Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].Cl[C:23](=[O:29])[C:24]([O:26]CC)=[O:25].[OH-].[Na+].Cl>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:23](=[O:29])[C:24]([OH:26])=[O:25]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(=O)NCCc1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Triethylamine (2.28 mL; 16.22 mmol) was added to the mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (1.53 g; 6.49 mmol) and ethyl 2-chloro-2-oxoacetate (0.815 mL; 7.14 mmol) in dichloromethane (50 mL) at 0° C. After addition, the mixture was stirred at room temperature for 30 minutes and washed with an aqueous solution of sodium carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. Ethanol (2 mL) and water (7.5 mL) were added to the resulting residue, followed by a 2M solution of sodium hydroxide (9.5 mL, 19 mmol). The mixture was stirred at room temperature for 20 minutes and the pH of the solution was adjusted to 1 by addition of a 6N hydrochloric acid. The precipitate was collected, and was dissolved in ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and was evaporated to dryness to give 1.36 g (81%) of 2-(2-(5-chloro-1H-indol-3-yl)ethylamino)-2-oxoacetic acid as a yellowish solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1.C(O)(=O)C>[CH:13]1([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc(NC2CCCCC2)cc1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of ethyl 4-aminobenzoate (20.00 g, 0.120 mol) and cyclohexanone (17.80 g, 0.180 mol) in tetrahydrofuran (100 ml) and acetic acid (10 ml) was added sodium triacetoxyborohydride (38.50 g, 0.180 mol) at room temperature, and the mixture was stirred for 2 hr. Water was added to the reaction mixture and the mixture was extracted with toluene. The organic layer was successively washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and hexane was added to the obtained residue. The precipitated solid was collected by filtration and washed with hexane. The obtained solid was dried in vacuo to give ethyl 4-cyclohexylaminobenzoate (25.20 g, yield 84%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:6]1=2.I.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](SC)=[NH:24]>CCO.C([O-])(O)=O.[Na+]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([NH:15][C:23]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)=[NH:24])[CH:13]=[CH:14][C:6]1=2
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCN1CCOc2cc(N)ccc21
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCN1CCOc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
A suspension of N,N-dimethyl-2-(7-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanamine (210 mg, 0.836 mmol) and Pd—C (10% wt, 89 mg, 0.084 mmol) in dry EtOH (15 mL) was purged with hydrogen gas. The reaction was stirred at room temperature for 3 hours under hydrogen atmosphere (balloon pressure). The reaction mixture was then filtered through a Celite pad and washed with EtOH (15 mL). The light purple filtrate was concentrated to give crude 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine. A solution of this crude 4-(2-(dimethylamino)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-amine (185 mg, 0.836 mmol) in dry EtOH (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (477 mg, 1.672 mmol) and stirred overnight at room temperature. The reaction was diluted with saturated NaHCO3 solution (50 mL) and the product was extracted into CH2Cl2 (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography on silica gel using 2:98 MeOH:CH2Cl2, followed by 5:95 (2M NH3 in MeOH):CH2Cl2, to give a yellow solid (150 mg, 54%). 1H-NMR (DMSO-d6) δ 7.69 (dd, J=3.6, 0.9 Hz, 1H), 7.56 (dd, J=5.1, 0.9 Hz, 1H), 7.07 (dd, J=5.1, 3.9 Hz, 1H), 6.64 (d, J=8.4 Hz, 1H), 6.35-6.26 (m, 4H), 4.14 (t, J=3.9 Hz, 2H), 3.33-3.29 (m, 4H), 2.42 (t, J=6.9 Hz, 2H), 2.19 (s, 6H); ESI-MS (m/z, %): 331 (MH+, 100), 260 (25); ESI-HRMS calculated for C17H23N4OS (MH+): 331.1587, Observed: 331.1594; HPLC purity: 99.0% by area.
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:12]([O:14][CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]12.C(N(CC)C1C=CC=CC=1)C.[Cl:36][CH2:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:50][O:51][CH3:52])[C:47](O)=[O:48])[N:45]=1)=[O:39]>C(Cl)Cl>[Cl:36][CH2:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:50][O:51][CH3:52])[C:47]([NH:1][CH:2]2[C:23](=[O:24])[N:4]3[C:5]([C:12]([O:14][CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:20])[CH3:21])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]23)=[O:48])[N:45]=1)=[O:39]
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Reactant: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Solvent: CCN(CC)c1ccccc1
Solvent: ClCCl
Product: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)CCl)n3)[C@H]2SC1
Temperature: -5 °C

