Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:22][CH2:23][CH:24]([OH:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCC(O)c1ccccc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: OC(CNC[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1)c1ccccc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-amino-1-phenylethanol in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=423.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C:6]([CH3:11])([CH2:9][OH:10])[CH2:7][OH:8].[CH:16](=O)[CH3:17]>CCCCCC>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][C:6]1([CH3:11])[CH2:9][O:10][CH:16]([CH3:17])[O:8][CH2:7]1
Reactant: CC=O
Reactant: CC(CO)(CO)OCc1ccccc1F
Solvent: CCCCCC
Product: CC1OCC(C)(OCc2ccccc2F)CO1

Procedure:
Using the procedure of Example 51, 2-(2-fluorobenzyloxy)-2-methyl-1,3-propanediol and acetaldehyde were reacted, using hexane as solvent to give, after separation by column chromatography, t-5-(2-fluorobenzyloxy)-r-2-methyl-5-methyl-1,3-dioxane, nD25 1.4902, and c-5-(2-fluorobenzyloxy)-r-2-methyl-5-methyl-1,3-dioxane, nD25 1.4939. The ir and nmr spectra were consistent with the assigned structures.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1>CO.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Yield: 105.8 %

Procedure:
A solution of 2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (20.0 g, 79 mmol) in MeOH (40 mL) was hydrogenated in presence of Raney Nickel (2.00 g, 34.1 mmol) at 40 psi for 3 h. The catalyst was removed via filtration, rinsed with MeOH and the filtrate concentrated to dryness to afford 5-((2-chloropyridin-4-yl)oxy)pyridin-2-amine (18.52 g, 105%) as a brown solid. MS (ESI) m/z: 222.0 (M+H+).
Reaction SMILES: N1C=CC=CC=1.[C:7]1([C:13]2[C:17]([CH:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[N+:27]([O-:29])=[O:28])[OH:19])=[C:16]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:15][N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:7]1([C:13]2[C:17]([C:18](=[O:19])[C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[N+:27]([O-:29])=[O:28])=[C:16]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:15][N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1[nH]nc(-c2ccccc2)c1C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1[nH]nc(-c2ccccc2)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
To a solution of dry pyridine (0.237 g, 300 mmol) in anhydrous methylene chloride (5 mL) was slowly added chromium trioxide (0.15 g, 1.5 mmol) to give a wine colored mixture which was stirred at room temperature for 10 minutes. A solution of ethyl 3-phenyl-4-[(4-chloro-2-nitrophenyl)(hydroxy)methyl]-1H-pyrazole-5-carboxylate (0.10 g, 0.25 mmol) in anhydrous methylene chloride (2 mL) was added to the wine red mixture in three portions over 25 minutes. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and the filtrate extracted with 3×20 mL 3N HCl. The combined organic extracts were dried with sodium sulfate and concentrated via rotary evaporation to give an oil (0.1 g) which was triturated with hexane:ethyl acetate (4:1) to give the title compound as a tan solid (0.075 g, 75%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][CH2:34]OS(C)(=O)=O)[O:13][CH:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:40].[Mg+2].[I-].O>CCOCC>[CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][CH2:34][I:40])[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:40]
Reactant: COC1O[C@H](CCOS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: O
Product: CO[C@H]1O[C@H](CCI)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2,3,4-tri-O-benzyl-6-deoxy-7-O-methylsulfonyl-D-glucoheptopyranoside (0.38 g, 0.83 mmol) in ether (5 mL) was added at 0° C. a 0.375M solution of magnesium iodide (6.7 mL). The mixture was stirred 15 min at 0° C. The excess of magnesium iodide was hydrolyzed with water. The reaction mixture was washed with sodium, thiosulfate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 2:8 mixture of ethyl acetate and hexane afforded the expected iodide methyl 2,3,4-tri-O-benzyl-6,7-dideoxy-7-iodo-α-D-glucoheptopyranoside which was crystallized from hexane (0.368 g, 91%); m.p. 66°-68° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(=[O:37])[NH:35][C:34](=[O:36])[CH:33]=[CH:32]1>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[NH:14][C:13]3[CH:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH2:28][O:29][CH3:30])[C:33]4[C:34](=[O:36])[NH:35][C:31](=[O:37])[C:32]=4[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CC(=O)N1
Reactant: COCCOc1ccccc1/C=C/c1cc2cc(OCc3ccccc3)ccc2[nH]1
Product: COCCOc1ccccc1-c1cc2[nH]c3ccc(OCc4ccccc4)cc3c2c2c1C(=O)NC2=O
Yield: 46 %

