Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[Cl-].[C]=O.[CH3:5][CH2:6][O-:7].[Na+].[CH2:9]([O:11][C:12](=[O:15])[CH2:13][Cl:14])[CH3:10].[CH2:16]([OH:18])C>C1(C)C=CC=CC=1>[CH2:6]([O:7][C:16](=[O:18])[CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:15])[CH3:5].[CH2:9]([O:11][C:12](=[O:15])[CH2:13][Cl:14])[CH3:10].[CH2:9]([O:11][C:12](=[O:15])[CH3:13])[CH3:10]
Reactant: CCO
Reactant: CC[O-]
Agent: [C]=O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(=O)CCl
Product: CCOC(=O)CC(=O)OCC
Product: CCOC(C)=O
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 1 %

Procedure:
In a pressure vessel of a capacity of 7.5 liters, equipped with a pH measuring system, 20 g of Co2 (CO)8, 10 g of NaCl as conducting salt, and 2.5 liters of ethanol denatured with toluene are combined. The apparatus is scavenged three times with carbon monoxide, and then a CO pressure of 7.5 atmospheres gauge is established. While the vessel is heated at 55° C., a solution of 20.5% sodium ethylate in ethanol is pumped in from a reservoir by means of a proportioning pump such that a pH of 7 to 8 is reached, the liquid and gas phases being thoroughly mixed by means of a circulating pump. After the reaction temperature is reached, 490 g (4 moles) Of chloroacetic acid ethyl ester is proportioned into the vessel at a constant CO pressure of 8.0 at. gauge over a period of 15 minutes, and a 20.6% solution of sodium ethylate is added through a second inlet so as to maintain a pH of approximately 7.0. Over a period of 6 hours, 1.12 kg (3.4 moles) of 20.6% sodium ethylate is pumped in. Then the vessel is cooled, the pressure is relieved, and the vessel is purged with nitrogen. The reaction solution is separated from the sodium chloride on a suction filter and distilled. 517 g of malonic acid diethyl ester is obtained (95% yield), plus 2.5 g of acetic acid ethyl ester (approx. 1% yield) and 5 g of high-boiling compounds plus 73 g of chloroacetic acid ethyl ester.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[C:8]2[CH:9]=[C:10]([O:14][CH3:15])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[NH:3]1.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1.[I-].[Cs+].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[O:30]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH3:15])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[N:3]1[CH2:37][C:36]1[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OC)cc2S(=O)(=O)N1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OC)cc2S(=O)(=O)N1Cc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (prepared according to WO 98/38182; 0.200 g, 0.404 mmol) in MeCN (5 ml) where added p-methoxybenzyl chloride (0.066 ml, 0.486 mmol), CsI (0.010 g, 0.038 mmol) and Cs2CO3 (0.263 g, 0.807 mmol) and the mixture was stirred at 60° C. for 4 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and 0.5M HCl (aq). The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was filtered through silica gel (DCM:EtOAc-9:1) to give the title compound in 0.257 g (˜quant) as an off-white solid. NMR (400 MHz, CDCl3): 0.60–0.75 (m, 6H), 0.75–1.20 (m, 8H), 1.25–1.45 (m, 2H), 1.80–2.00 (m, 2H), 3.80 (s, 3H), 3.90 (s, 3H), 4.05–4.30 (m, 2H), 4.45–4.65 (m, 2H), 6.70–7.45 (m, 11H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.[F:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1>>[F:23][C:10]1[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]4)[C:14]=2[CH:13]=[C:12]([C:39]2[CH:38]=[CH:37][N:36]=[C:35]([F:34])[CH:40]=2)[N:11]=1)=[CH:3][C:2]([C:30]1[C:25]([F:24])=[N:26][CH:27]=[CH:28][CH:29]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1ccnc(F)c1
Reactant: NC1=N[C@@]2(CCO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1cccnc1F
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1c2cc(-c2ccnc(F)c2)nc1F

Procedure:
The title compound was synthesized by steps analogous to those described in method A1 above, but using intermediate 15B, 2-fluoropyridin-3-ylboronic acid and 2-fluoropyridin-4-ylboronic acid. MS m/z=476.0 [M+H]+. Calculated for C25H16F3N5O3: 475.13
