3c(C(=O)O)cnc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COc1ccc(CN(c2ccc(C)cn2)c2cc(Cl)nn3c(C(=O)Nc4ccncc4)cnc23)cc1
Yield: 38.8 %

Procedure:
A solution of 6-chloro-8-((4-methoxybenzyl)(5-methylpyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid (0.07 g, 0.165 mmol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (0.047 g, 0.248 mmol), 1-hydroxybenzotriazole (0.033 g, 0.248 mmol), TEA (0.069 mL, 0.495 mmol) and pyridin-4-amine (0.023 g, 0.248 mmol) in acetonitrile (2 mL) was heated to 80° C. for 16 hours. The solution was quenched with EA/water. The organic layer was washed with sat NaHCO3 and sat NaCl. The organic layer was dried with Na2SO4, filtered and concentrated in vacuo to give the crude product mixture. The crude product was purified by ISCO (5% EtOAC/DCM; 12 g column), followed by ISCO (5% MeOH/DCM; 12 g column) to afford the title compound (32 mg). [M+H]=500.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][CH2:20][CH2:21][C:22]3[CH:31]=[CH:30][C:29]4[CH2:28][CH2:27][CH2:26][NH:25][C:24]=4[N:23]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH2:7][CH2:8][CH3:9])C.[OH-].[Na+].Cl>C1COCC1.O>[N:23]1[C:24]2[NH:25][CH2:26][CH2:27][CH2:28][C:29]=2[CH:30]=[CH:31][C:22]=1[CH2:21][CH2:20][CH2:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:32])=[O:3])[CH:11]=[CH:12]2
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(CCCc3ccc4c(n3)NCCC4)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(CC(=O)O)n1ccc2cc(CCCc3ccc4c(n3)NCCC4)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 65 %

Procedure:
A mixture of 3-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-indol-1-yl}-hexanoic acid ethyl ester (83.0 mg, 0.218 mmol) and NaOH (52.0 mg, 1.31 mmol) in THF/H2O (3:1) was stirred at room temperature for 2 days. Aqueous HCl solution (1 N) was added to adjust the pH to 4–5. The crude product was extracted with ethyl acetate, and the combined organic layers were washed with brine and dried over Na2SO4. Removal of solvent gave the crude product, which was purified via column chromatography, eluting with 5% methanol in methylene chloride, to give the title compound (65% yield). 1H NMR (CDCl3) δ 9.35 (br, 1H), 7.42 (d, J=8.1 Hz, 1H) 7.27 (m, H), 7.16–7.20 (m, 2H), 6.95 (d, J=7.9 Hz, 1H), 6.40 (d, J=2.5 Hz, 1H), 6.22 (d, J=7.2 Hz, 1H), 4.91 (br, 1H), 3.40 (m, 2H), 2.56–2.82 (m, 10 H), 1.84–2.05 (m, 6H), 0.86 (m, 3H). Mass Spectrum (LCMS, ESI) calculated for C25H32N3O2 406.3 (M+H); found 406.4.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH:4]=[CH:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].C1(C=CC(O)=CC=1)O>C(#N)C>[CH2:3]([CH:4]1[CH2:15][CH:14]([C:13]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]1[N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH:2]([CH3:12])[CH3:1]
Reactant: C=CC(=O)OCC
Reactant: CC(C)CC=CN1CCCCC1
Agent: Oc1ccc(O)cc1
Solvent: CC#N
Product: CCOC(=O)C1CC(CC(C)C)C1N1CCCCC1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
1-(4-Methyl-1-pentenyl)piperidine (844 g) and acetonitrile (70 mL) were mixed. The ethyl acrylate (443 mL) and hydroquinone (447 mg) were added to the mixture. The resulting mixture was stirred at 95° C. overnight. The reaction mixture was concentrated in vacuo to give the title compound (994.08 g) as a crude product.
Reaction SMILES: C([O:5][C:6]1[C:9](=[O:10])[C:8](=O)[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1)CCC.[OH-].[NH4+:31].O>CO>[NH2:31][C:8]1[C:9](=[O:10])[C:6](=[O:5])[C:7]=1[NH:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:18]=1
Reactant: CCCCOc1c(NCCCOc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1c(NCCCOc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 41 h
Yield: 77 %