Procedure:
Reaction of (852) with maleimide using the procedure described in method 4a gave the adduct (CIII; Ar=2-(2-methoxyethoxy)phenyl, R10═H (853), which was used without further purification. Aromatisation of (853) with MnO2 using the procedure described in example 79 gave (854) (46%) as an orange solid, mp 157–159° C., which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])=[CH:24][CH:23]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccc(OC)cc3)s2)c(C)[nH]c1=O

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 4-methoxy-benzyl amine as described in Step 5, Example 24 to give the title compound. MS: m/e 419 (M+H). 1H NMR (δ ppm): 11.83 (s, 1H); 8.33 (t, 1H, J=6.3 Hz); 7.49 (d, 1H, J=3.7 Hz); 7.28 (s, 1H); 7.16 (d, 2H, J=8.6 Hz); 7.10 (d, 1H, J=3.7 Hz); 6.84 (d, 1H; J=8.6 Hz); 4.05 (d, 2H, J=6.3 Hz); 3.70 (s, 3H); 2.40 (q, 2H, J=7.4 Hz); 2.28 (s, 3H); 1.10 (t, 3H, J=7.4 Hz).
Reaction SMILES: CS(O[CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24])(=O)=O.[O:29]=[C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[N-:31]1.[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:26]1([NH:25][C:23]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=3)[C:7]=2[CH2:6][N:31]2[C:32](=[O:39])[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:30]2=[O:29])=[O:24])[CH2:27][CH2:28]1
Reactant: O=C1[N-]C(=O)c2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2COS(C)(=O)=O)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
(4-[(Cyclopropylamino)carbonyl]-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazol-5-yl)methyl methanesulfonate (1.02 g, 2.5 mmol) obtained in Example 126a) and potassium 1,3-dioxo-1,3-dihydroisoindol-2-ide (463 mg, 2.5 mmol, 1.0 eq.) were dissolved in DMF (10 ml), and the mixture was stirred at 50° C. for 30 min. The reaction mixture was diluted with ethyl acetate (20 ml), and the precipitate was collected by filtration, washed with water and dried to give the title compound as a white powder (1.0 g, 87.7%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[CH:13]=[CH:12][N:11]([CH3:14])[C:9]=2[N:10]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:23][NH:24][CH3:25].O>C(O)CCC>[CH2:1]([NH:4][C:5]1[N:6]=[C:7]([N:24]([CH3:25])[CH3:23])[C:8]2[CH:13]=[CH:12][N:11]([CH3:14])[C:9]=2[N:10]=1)[CH2:2][CH3:3]
Reactant: CNC
Reactant: CCCNc1nc(Cl)c2ccn(C)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: CCCNc1nc(N(C)C)c2ccn(C)c2n1
Temperature: 25 °C
Yield: 76 %