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:28])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[N:11]2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])=[CH:6][C:5]=1[N+:29]([O-])=O)=[N+]=[N-].O1CCCC1.O.C([O-])=O.[NH4+]>C(OCC)(=O)C.[Fe]>[Cl:26][C:22]1[C:21]([F:27])=[C:20]([N:11]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([NH2:29])[CH:6]=3)([OH:28])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:19])[CH:25]=[CH:24][CH:23]=1
Reactant: [N-]=[N+]=Nc1ccc(C2(O)c3ccccc3C(=O)N2c2cccc(Cl)c2F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(C2(O)c3ccccc3C(=O)N2c2cccc(Cl)c2F)cc1N
Temperature: 25 °C
Reaction time: 5.33 h
Yield: 55.7 %

Procedure:
To a solution of 3-(4-azido-3-nitrophenyl)-2-(3-chloro-2-fluorophenyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (7.0 g, 16.00 mmol) in a mixture tetrahydrofurane-water (1:1, 15.0 ml) ammonium formate (5.0 g, 79.30 mmol), was added followed by the addition of iron (4.0 g, 71.60 mmol). The reaction mixture was heated to reflux and stirred for 320 minutes. It was cooled to room temperature and diluted with ethyl acetate (70 mL). The resulting slurry was filtered through a pad of Celite and washed with ethyl acetate (3×30 mL). It was partitioned with water and the organic layer was washed with water (30 mL), brine (30 mL) and dried over anhydrous sodium sulfate. Filtration and concentration resulted in a yellow oily product. It was crystallized from diethyl ether by the addition of hexane. The product was collected by filtration, dried in vacuo, to provide 2-(3-chloro-2-fluorophenyl)-3-(3,4-diaminophenyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (3.42 g, 56% yield). 1H NMR (400 MHz, CD3OD): 7.85 (d, J=7.6 Hz, 1H), 7.65-7.58 (m, 2H), 7.41-7.34 (m, 2H), 7.17 (t, J=6.4 Hz. 1H), 7.05 (t, J=8 Hz, 1H), 6.69 (s, 1H), 6.57 (s, 2H); MS (EI) for C20H15CFN3O2: 382 (M−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](=O)[CH2:30][C:31](OCC)=[O:32])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:38][NH2:39]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:11](=[O:26])[C@:10]([CH2:28][C:29]3[NH:39][N:38]=[C:31]([OH:32])[CH:30]=3)([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Solvent: CCO
Solvent: O
Product: CCC(CC)N1C(=O)[C@@](C)(Cc2cc(O)n[nH]2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 65 °C

Procedure:
To a solution of 42 mg (0.08 mmol) of ethyl 4-43R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-3-oxobutanoate (Example 79, Step B) in ethanol (4 mL) was added 36 μL (0.48 mmol) hydrazine monohydrate (64-65% weight percent hydrazine). The resulting colorless solution was heated at 65° C. for 3.5 h, and then was concentrated under reduced pressure. Purification of the residue by reversed phase prep. HPLC (Sunfire Prep C18 OBD 10 μm column, gradient elution of 45% MeCN in water to 80% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10](C(F)(F)F)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[C:22]([Cl:25])(Cl)=[O:23].[CH3:26][O:27]CCOC>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:22]([Cl:25])=[O:23])=[CH:11][C:10]([O:27][CH3:26])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccn(-c2ncccc2Cl)n1
Reactant: COCCOC
Reactant: O=C(Cl)Cl
Agent: CC(C)[Mg]Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)Cl)n(-c2ncccc2Cl)n1
Temperature: 0 °C

Procedure:
In a reaction vessel equipped with a thermometer, septum, nitrogen inlet and stirring bar 1-(3-chloro-2-pyridyl)-3-trifloromethyl-1H-pyrazole (2.0 g, 0.01 mol) were dissolved in dry 1,2-dimethoxyethane (15 mL) and cooled to 0° C. By means of a syringe isopropyl magnesium chloride (11.4 mL of a 2 M solution in tetrahydrofuran) was added dropwise with stirring, while cooling the vessel with an ice bath and keeping the internal temperature below 5° C. After 3 h at this temperature a 20% (w/w) solution of phosgene in toluene (17 mL) were added dropwise with stirring. The mixture was allowed to warm