Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: c1cncc(CC2CCCN2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ncoc1-c1ccccc1)N1CCCC1Cc1cccnc1
Temperature: 25 °C

Procedure:
5-Phenyl-1,3-oxazole-4-carboxylic acid (40 mg, 0.211 mmol), 3-(pyrrolidin-2-ylmethyl)pyridine (50.5 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C20H19N3O2: 333.1477, found 333.1484.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11](=[O:12])[C:10]([O:13][CH3:14])=[CH:9][N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:7]=1)=[O:5].[CH3:22][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[C:4]([C:6]1[C:11](=[O:12])[C:10]([O:13][CH3:14])=[CH:9][N:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:7]=1)(=[O:5])[CH3:22]
Reactant: C[Mg]Br
Reactant: COc1cn(-c2ccccc2)nc(C(=O)N(C)OC)c1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cn(-c2ccccc2)nc(C(C)=O)c1=O
Temperature: -69 °C
Reaction time: 1.5 h

Procedure:
Under an argon atmosphere, to a stirring solution of N,5-dimethoxy-N-methyl-4-oxo-1-phenyl-1,4-dihydropyridazine-3-carboxamide (20 g) in tetrahydrofuran (1 L) was added dropwise, under cooling at −69° C., methyl magnesium bromide solution (1 M in THF, 138 mL). After stirring at −69° C. for 1.5 hr, a saturated aqueous ammonium chloride solution was added. Thereafter, the mixture was warmed to room temperature in 1.5 hr, and the reaction mixture was partitioned. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The aqueous layer was extracted with ethyl acetate, and the obtained extract was dried over anhydrous magnesium sulfate. The organic layer and the extract were combined, and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (13.22 g) as a pale-yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][CH2:9][C:10]1[N:11]([CH2:23][C:24]2([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH3:7].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:6]([O:8][CH2:9][C:10]1[N:11]([CH2:23][C:24]2([NH:30][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=1)[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(N)CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(NS(C)(=O)=O)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Methanesulfonyl chloride (0.75 mL, 9.75 mmol) was added to a 0° C. solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanamine (2.75 g, 8.13 mmol), 4-dimethylaminopyridine (DMAP, 2.75 g) and pyridine (11 mL) in dichloromethane (28 mL). The solution was stirred at 0° C. for 2 h, then at rt for 1 h. The reaction was washed with water (100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a light yellow oil. Purification by flash chromatography (silica gel, 20% methanol/ethyl acetate) afforded N-(1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexyl)methanesulfonamide as a white solid (2.72 g, 80%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].Cl.[CH2:14](N)[CH2:15][NH2:16].[OH-].[Na+]>CCO>[NH:2]1[CH2:14][CH2:15][N:16]=[C:1]1[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: NCCN
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(C2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-cyanophenyl)acetic acid (131 mg, 0.816 mmol) in EtOH (0.5 mL) at 0° C. was bubbled HCl(g) until saturation. Reaction mixture was allowed to warm to room temperature slowly. After overnight stirring, the crude reaction mixture was concentrated in vacuo. This residue was taken up in EtOH (4 mL) and ethylene diamine (0.1 mL, 1.49 mmol) was added. After stirring at room temperature for two hours, the crude reaction mixture was concentrated under reduced pressure and then re-dissolved in DMF (2 mL). To this solution was added 1M NaOH (2 mL, 2 mmol) and the reaction stirred at room temperature for three hours. Crude reaction mixture was neutralized with 1M HCl to a pH 6 and extracted with CHCl3 (4×15 mL). Product was found in the water layer, so combined all layers and concentrated in vacuo, re-dissolved in CHCl3/MeOH, and filtered to remove precipitate. Concentration of the filtrate gives [4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]acetic acid, which was used without further purification. LCMS (ES) 205.1 m/z (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].C1(C2[O:40][CH2:39][CH:38]([O:41][NH2:42])[CH2:37][O:36]2)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[OH:36][CH2:37][CH:38]([O:41][NH:42][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21])[CH2:39][OH:40]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: NOC1COC(c2ccccc2)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NOC(CO)CO)c(=O)n(C)c1=O
Temperature: 50 °C