Procedure:
To 2-(n-propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (1.0 g, 4.5 mmol) (CXXIV) in n-butanol (20 mL) was added potassium carbonate (3.7 g, 27 mmol) and dimethylamine hydrochloride (1.0 g (22 mmol). The mixture was stirred in an autoclave equipped with a stirrer at 120° C. for 16 h. After cooling to room temperature, water was added (20 mL), and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then with a brine solution, and dried over anhydrous Na2SO4. The solvents were removed in vacuo and the residue was purified by flash column chromatography (PE/EtOAc=6/1) to yield 2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolo[2,3-d]pyrimidine (CXXVII, 800 mg, 76%) as a yellow solid. LCMS (ESI) m/z=234 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31].C(N(CC)CC)C.Cl>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2)=[O:31]
Reactant: O=C=Nc1ccccc1Cl
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccccc4Cl)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.40 mmol) and 2-chlorophenylisocyanate (0.16 mL, 1.40 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.38 mL, 2.7 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (40 mL) was added and the solids were isolated by filtration and washed with water (20 mL). The crude product was triturated in EtOAc (50 mL) for 0.5 h. The product was isolated by filtration and dried in vacuo to give 1-(2-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.56 g, 97% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.35 min (98.37%); mp: 235-237° C.; 1H NMR (DMSO-d6) δ 1.77-2.14 (m, 1H, CHH), 2.23-2.47 (m, 1H, CHH), 2.60 (d, J=17.2 Hz, 1H, CHH), 2.77-3.04 (m, 1H, CHH), 4.32 (d, J=17.4 Hz, 1H, CHH), 4.39-4.61 (m, 3H, CHH, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, CH), 6.88-7.04 (m, 1H, Ar), 7.15-7.32 (m, 1H, Ar), 7.34-7.50 (m, 2H, Ar), 7.54 (s, 1H, NH), 7.58 (t, J=5.8 Hz, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 8.17 (d, J=6.0 Hz, 2H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 31.21, 42.83, 47.14, 51.59, 120.86, 121.28, 122.01, 122.61, 123.03, 127.00, 127.45, 129.08, 130.44, 136.57, 142.48, 144.30, 154.83, 167.92, 171.00, 172.85; LCMS: MH=427/429; Anal Calcd for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 58.86; H, 4.26; N, 12.88; Cl, 8.32.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[NH:11][C:10]2[C:12]([CH:27]3[CH2:31][CH2:30][CH2:29][O:28]3)=[C:13]([F:26])[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[N:20][CH:21]=3)=[CH:15][C:9]=2[N:8]=1)=[O:5])[CH3:2]>CCO.CCOCC>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[NH:11][C:10]2[C:12]([C@H:27]3[CH2:31][CH2:30][CH2:29][O:28]3)=[C:13]([F:26])[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[N:20][CH:21]=3)=[CH:15][C:9]=2[N:8]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c(C3CCCO3)c2[nH]1
Solvent: CCO
Solvent: CCOCC
Product: CCNC(=O)Nc1nc2cc(-c3cnc(C(C)(C)O)nc3)c(F)c([C@H]3CCCO3)c2[nH]1
Reaction time: 0.17 h
Yield: 45.4 %

Procedure:
A racemic sample of 1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-tetrahydrofuran-2-yl-1H-benzimidazol-2-yl]urea (133.60 g) was resolved on a CHIRALPAK® IC® column (by Chiral Technologies) eluting with DCM/MeOH/TEA (60/40/0.1) at 25° C. giving the desired enantiomer as an off-white solid (66.8 g, 99.8% HPLC purity, 99+% ee). Analytical chiral HPLC retention time was 7.7 min (CHIRALPAK® IC® 4.6×250 mm column, 1 mL/min flow rate, 30° C.). The solid was suspended in 2:1 EtOH/Et2O (5 volumes), stirred for 10 minutes, collected by filtration, washed with 2:1 EtOH/Et2O, and dried under reduced pressure giving a white solid (60.6 g). 1H NMR (300 MHz, MeOD) δ 8.95 (d, J=1.6 Hz, 2H), 7.45 (d, J=6.5 Hz, 1H), 5.38 (br.s, 1H), 4.27 (dd, J=14.9, 7.1 Hz, 1H), 4.01 (dd, J=15.1, 7.0 Hz, 1H), 3.37-3.29 (m, 2H), 2.55 (br.s, 1H), 2.19-2.07 (m, 2H), 2.02-1.82 (br.s, 1H), 1.63 (s, 6H), 1.21 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].Cl.[CH2:15](O)[CH3:16]>>[CH2:15]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([OH:1])[CH:3]=1)[CH3:16]
Reactant: CCO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: Cl
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(O)c1
Yield: 1492.2 %