to 23° C. and stirred for further 1 h at room temperature. The thus obtained reaction mixture was evaporated to dryness, redissolved in toluene and stirred for further 30 min. at 50° C. Solids were removed by filtration and washed with toluene. The combined filtrates were evaporated to dryness to yield 0.63 g of the title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.N1C=CC=CC=1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH2:34][NH2:35])=[CH:28][CH:27]=1)([O-:25])=[O:24]>COCCOCCOC>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:35][CH2:34][CH2:33][NH:32][C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:31][CH:30]=2)[CH:3]=1
Reactant: NCCNc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C)nc(OS(=O)(=O)C(F)(F)F)c1
Solvent: COCCOCCOC
Solvent: c1ccncc1
Product: Cc1cc(C)nc(NCCNc2ccc([N+](=O)[O-])cc2)c1
Temperature: 165 °C
Yield: 55 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 4,6-dimethyl-pyridin-2-yl ester (prepared according to J. Org. Chem., 63, 10048-51, 1998), using pyridine as base. 0.6 g, 2.35 mmol) in diglyme (2 mL) was added N*1*-(4-nitro-phenyl)-ethane-1,2-diamine (0.51 g, 2.82 mmol). The reaction mixture was heated to 165° C. for 24 h. The resulting reaction mixture was concentrated under reduced pressure and the residue diluted with chloroform. The organic layer was washed with brine and water and dried over sodium sulfate. The solvent was evaporated and the crude residue was purified by column chromatography (60-120 mesh) using 20% ethyl acetate/petroleum ether as eluent to afford N-(4,6-dimethyl-pyridin-2-yl)-N′-(4-nitro-phenyl)-ethane-1,2-diamine (0.38 g, 55%) as a cream solid.
Reaction SMILES: C[C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.C(O)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:19]1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][CH:13]([CH3:12])[CH2:14][CH2:15][CH2:16][C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:2][CH3:10])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCCC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a stirred solution of Meldrum's Acid (2.0 g, 13.9 mmol) in 100 mL of CH2Cl2, hexanoic acid (1.61 g, 13.9 mmol) was added followed by DMAP (3.39 g, 27.8 mmol) and finally DCC (2.86 g, 13.9 mmol). The reaction stirred overnight at room temperature. The mixture was then filtered and the filtrate washed with 1M HCl, H2O and Brine. The organics were then dried over sodium sulfate, filtered and concentrated to a yellow oil. The material was then dissolved in 100 mL of EtOH and refluxed overnight. The reaction mixture was concentrated to yield 2.58 g (99%) of a clear oil. No purification performed: 1H NMR (CDCl3, 400 MHz) δ 4.22–4.12 (q, 2H, J=7.07), 3.40 (s, 2H), 2.56–2.44 (t, 2H, J=7.42), 1.69–1.43 (m, 3H), 1.30–1.21 (t, 3H, J=7.07), 1.19–1.09 (m, 2H), 0.89–0.81 (d, 6H, J=6.55).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(O)C>[C:1]1([C:7]2[C:8]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27][C:35](=[O:37])[CH3:36])=[CH:22][CH:21]=3)=[N:9][C:10]3[CH:11]=[CH:12][N:13]4[CH:19]=[N:18][N:17]=[C:14]4[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)NCc1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 4-3 (0.02 g, 0.06 mMol) and triethylamine (0.02 mL, 0.2 mMol) in absolute ethanol (0.5 mL) was added acetic anhydride (0.02 mL, 0.2 mMol). The reaction was complete after 10 minutes and was purified directly on a C18 reverse phase HPLC to give 18-1 as a solid. LC/MS (M+1) calculated: 394.5; observed: 394.2
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].[CH:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:25]=[CH:24][N:23]=[C:22]3[C:13]=2[CH:14]=[CH:15][C:16]2[C:21]3=[N:20][CH:19]=[CH:18][C:17]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.O>C1COCC1.C1(C)C=CC=CC=1>[C:26]1([C:17]2[C:16]3[C:21](=[C:22]4[C:13](=[CH:14][CH:15]=3)[C:12]([C:9]3[CH:8]=[CH:7][CH:6]=[CH:11][CH:10]=3)=[CH:25][C:24]([C:14]3[CH:2]=[C:1]([CH3:4])[CH:3]=[CH:22][CH:13]=3)=[N:23]4)[N:20]=[C:19]([C:7]3[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][CH:6]=3)[CH:18]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Reactant: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2cc(-c3ccccc3)c3ccc4c(-c5ccccc5)cc(-c5cccc(C)c5)nc4c3n2)c1