Procedure:
Meanwhile, 121 mg of pivaloyloxymethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate and 141 mg of N,N-diethylaniline were dissolved in 5 ml of methylene chloride and stirred at -5° C. The resulting mixture was added dropwise to the mixture containing 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid prepared as described above. The reaction mixture was stirred for 15 minutes and then concentrated by evaporation under reduced pressure. To the residue were added 20 ml of ethyl acetate and 5 ml of water, and the ethyl acetate layer was separated, washed, in turn, with 5 ml of a saturated aqueous solution of sodium bicarbonate, 5 ml of a 5% w/v aqueous solution of hydrogen chloride and 5 ml of a saturated aqueous solution of sodium chloride, and finally dried over anhydrous magnesium sulphate. The drying agent was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 10 g of silica gel eluted with a 2:1 by volume mixture of ethyl acetate and hexane, to afford 55 mg of pivaloyloxymethyl 7-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.BrCCC1C=CC=CC=1.[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][C:35]=1[F:46])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CS(O[CH2:52][CH2:53][CH2:54][CH:55]1[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]1)(=O)=O>>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][N:43]([CH2:52][CH2:53][CH2:54][CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)[CH2:42][CH2:41]2)=[CH:36][C:35]=1[F:46])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)OCCCC1CCCCC1
Reactant: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Agent: BrCCc1ccccc1
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: Fc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Yield: 99.4 %

Procedure:
Production Example 1 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and (2-bromoethyl)-benzene were replaced with 1-(4-benzyloxy-3-fluorophenyl)piperazine (1.33 g) and 3-cyclohexylpropyl methanesulfonate (1.02 g), respectively, to provide crude 1-(4-benzyloxy-3-fluorophenyl)-4-(3-cyclohexylpropyl)piperazine (1.89 g).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11](OC)(=[O:15])[C:12]([CH3:14])=[CH2:13].COC1C=CC(O)=CC=1.CO.C(OC)(=O)C(C)=C>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:11]([O:10][CH2:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: OCCCC1CCCCC1
Reactant: C=C(C)C(=O)OC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: COc1ccc(O)cc1
Solvent: CO
Product: C=C(C)C(=O)OCCCC1CCCCC1
Yield: 91.5 %

Procedure:
In a 4 liter three-neck round bottomed flask equipped with a thermometer, a reflux condenser with distillation attachment, and a stirrer, 852 g (6 mol) 3-cyclohexyl-1-propanol, 1800 g (18 mol) methyl methacrylate, 0.18 g p-methoxyphenol, and 26 g isopropyl titanate were heated to boiling, while passing air through the mixture, and a methanol/methyl methacrylate azeotrope was drawn off, until complete conversion was achieved (c. 3.5 hr). The excess methyl methacrylate was removed in a rotary evaporator, and the residue was distilled. 3-Cyclohexylpropyl methacrylate was obtained in 91.5% yield. Purity as determined by gas-chromatography:>98% B.p. (0.8 mm):88° C. nD20 :1.464.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.[OH-].[Na+]>[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([C:13]([C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[O:15])[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccccc1Nc1ccc2[nH]ncc2c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1ccccc1Nc1ccc2[nH]ncc2c1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 97.9 %

Procedure:
To a solution of 2-(1H-indazol-5-ylamino)benzoic acid (102 mg, 0.402 mmol) in N,N-dimethylformamide (0.5 ml) were added 1-benzylpiperazine (210 μl, 1.21 mmol), 1-hydroxybenzotriazole (74 mg, 0.484 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (94 mg, 0.490 mmol) in that order, and the resulting mixture was stirred at room temperature for 21 hours. The mixture was dissolved in a 2N-aqueous sodium hydroxide solution (10 ml) and then extracted twice with ethyl acetate/toluene/tetrahydrofuran (2/2/1, 10 ml). The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby a crude product was obtained. The crude product was purified by a silica gel column chromatography (eluent: chloroform/methanol=100/3) to obtain N-{2-[(4-benzylpiperazin-1-yl)carbonyl]phenyl}-1H-indazol-5-amine (162 mg, 100%).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH3:18])=[C:13]([N+:19]([O-])=O)[CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])[CH3:2]>C(O)C.[Pd].[H][H]>[CH2:1]([O:3][P:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH3:18])=[C:13]([NH2:19])[CH:12]=1)([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCCCCP(=O)(OCC)c1ccc(NC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCP(=O)(OCC)c1ccc(NC)c(N)c1

Procedure:
Prepared analogously to Example 1c from ethyl(4-methylamino-3-nitro-phenyl)-n-pentyl-phosphinate and palladium on activated charcoal/hydrogen in ethanol.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[O:14][C:15](=[O:29])[CH:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C:18](=[O:28])[CH2:17]4)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[BH4-].[Na+].[Cl-].[NH4+]>CO.ClCCl>[OH:28][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([C:15](=[O:29])[O:14][C:13]3[C@H:12]4[C@:26]([CH3:27])([CH2:25][CH2:24][C:23]=32)[C@@H:9]([C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:10][CH2:11]4)[CH2:17]1
Reactant: CC(C)CCC[C@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)CC1C(=O)O3
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@@H]1C(=O)O3
Reaction time: 0.33 h
Yield: 90.3 %