Procedure:
3-Hydroxy-4-nitrobenzoic acid (20.0 g, 109 mmol) in ethanol (250 mg) was refluxed for 6 hr in the presence of dry hydrogen chloride (5 g). The solvent was evaporated and the residue was dissolved in methylene chloride. The solution was washed with sodium bicarbonate until the unreacted material was removed as a precipitate. The organic fraction was finally washed with brine, dried over magnesium sulfate to give a brown solid of 3- hydroxy-4-nitrobenzoic acid ethyl ester (17.1 g): mp 80°-81° C. (crystallized from diethyl ether-hexane); Anal. Calcd for C9H9NO5 : C, 51.19% H, 4.30% N, 6.63% and Found: C, 51.23% H, 4.30% N, 6.79%; ir(CHCl3) 3,260, 1,720, 1,535 and 1,320 cm-1 ; and nmr(CDCl3)δ 1.35 (3H, t), 4.3 (2H, q), 7.7 (3H, m) and 10.4 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([CH:25]=1)[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([CH:25]=1)[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCCOCc1cc(Br)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(Br)cc1COCCCC1CCCCN1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
3-(5-Bromo-2-fluorobenzyloxy)-1-[1-(t-butoxycarbonyl)piperidin-2-yl]propane (590 mg, 1.37 mmol) was dissolved in methylene chloride (11 ml), cooled to 0° C., and treated with 3 ml of trifluoroacetic acid. The reaction mixture was stirred at 0° C. for 20 minutes, then warmed to ambient temperature, and stirred an additional ten minutes. The reaction mixture was diluted with methylene chloride and quenched with saturated sodium bicarbonate. The pH was adjusted to about 10 with 1 N sodium hydroxide. The aqueous fraction was back-extracted with methylene chloride. The organic fractions were combined, dried over sodium sulfate, filtered, and concentrated.
Reaction SMILES: [OH-].[Li+].[OH:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1COCC1>[OH:3][CH:4]([C:10]1[CH:11]=[CH:12][C:13]([N:16]([CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(O)c1ccc(N(CC#CCCCC(=O)OC)C(C)=O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(O)c1ccc(N(CC#CCCCC(=O)O)C(C)=O)cc1
Reaction time: 16 h
Yield: 76.3 %

Procedure:
Lithium hydroxide (0.3 mL of a 0.5N solution in H2O, 0.14 mmol) was added to a solution of the ester 105 (23 mg, 0.062 mmol) in THF (0.3 mL) at 23° C. After stirring for 16 h the reaction was acidified with 10% citric acid and extracted with EtOAc. The organic portion was washed with brine twice and then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FCC (silica gel, 9:1 CH2Cl2/MeOH) to afford 17 mg (77%) of the acid 106.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]2[O:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]2[O:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Sc2c(NCc3ccco3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Sc2c(NCc3ccco3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C

Procedure:
The mixture of 2.3 g of 4-(4-acetamidophenylmercapto)-3-furfurylamino-5-sulfamoylbenzoic acid and 23 ml of 2N aqueous sodium hydroxide is refluxed for one hour under nitrogen. After cooling to room temperature it is acidified to pH = 5 and the precipitate formed filtered off. It is dissolved in 25 ml of 50% hot aqueous ethanol, the solution cooled to room temperature and decanted from some amorphous substance. The supernatant solution is allowed to stand at room temperature for a longer period of time, the precipitate formed filtered off and this recrystallization procedure repeated several times, to yield the 4-(4-aminophenylmercapto)-3-furfurylamino-5-sulfamoylbenzoic acid, starting to melt at about 125°.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:11])[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](O)=[O:13]>>[CH:12]([NH:10][NH:9][C:8]([NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:11])=[O:13]
Reactant: O=CO
Reactant: NNC(=O)Nc1ccccc1
Product: O=CNNC(=O)Nc1ccccc1