Procedure:
Phenyl 6-(2-fluoro-4-iodophenylamino)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (compound 2A, 100 mg, 0.2 mmol, 1 eq) and O-(2-phenyl-1,3-dioxan-5-yl)hydroxylamine (79 mg, 0.404 mmol, 2 eq) (see, Vonhoff et al., Helv. Chim. Acta, 81(9), 1998; 1710-1725; European Patent Application No. EP1666485) were mixed in THF and subjected to microwave irradiation at 100° C. for 45 minutes. The reaction was complete by LCMS. Upon cooling, the intended product precipitated as a tan solid. 62 mg (51%). This solid was then dissolved in methanol (2 ml) and THF (2 ml) with ethylene glycol (100 μl). p-Toluenesulfonic acid (18 mg, 1 eq) was added and the mixture heated at 50° C. for 30 minutes. Purification by HPLC chromatography afforded the title compound as a white solid. 28 mg (53%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.96 (s, 3H) 3.22 (s, 3H) 3.42-3.58 (m, 4H) 4.00-4.08 (m, J=1.67, 0.78, 0.78, 0.78, 0.78 Hz, 2H) 4.75 (t, J=5.94 Hz, 2H) 5.76 (s, 1H) 7.53-7.62 (m, 1H) 7.80 (dd, J=9.73, 1.39 Hz, 1H) 11.99 (s, 1H) 12.23 (s, 1H) [M+H] calc'd for C16H18FIN4O6, 509. found, 509.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][N:14]=[C:15]([C:22]#[N:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(O)=[O:2].CN(C)C=O.S(Cl)([Cl:31])=O>>[Cl:31][C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][N:14]=[C:15]([C:22]#[N:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: N#CC(=NOS(=O)(=O)c1ccc(C(=O)O)cc1)c1ccccc1
Solvent: CN(C)C=O
Product: N#CC(=NOS(=O)(=O)c1ccc(C(=O)Cl)cc1)c1ccccc1
Temperature: 50 °C

Procedure:
4 g of the product of Example 14 are suspended in 20 g of thionyl chloride, and 0.5 ml of dimethylformamide are added. The reaction mixture is then heated to 50° C. until the evolution of gas ceases (2 hours) and a clear solution has formed. Part of the excess thionyl chloride is evaporated off, affording a crystaline product which is isolated by filtration and recrystallised from dichloromethane. Melting point: 193°-195° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:10]=3[C:9]=2[C:19]([O:21]C)=[O:20])=[CH:4][CH:3]=1.C1COCC1.[OH-].[Li+].Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:10]=3[C:9]=2[C:19]([OH:21])=[O:20])=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)sc2ccc(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2sc(-c3ccc(F)cc3)c(C(=O)O)c2c1
Temperature: 50 °C

Procedure:
To a solution containing methyl 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylate (0.59 g, 1.9 mmol), THF (13.5 mL) and methanol (8.5 mL) was added aqueous lithium hydroxide (9.3 mL, 2.0 M). The solution was maintained at 50° C. for 15 h. The solution was cooled to room temperature, adjusted to below pH 4 with aqueous HCl (22 mL, 1.0 N) and extracted with ethyl acetate (3×15 mL). The combined organic portions were washed with brine (15 mL), dried over MgSO4, filtered and concentrated to afford 2-(4-fluorophenyl)-5-methoxybenzo[b]thiophene-3-carboxylic acid as white solid which was used without further purification. 1H NMR (500 MHz, DMSO-D6) δ ppm 12.99 (s, 1H), 7.93 (d, J=8.55 Hz, 1H), 7.80 (d, J=2.44 Hz, 1H), 7.59 (dd, J=8.55, 5.49 Hz, 2H), 7.32 (t, J=8.70 Hz, 2H), 7.11 (dd, J=8.85, 2.44 Hz, 1H), 3.82-3.87 (m, 3H). LCMS: retention time: 1.532 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 303 (MH−).
Reaction SMILES: Cl.C[C:3]1[S:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8](O)=[O:9].[NH2:12][C:13](N)=[O:14].[OH-].[Na+].Cl>>[N:11]1[C:6]2=[CH:5][S:4][CH:3]=[C:7]2[C:8]([OH:9])=[N:12][C:13]=1[OH:14]
Reactant: NC(N)=O
Reactant: Cc1scc(N)c1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1nc(O)c2cscc2n1
Temperature: 180 °C
Reaction time: 1.5 h
Yield: 115.1 %