Reaction time: 2 h
Yield: 75 %

Procedure:
Under a nitrogen atmosphere, 8.8 ml of a 1.7 mol/l t-butyllithium solution (15 mmole) was added dropwise to a solution of 2.55 g of 2-bromo-toluence in 20 ml of THF at 0° C. The resulting mixture was stirred for another 2 hours, and then transferred to a stirred suspension of 1.0 g of bathophenanthroline (3 mmole) in 40 ml of toluene in an ice bath. The resulting deep-red solution was stirred overnight at room temperature, and 10 ml of water was then added. The organic layer was separated, and the aqueous layer was extracted with 30 ml of dicholormethane three times. The combined extracts were stirred with 15 g MnO2 for 2 hours. The mixture then was dried over 15 g of anhydrous MgSO4, filtered, and evaporated to dryness. The clean product was obtained after running chromatography in a silica/CH2Cl2 column with a yield of 75 percent. 1H NMR (500 MHz, CDCl3), ppm: 8.50 (s, 2H), 8.22 (d, J=7.5 Hz, 2H), 8.09 (s, 2H), 7.80 (s, 2H), 7.63-7.48 (m, 10H), 7.45 (dd, J=7.0, 7.0 Hz, 2H), 7.31 (d, J=7.0 Hz, 2H), 2.54 (s, 6H). Analysis for m-TBP. Found: C, 88.29, H, 5.40, N, 5.57. Calculated: C, 89.03, H, 5.51, N, 5.46.
Reaction SMILES: C([O:5][P:6]([CH2:18][CH:19]([CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:20]([O:22]C(C)(C)C)=[O:21])([CH2:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:12]1([C:10]([NH:9][CH2:8][P:6]([CH2:18][CH:19]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:20]([OH:22])=[O:21])([OH:7])=[O:5])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)CCC(CP(=O)(CNC(=O)c1ccccc1)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(CP(=O)(O)CNC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.3 %

Procedure:
To a solution of di-tert-butyl 2-({(tert-butoxy)-[(phenylcarbonylamino)methyl]phosphoryl}methyl)pentane-1,5-dioate (1.230 g, 2.4 mmol) in dichloromethane (10 ML) was added trifluoroacetic acid (5 mL) at room temperature, and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure. The residual oil was taken up with dichloromethane (10 mL) and concentrated. This process was repeated three times to remove trifluoroacetic acid completely. The resulting oil was crystallized from acetonitrile-water to give 0.620 g of white solid (75% yield).
Reaction SMILES: [NH2:1]N.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.O.NN>C(=O)([O-])[O-].[K+].[K+]>[NH2:1][C:11]1[C:12](=[O:15])[NH:13][N:14]=[C:9]([C:6]2[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=2)[CH:10]=1
Reactant: NN
Reactant: O=c1ccc(-c2ccncc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: Oc1ccc(-c2ccncc2)nn1
Agent: [K+]
Solvent: O
Product: Nc1cc(-c2ccncc2)n[nH]c1=O
Yield: 69 %

Procedure:
The following procedure describes the preparation of the entitled compound by reacting hydrazine with 6-(4-pyridinyl)-3(2H)-pyridazinone, the tautomeric form of 6-(4-pyridinyl)-3-pyridazinol. A mixture containing 10 g. of 6-(4-pyridinyl)-3(2H)-pyridazinone and 70 ml. of hydrazine hydrate was heated on a steam bath for 3 days and the excess hydrazine distilled off in vacuo. The remaining residue was heated with about 300 ml. of methanol and the solid was collected by filtration. The solid was combined with the corresponding solid obtained from another run starting with 15.7 g. of 6-(4-pyridinyl)-3(2H)-pyridazinone and 21 ml. of hydrazine hydrate and the combined solids were dissolved in aqueous potassium carbonate solution and reprecipitated by addition of acetic acid. The precipitate was dried for 9 hours at 40° C. over P2O5 and then overnight at 80° C. After its NMR spectrum had shown the solid still to contain acetic acid, it was next dried in a vacuum oven at 80° C. for 2 days to yield 18.2 g. (69% yield) of 4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone, m.p. >300° C.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7](C)[CH:6](NC=O)[N:5]=2)[CH2:3][CH2:2]1.[CH2:13]([N:15](CC)[CH2:16]C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH2:16][N+:15]#[C-:13])[N:5]=2)[CH2:2][CH2:3]1