Procedure:
Other known methods for the preparation of 4-aryl-1,2,4-triazol-3-ones involve the use of hydrazine as a raw material. In one such method, phenylurea is reacted with hydrazine to give a 4-phenylsemicarbazide. The semicarbazide is then condensed with ethyl formate to give the 4-phenyltriazolone. The overall yield from this method is about 20%. In another method, a 4-phenylsemicarbazide is reacted with formic acid to form the 1-formyl-4-phenylsemicarbazide intermediate, followed by intramolecular condensation to the 4-phenyltriazolone. The yield obtained by this method is about 40%. In yet another method, a substituted aniline is converted to the phenylcarbamate derivative. The phenylcarbamate is treated with hydrazine to give the phenylsemicarbazide derivative, followed by condensation with formamidine acetate to give the 4-phenyltriazolone. Each of these methods requires the use of the toxic compound hydrazine. In addition, the methods suffer from low overall yield.
Reaction SMILES: Cl[Si](C)(C)C.[I-].[Na+].C[O:9][C:10]1[C:15]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[CH:18][CH:17]=2)=[N:14][N:13]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:12](=[O:37])[CH:11]=1.O>CC#N>[OH:37][C:12]1[N:13]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=2)[N:14]=[C:15]([C:16]2[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=[CH:18][CH:17]=2)[C:10](=[O:9])[CH:11]=1
Reactant: COc1cc(=O)n(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=c1cc(O)n(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
Chlorotrimethylsilane (0.46 mL, 3.6 mmol) was added to a solution of sodium iodide (0.55 g, 0.73 mmol) in MeCN (20 mL) at room temperature. After stirring for 30 min, 5-methoxy-6-(1-phenyl-1H-pyrazol-5-yl)-2-[3-(trifluoromethyl)phenyl]pyridazin-3(2H)-one (0.30 g, 0.73 mmol) was added to the resulting suspension. The mixture was stirred at room temperature for 1 h, and then refluxed for 3 h. After cooling to room temperature, the mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with diisopropyl ether/hexane and recrystallized from AcOEt/hexane to give the title compound (0.21 g, 73% yield) as white crystals: mp 241-243° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 6.16 (1H, s), 6.88 (1H, d, J=1.9. Hz), 7.36-7.42 (3H, m), 7.45-7.54 (4H, m), 7.59 (1H, t, J=7.9 Hz), 7.70 (1H, d, J=7.9 Hz), 7.82 (1H, d, J=1.9 Hz), 12.23 (1H, brs). LC-MS (ESI) m/z 399 [M+H]+. Anal. Calcd for C20H13F3N4O2: C, 60.30; H, 3.29; N, 14.07. Found: C, 60.35; H, 3.37; N, 14.10.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-:11].[Na+].C1OCCOCCOCCOCCOC1>C(#N)C>[C:1]1([O:7][C:8]([F:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: O=C(F)Oc1ccccc1
Temperature: 40 °C

Procedure:
To a solution of phenylchloroformate in acetonitrile is charged sodium fluoride. To this mixture is charged the 15-crown-5 (“15C5”) at ambient temperature. The reaction mixture is then heated to 40° C. for approximately 16 hrs. Reaction completion is monitored by gas chromatography (“G.C.”).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>S(Cl)(Cl)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-methylbenzoic acid (20 g, 146.90 mmol, 1.00 equiv) in thionyl chloride (60 g). The mixture was stirred for 2 h at 80° C. The mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (200 mL). This was followed by the addition of triethylamine (29.7 g, 293.51 mmol, 2.00 equiv) dropwise with stirring at 0° C. To this was added aniline (13.6 g, 146.04 mmol, 1.00 equiv) dropwise with stirring at 0° C. The resulting solution was allowed to react, with stirring overnight at room temperature. The resulting mixture was washed with 3×100 mL of hydrogen chloride (5%) and 2×100 mL NaOH (5%). The mixture was washed with 3×100 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 19.37 g (62%) of 4-methyl-N-phenylbenzamide as a white solid. MS (ESI) m/z 212 ([M+H]+).