Procedure:
A mixture of methyl 4-aminothiophene-3-carboxylic acid mono hydrochloride (1.00 g) and urea (1.8 g) was stirred at 180° C. for 1.5 h. The mixture was left stand for cooling to room temperature, followed by addition of 1 M aqueous sodium hydroxide to dissolve the solids, and the mixture was neutralized with 1 M hydrochloric acid. The precipitated crystals were collected by filtration to obtain thieno[3,4-d]pyrimidine-2,4-diol (1.0 g). (2) To a mixture of thieno[3,4-d]pyrimidine-2,4-diol (1.00 g) and phosphorus oxychloride (10 mL) was added N,N-dimethylaniline (2.0 mL) at room temperature, and the mixture was stirred at 100° C. for 2.5 h. The reaction solution was added dropwise to water (30 g) with ice cooling, and the aqueous layer was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel, chloroform) to obtain 2,4-dichlorothieno[3,4-d]pyrimidine (0.52 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][CH:17]([CH2:19][N:20]=[N+]=[N-])[O:16][C:15]2=[O:23])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1>CO.C(OCC)(=O)C.[Pd]>[NH2:20][CH2:19][C@@H:17]1[O:16][C:15](=[O:23])[N:14]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]3)=[C:2]([F:1])[CH:3]=2)[CH2:18]1
Reactant: Cc1cn(-c2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)nn1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cn(-c2ccc(N3C[C@H](CN)OC3=O)cc2F)nn1
Reaction time: 4 h
Yield: 55.6 %

Procedure:
3-[3-Fluoro-4-(4-methyl-1,2,3-triazol-1-yl)phenyl]-5-(azidomethyl)-oxazolidin-2-one (Intermediate 17) (2.0 g, 6.30 mmol) was dissolved in methanol/ethyl acetate (50 ml, 1:1) and hydrogenated over palladium on carbon (10%, 0.2 g) at room temperature and normal pressure for 4 hours. The resulting mixture was filtered through the celite and concentrated under reduced pressure to give 1.02 g of the title compound as a solid, which was used without further purification in the next step.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:23]=[C:22]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=2)[N:21]=[C:20]([N:18]2[CH:19]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[N:16]=[CH:17]2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.5 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.128 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH/hexane) to yield the title compound as a white solid (0.079 g, 10%). MS (ISP) 514.3 [(M+H)+]; mp 198° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O)[O:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].C(O)C>[Fe].O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:12][C:13]2[CH:18]=[N:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:23]=[CH:24][C:25]=1[NH2:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cn1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OCc3ccccc3)c2)cn1
Temperature: 40 °C
Yield: 100.4 %

Procedure:
A mixture of 5-[3-(benzyloxy)-4-nitrophenoxy]-2-(methylsulfonyl)pyridine (28.0 g), calcium chloride (0.78 g), iron (powder, 19.0 g), ethanol (500 mL) and water (110 mL) was refluxed for 5 h. The mixture was cooled to 40° C. and filtered through a celite pad. The filtrate was concentrated in vacuo to remove ethanol. The residue was partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexane=2:1, volume ratio) to give the title compound (26.0 g, 100%) as light brown crystals. MS 371 (MH+).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:3]1=[O:15].[I-:16].[Na+]>CC(C)=O>[I:16][CH:2]1[CH2:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:3]1=[O:15]
Reactant: O=C1CC(Br)C(=O)N1c1ccc(F)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CC(I)C(=O)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.2 g. (0.1 mole) of the 3-bromo-1-(4-fluorophenyl)-2,5-pyrrolidinedione prepared according to Example 1 were dissolved in 140 ml. acetone and a solution of 15.75 g. (0.105 mole) sodium iodide in acetone added thereto. The mixture was stirred for 2 hours at room temperature and then heated to reflux for 1 hour. Subsequently, it was cooled, filtered off from resultant sodium bromide and the filtrate evaporated. The residue was recrystallised from methanol/water (3:1) and gave the desired product with 70.5% of theory. The melting point of the derivative lay at 118° C.
Reaction SMILES: O(C(C(F)(F)F)(C(F)(F)F)[F:4])[K].[N+:13]([C:16]([N+]([O-])=O)([N+:20]([O-:22])=[O:21])[N+:17]([O-:19])=[O:18])([O-:15])=[O:14]>CN(C=O)C>[F:4][C:16]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])C([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Reactant: FC(F)(F)C(F)(O[K])C(F)(F)F
Solvent: CN(C)C=O
Product: O=[N+]([O-])C(F)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
In run 1 (control), 5 ml of 2.2 molar KOCF(CF3)2 in anhydrous DMF was added to a reaction vessel and diluted to 5.0 ml with anhydrous DMF. The reaction vessel consisted of a 50 ml round-bottom, three-neck flask which was equipped with a dropping funnel, an inlet tube with a safety trap, and an exit tube with a -80° C. cooled trap. Tetranitromethane (1.0 g, 5.10 mmoles) was placed in the dropping funnel and diluted with 10 ml of DMF. The system was flushed with nitrogen at 40 cc/min for 2 to 3 minutes. The C(NO2)4 -DMF solution was added to the KOCF(CF3)2 at ambient temperature. Fluorotrinitromethane yields and tetranitromethane conversions were obtained by gas-liquid chromatographic analyses of the reaction mixture as a function of reaction time.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:26][CH:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:5]=[C:6]([F:21])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]1.F[C:34](F)(F)[C:35](O)=O>C(Cl)Cl>[F:21][C:6]1[CH:5]=[C:4]([N:22]2[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[O:31])[CH3:30])[O:24][C:23]2=[O:32])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:9][N:8]2[CH2:35][CH2:34][CH2:3][CH2:2][CH2:7]2)[CH2:12][CH2:13]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)NCC1CN(c2cc(F)c(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCN(CCN4CCCCC4)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
The N-[[3-[3,5-difluoro-4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (1.00 g, 2.20 mmol) was dissolved in CH2Cl2 (6 mL) and cooled to 0° C. with an ice bath. Trifluoroacetic acid (20 mL) was added, the cooling bath removed, and the reaction mixture allowed to warm to ambient temperature over 1 h. The reaction mixture was then concentrated in vacuo and the residue dissolved in H2O (15 mL). The resultant solution was added to Bio Rad AG-1-X8 ion exchange resin (12 mL; OH- form, washed with H2O until neutral), additional H2O (5 mL) was added, and the mixture stirred for 10 min. The mixture was then filtered and the resin washed with additional H2O (3×5 mL). The aqueous filtrate was lyophilized to give 0.559 g (72%) of the title compound as a white solid with mp 108°-112° C. (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:20](=[O:21])[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[C:12]2=[O:13])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:20](=[O:21])[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[C:12]2=[O:13])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2ccncc2C1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2ccncc2C1=O