Reactant: CCN(CC)CC
Reactant: CN1OC(C2CC2)=NC1NC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: [C-]#[N+]Cc1noc(C2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 5-cyclopropyl-3-formylamino-methyl-1,2,4-oxadiazole (60 mmol) and triethylamine (176 mmol) in CH2Cl2 (100 ml) was charged dropwise with POCL3 (60 mmol) at 0° C. The mixture was then left for 30 minutes with stirring at 0° C., whereafter a solution of Na2CO3 (60 mmol) in H2O (50 ml) was added. The mixture was heated to room temperature, whereafter the organic phase was separated, dried and evaporated in vacuo. The residue was treated with ether, decanted and the solution was evaporated to give the title compound as an oil. The oil was processed without any further purification. The compound was characterized by its IR absorbtion band at 2160 cm-1.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[N+:36]([O-:38])=[O:37])[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][C:32]=5[N+:36]([O-:38])=[O:37])[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5c([N+](=O)[O-])cccc5n4)cc3CC[C@@H]12
Yield: 55.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (31 mg, 0.12 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-5-nitroquinoline (30 mg, 0.14 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 29 mg (56%) of the title compound as an amorphous foam. mp 149°-154°. FDMS: m/e=433. α[D]589 =+60.00 (c=0.10, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:5]2[O:10][CH:9]([C:11]([F:12])([F:14])[F:13])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(-c3ccc(Cl)cc3)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1=Cc2cc(Cl)cc(-c3ccc(Cl)cc3)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
The ester from Step 1 (0.500 g, 1.20 mmol) was dissolved in a solution of THF:ethanol:water (7:2:1; 10 mL), treated with sodium hydroxide (0.48 mL, 1.20 mmol of a 2.5 N solution), and stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in water (10 mL). Diethyl ether (10 mL) was added and the mixture acidified with concentrated HCl. The organic layer was separated, and the aqueous phase was extracted with diethyl ether (2×10 mL). The combined extracts were dried over MgSO4, filtered, and evaporated to yield a white solid, which was recrystallized in diethyl ether-hexane to afford the title compound as a white solid (0.40 g, 86%): mp 205.5–207.3° C. 1H NMR (CDCl3/300 MHz) 7.81 (s, 1H), 7.42(s, 4H), 7.34 (d, 1H, J=2.4 Hz), 7.25 (s, 1H), 5.69 (q, 1H, J=6.8 Hz). FABLRMS m/z 387 (M−H). ESHRMS m/z 386.9788 (M−H, Calc'd. 386.980259). Anal. Calc'd. for C17H9Cl2F3O3: C, 52.47; H, 2.33; Cl, 18.22. Found: C, 52.38; H, 2.47; Cl, 18.20.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[C:14]=1[O:26][C:27]1[CH:31]=[C:30]([CH3:32])[NH:29][N:28]=1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:29]1[C:30]([CH3:32])=[CH:31][C:27]([O:26][C:14]2[C:15]([N+:23]([O-:25])=[O:24])=[CH:16][C:17]([C:19]([F:20])([F:21])[F:22])=[CH:18][C:13]=2[Cl:12])=[N:28]1)=[O:11])[CH3:8]
Reactant: CCN=C=O
Reactant: Cc1cc(Oc2c(Cl)cc(C(F)(F)F)cc2[N+](=O)[O-])n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2[N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
Potassium carbonate (0.30 g, 2.2 mmol) and ethyl isocyanate (0.14 g, 2.0 mmol) were added to a solution of 3-(2-chloro-6-nitro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.64 g, 2.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a yellowish solid of N-ethyl-3-(2-chloro-6-nitro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.13 g, yield: 16.6%). mp: 98-99° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.18 (t, J=7.2 Hz, 3H), 2.60 (d, J=0.5 Hz, 3H), 3.32 (dq, J=6.0 and 7.2 Hz, 2H), 5.87 (q, J=0.5 Hz, 1H), 6.40-6.65 (m, 1H), 8.01 (d, J=2.0 Hz, 1H), 8.17 (m, 1H).