Procedure:
Compound 1 (400 mg, 0.999 mmol) obtained in Example 1 was dissolved in a mixed solvent of methanol (6.0 mL) and dichloromethane (4.0 mL), and sodium borohydride (37.8 mg, 0.999 mmol) was added thereto at 0° C., followed by stirring at 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography to obtain the title compound (363 mg, 90%).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][C:8]=2[C:7](=[O:22])[N:6]([CH3:23])[C:5]2[CH:24]=[CH:25][CH:26]=[N:27][C:4]1=2)[CH3:2].[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12](/[CH:14]=[CH:15]\[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][C:8]=2[C:7](=[O:22])[N:6]([CH3:23])[C:5]2[CH:24]=[CH:25][CH:26]=[N:27][C:4]1=2)[CH3:2]
Reactant: CCN1c2ncc(C#Cc3ccccc3)cc2C(=O)N(C)c2cccnc21
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CCN1c2ncc(/C=C\c3ccccc3)cc2C(=O)N(C)c2cccnc21
Yield: 16.5 %

Procedure:
5,11-Dihydro-11-ethyl-5-methyl-8-phenylethynyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.12 g, 0.34 mmol) was hydrogenated over Lindlar catalyst in ethanol under 50 p.s.i. of hydrogen. Workup and purification as described in Example 42 afforded 20 mg of the title compound as a yellow-orange oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[O:12]=[C:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:22](=[S:24])[NH2:23])[C:16]=2[CH2:15][NH:14]1>>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:23]=[C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH2:15][NH:14][C:13]3=[O:12])[S:24][CH:2]=1
Reactant: NC(=S)c1cccc2c1CNC2=O
Reactant: Cc1ccncc1C(=O)CBr
Product: Cc1ccncc1-c1csc(-c2cccc3c2CNC3=O)n1

Procedure:
By the reaction in the same manner as in Example 25-ii) using 1-oxo-4-isoindolincarbonitrile (310 mg), 1-oxoisoindolin-4-carbothioamide was obtained as pale-green powder. Then, by the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (520 mg) and 1-oxoisoindolin-4-carbothioamide, the title compound (51 mg) was obtained as colorless powder crystals.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:15]2[CH:16]=[C:17]([NH2:18])[CH:19]=[CH:20][CH:21]=2)[CH:2]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: Nc1cccc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2cnc3ccccc3c2)c1
Temperature: 25 °C
Yield: 53 %

Procedure:
Quinoline-3-boronic acid (0.120 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in dimethoxyethane (DME, 2 mL) in a flame-dried, round-bottom flask. Sodium carbonate (Na2CO3, 2M, 0.485 mL, 0.970 mmol) and tetrakis[triphenylphosphine]palladium(0) (Pd(PPh3)4, 0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum, and the residue was resuspended in H20 and extracted with methylene chloride (CH2Cl2). The organic phase was dried over magnesium sulfate (MgSO4) and concentrated under vacuum. The crude product was purified by silica column chromatography (0-5% methanol (MeOH)/CH2Cl2). The purification was monitored by thin layer chromatography (TLC). The solvent was removed under vacuum from fractions containing product, resulting in 0.054 g in 53% yield.
Reaction SMILES: O1C=NC=N1.N1C(=O)CC=N1.[OH-].[K+].[CH3:14][C:15]1[O:19][N:18]=[C:17]([CH2:20][C:21]([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:25]=2[Cl:32])=[O:22])[N:16]=1>C(O)C>[C:15]([NH:16][C:17]1[CH2:20][C:21](=[O:22])[N:23]([C:24]2[C:29]([Cl:30])=[CH:28][C:27]([Cl:31])=[CH:26][C:25]=2[Cl:32])[N:18]=1)(=[O:19])[CH3:14]
Reactant: Cc1nc(CC(=O)Nc2c(Cl)cc(Cl)cc2Cl)no1
Agent: O=C1CC=NN1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Temperature: 80 °C

Procedure:
The method of the invention is then used to convert the 1,2,4-oxadiazole to the 2-pyrazolin-5-one. As previously described, the method comprises forming a liquid reaction system of a base catalyst and the 1,2,4-oxadiazole in an organic liquid reaction medium and heating the reaction system to a temperature sufficient to cause the 1,2,4-oxadiazole to be rearranged to the 2-pyrazolin-5-one, e.g., heating a solution of potassium hydroxide and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-2',4',6'-trichloroacetanilide in anhydrous ethanol under reflux at a temperature of 80° C. for 8 to 14 hours to yield 3-acetamido-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one, i.e., ##STR7##
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.[Cl:16][C:17]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][N:20]=[C:19]2[N:29]([CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[N:30]=[C:31](I)[C:18]=12>>[Cl:16][C:17]1[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:21][N:20]=[C:19]2[N:29]([CH2:33][CH2:34][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[N:30]=[C:31]([C:4]3[CH2:3][CH2:2][O:1][CH2:6][CH:5]=3)[C:18]=12
Reactant: Clc1c(-c2ccccc2)nnc2c1c(I)nn2CCN1CCCC1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: Clc1c(-c2ccccc2)nnc2c1c(C1=CCOCC1)nn2CCN1CCCC1