Procedure:
The mixture of 2.5 g of N-(4-nitro-o-tolyl)-pyridine-3,4- dicarboximide, 1.2 g of Raney nickel and 575 ml of ethyl acetate is hydrogenated at 3.4 atm. and room temperature until the hydrogen uptake ceases. It is filtered, evaporated and the residue thoroughly leached with hot benzene. The filtrate is evaporated, the residue chromatographed on silica gel and eluted with ethyl acetate, to yield the N-(4-amino-o-tolyl)-pyridine-3,4-dicarboximide as an oil, the mass spectrum of which shows the expected molecular ion of 253.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[CH2:22][C:23]([NH2:25])=[O:24])[N:9]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].[CH3:30][CH:31]([OH:33])[CH3:32].[H-].[Na+].O>CN(C=O)C>[CH:31]([O:33][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[CH2:22][C:23]([NH2:25])=[O:24])[N:9]=2)=[CH:4][C:3]=1[C:26]([F:27])([F:29])[F:28])([CH3:32])[CH3:30]
Reactant: NC(=O)Cn1ccc2c(-c3noc(-c4ccc(F)c(C(F)(F)F)c4)n3)cccc21
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution of 2-(4-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (100 mg) and 2-propanol (35 μl) in DMF (3 ml) was added 60% NaH (12 mg) at 0° C., followed by stirring at room temperature for 9 hours. The reaction solution was added with water (5 ml) to complete the reaction, and extracted with as a mixed solvent of chloroform:CH3OH (8:2). The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=98:2 to 93:7), and crystallized with diethyl ether to obtain 2-(4-{5-[4-isopropoxy-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-1-yl)acetamide (25 mg) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25](OCC)(=[O:27])[CH3:26].O.N>C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([N:16]([C:25](=[O:27])[CH3:26])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(C)=O
Reactant: COc1ccc(NC2=NN(c3ccc([N+](=O)[O-])cc3)C(=O)C2)cc1
Agent: N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(N(C(C)=O)C2=NN(c3ccc([N+](=O)[O-])cc3)C(=O)C2)cc1
Temperature: 5 °C

Procedure:
32.6 g of 1-(4-nitrophenyl)-3-(4-methoxyanilino)-5-oxo-2-pyrazoline was dispersed in 110 g of acetic anhydride and 2.7 g of zinc chloride was added thereto and heated (70° to 80° C) on a steam bath with stirring. The mixture became a uniform solution as the reaction proceeded. After the completion of the reaction, 500 ml of ethyl acetate and 500 ml of water were added the reaction mixture and concentrated aqueous ammonia (28%) was added dropwise thereto under cooling to completely decompose the excess acetic anhydride. The crystals deposited in the ethyl acetate were collected by filtration. The filtrate was sufficiently washed with water and the ethyl acetate solution was concentrated to one-third of its original volume and cooled (5° C) to yield a second amount of crystals which was added to the first crystals obtained. Total yield of the product was 31 g. The melting point was 165° to 167° C.