Procedure:
To a solution of 1-butoxy-2-[3-(3-piperidinomethylphenoxy)propylamino]-1-cyclobutene-3,4-dione [prepared in Example 2] (4.06 g, 0.01014 mole) in methanol (40 mL) was added 14M aqueous ammonium hydroxide (1.5 mL, 0.021 mole). The mixture was stirred at ambient temperature for 41 hours. Water (40 mL) was added and stirring was continued for 10 minutes. The precipitate was collected by filtration, washed with methanol:water (1:1) (20 mL), and dried in vacuo to give 2.68 g (77.0% yield) of the title compound. A sample purified by chromatography showed spectral data identical to that of an authentic sample.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:9](O)(=O)[CH:10](C)[CH3:11].S(=O)(=O)(O)O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[OH-].[NH4+]>C(#N)C.C1S(=O)(=O)CCC1.O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[CH:10]([CH3:11])[CH3:9]
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)C(=O)O
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O=S1(=O)CCCC1
Solvent: O
Solvent: CC#N
Product: CC(C)c1cc(Cl)nnc1Cl
Temperature: 55 °C
Reaction time: 24 h
Yield: 67.2 %

Procedure:
A solution of 3,6-dichloropyridazine (22.5 g, 0.15 mol) in acetonitrile (35 mL), tetramethylene sulfone (107 mL) and water (245 mL) at room temperature was treated with isobutyric acid (14 mL, 0.151 mol) followed by silver nitrate (13 g, 0.075 mol). The reaction mixture was heated to 55° C. A solution of concentrated sulfuric acid (24 mL) in water (75 mL) was added in one portion followed by the dropwise addition over 35 min of a solution of ammonium persulfate (51.5 g, 0.22 mol) in water (75 mL). The reaction mixture was heated to 70° C. for 20 min and then cooled to room temperature and stirred for 24 h. At this time, the reaction was cooled to 0° C. and 28-30% ammonium hydroxide (100 mL) was added slowly dropwise to bring the reaction to pH=8. The reaction was diluted with water (500 mL) and was filtered over celite and washed well with ethyl acetate (500 mL). The water layer and the organic layer were separated. The organic layer was saved. The aqueous layer was extracted with ethyl acetate (2×500 mL). The combined organics were washed with water (1×400 mL) and a saturated aqueous sodium chloride solution (1×400 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting oil was purified by column chromatography using silica gel eluted with petroleum ether followed by 10% ethyl acetate in petroleum ether to afford 3,6-dichloro-4-isopropyl pyridazine (7) (19.26 g, 67%) as an oil; (+)-HRMS m/z calcd for C7H8Cl2N2 (M+) 190.0065, found 190.0059. Molecular Weight=191.0612; Exact Mass=190.0065
Reaction SMILES: [N:1]1([C:11]([NH2:13])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].N1C2C(=CC=CC=2)CC1=O.[Cl:24][S:25](N=C=O)(=[O:27])=[O:26]>>[Cl:24][S:25]([NH:13][C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10])=[O:12])(=[O:27])=[O:26]
Reactant: NC(=O)N1C(=O)Cc2ccccc21
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C1Cc2ccccc2N1
Product: O=C1Cc2ccccc2N1C(=O)NS(=O)(=O)Cl

Procedure:
In the second method for preparing the 2-oxindole-1-carboxamide compounds of the formula II, a 2-oxindole of the formula VI is reacted with chlorosulfonyl isocyanate to give the intermediate N-chlorosulfonyl-2-oxindole-1-carboxamide of formula VII, followed by removal of the chlorosulfonyl group by hydrolysis, viz., ##STR10##