Procedure:
Compound Is was synthesized according to Example 1, using 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-chloro-3-iodo-5-phenyl-1-(2-pyrrolidin-1-ylethyl)pyrazolo[3,4-c]pyridazine instead of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine in Step 8.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].CS(Cl)(=O)=O.CS(C)=O.[BH4-].[Na+].[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:1]([N:3]1[CH2:6][CH2:7][CH:4]1[CH2:5][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: CCN(CC)CC
Reactant: c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(CC2CCN2C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6.0 g of threo-1-benzhydryl-2-(α-hydroxybenzyl)-azetidine and 1.84 g of triethylamine in 100 ml of dry benzene, maintained below 10° C., add 2.08 g of methanesulfonyl chloride. Allow the stirred solution to stand at 6°-10° C. for 2 hours. Add to the mixture, 150 ml of dry dimethyl sulfoxide and 1.40 g of sodium borohydride. Stir at room temperature for 85 hours. Add ether and water, separate the resultant layers, and re-extract the aqueous layer with additional ether. Wash the combined organic phases successively with water and brine, dry over anhydrous sodium sulfate, and remove solvent in vacuo. Chromatograph the resultant oil on 275 g of silica gel, eluting with 1/20 (v/v) ethyl acetate-hexane, to obtain the analytically pure product of this example, m.p. 87.5°-89.5° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH3:10][C:11]1([CH3:19])[CH2:16][CH2:15][CH2:14][C:13]([CH3:18])([CH3:17])[NH:12]1>CCCCCC>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:12]2[C:13]([CH3:18])([CH3:17])[CH2:14][CH2:15][CH2:16][C:11]2([CH3:19])[CH3:10])[N:3]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCCCCC
Product: CC1(C)CCCC(C)(C)N1c1nc(Cl)cc(Cl)n1

Procedure:
A mixture containing 25 g (136.3 mmoles) of 2,4,6-trichloropyrimidine and 46.3 ml (272.6 mmoles) of 2,2,6,6,-tetramethylpiperidine is boiled under reflux for 50 hours, then the reaction mixture is cooled down and suspended in 250 ml of hexane. The insoluble part is filtered off, the filtrate (mother liquor) is evaporated and the residue is distributed between 300 ml of chloroform and 50 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 100 ml of water each, dried and evaporated. The residue is purified by chromatography on a silica gel column by using hexane as eluent. After recrystallization from hexane the title compound is obtained in a yield of 8.04 g (20.47%), m.p.:89°-900° C.
Reaction SMILES: ClCl.[C:3]([CH2:5][CH2:6][SH:7])#[N:4].[C:8]1(=[O:18])[NH:12][C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl.CN(C=O)C>[C:3]([CH2:5][CH2:6][S:7][N:12]1[C:11](=[O:13])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]2[C:8]1=[O:18])#[N:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#CCCS
Agent: ClCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCCSN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A Solution of chlorine in dichloromethane (1.4 mol dm-3, 10.0 cm3, 14.0 mmol) was added dropwise to a stirred solution of 2-cyanoethyl mercaptan, (see, for example, Bauer and Welsh, loc cit), (1.22 g, 14.0 mmol) in dichloromethane (21 cm3) at 0° C. (ice-water bath). After the products had been allowed to warm to room temperature, they were added dropwise to a stirred slurry of phthalimide (1.47 g, 10.0 mmol) and triethylamine (1.94 cm3, 14.0 mmol) in dry DMF (12 cm3) at 0° C. (ice-water bath). The stirred reactants were allowed to warm to room temperature. After 2 h, the products were poured into saturated aqueous sodium hydrogen carbonate (25 cm3) and the resulting mixture was extracted with dichloromethane (2×50 cm3). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized from ethanol to give N-(2-cyanoethylmercapto)phthalimide 21 as colourless needles (1.345 g, 58%) (Found: C, 57.0; H, 3.4; N, 11.8. C11H8 N2O2S requires: C, 56.9; H, 3.5; N, 12.1%), m.p. 162°-164° C.; δH [CDCl3 ] 2.79 (2 H, t, J7.2), 3.12 (2 H, t, J7.2), 7.83 (2 H, m), 7.95 (2 H, m); δC [CDCl3 ] 18.7, 34.5, 117.5, 124.1, 131.7, 134.9, 168.1.