Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.Br[CH:22]=[C:23]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[CH3:24].N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:22]=[C:23](/[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)\[CH3:24])[C:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(=CBr)c1ccc(F)cc1
Reactant: CC(C)(O)CCN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(CCC(C)(C)O)CC2)c1ccc(F)cc1
Temperature: 95 °C
Yield: 65.6 %

Procedure:
4-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl-)2-methyl butan-2-ol (292 mg, 1.0 mmol), 1-((1-bromoprop-1-en-2-yl)-4-fluorobenzene (322 mg, 1.5 mmol), L-proline (23 mg, 0.2 mmol), Cuprous (I) iodide (19 mg, 0.1 mmol), potassium phosphate (636 mg, 3.0 mmol) in DMF (5 mL) were charged in a reaction vessel and nitrogen gas purged into the reaction mixture. The reaction mixture was heated at 95° C. overnight. The reaction was monitored by TLC/LCMS. The reaction mixture was diluted with water (20 mL) and the desired compound extracted with DCM (20 mL×3). The organic layer was dried over sodium sulfate and concentrated under vacuum to obtain the crude compound which was purified by reverse phase HPLC to obtain 280 mg of desired product as the free base. The free base compound was converted to HCl salt by treatment with ethanolic HCl. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.68 (m, 2H), 7.58 (s, 1H), 7.20 (m, 4H), 6.98 (s, 1H), 4.80 (m, 1H), 4.40 (m, 1H), 3.98 (m, 1H), 3.61 (m, 1H), 3.55 (m, 2H), 3.20 (m, 2H), 2.06 (m, 2H), 1.96 (s, 3H), 1.35 (s, 6H).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([OH:37])=[C:21]([CH:36]=1)[CH2:22][N:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][N:27]=1)[CH2:24][CH3:25]>CN(C=O)C.O>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([O:37][CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=2)=[C:21]([CH:36]=1)[CH2:22][N:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][N:27]=1)[CH2:24][CH3:25]
Reactant: ClCc1ccncc1
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)OC)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(Cc1cc(Br)ccc1OCc1ccncc1)c1ccc(C(=O)OC)cn1
Reaction time: 24 h
Yield: 64.5 %

Procedure:
A solution of 4-chloromethylpyridine hydrochloride (0.12 g, 0.73 mmol) in DMF (3 ml) was treated with potassium carbonate (0.29 g, 2.10 mmol). A solution of methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-5-carboxylate (0.26 g, 0.71 mmol) in DMF (4 ml) was added. The reaction was stirred for 24 hours and then the reaction was diluted with water and extracted with ethyl acetate (×3). The organic phases were combined and washed with water and brine once, dried (MgSO4) and evaporated. Chromatography eluant: ethyl acetate/hexane gave methyl 2-[N-(5-bromo-2-(4-pyridylmethoxy)benzyl)-N-ethylamino]pyridine-5-carboxylate as a white solid (0.209 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=[C:6]2[N:5]=[C:4]([CH3:16])[C:3]=1[C@H:17]([OH:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl(O)(=O)(=O)=O>C(Cl)Cl.C(OC(C)(C)C)(=O)C>[C:3]([O:23][C@@H:17]([C:3]1[C:4]([CH3:16])=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=2)[C:2]=1[Cl:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:17])([CH3:4])[CH3:2]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](O)C(=O)OCC)c(Cl)n2n1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(Cl)n2n1
Reaction time: 3 h
Yield: 172 %

Procedure:
To a stirred solution of (S)-ethyl 7-chloro-6-(2-ethoxy-1-hydroxy-2-oxoethyl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (200 mg, 0.585 mmol) in CH2Cl2 (6 mL) and t-butyl acetate (4 mL) at rt was added perchloric acid (0.151 mL, 1.756 mmol). The reaction flask was sealed. After stirring for 3 h, the reaction mixture was diluted with CH2Cl2 (50 mL), carefully quenched with sat. aq. NaHCO3 (5 mL). The organic layer was separated and washed with brine (5 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a yellow liquid. This crude product was purified by flash column chromatography on a silica gel column using (10-50% EtOAc/Hex as eluant) to afford the desired (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (200 mg, 0.503 mmol, 86% yield) as viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.19 (s, 1H), 5.66 (s, 1H), 4.52 (q, J=7.2 Hz, 2H), 4.25-4.19 (m, 2H), 2.72 (s, 3H), 1.51-1.45 (m, 3H), 1.28 (s, 9H), 1.26-1.21 (m, 3H). LCMS (M+1)=398.25.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][CH:4]=1)=O.[CH2:13]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCC1>C(O)C>[C:3]1([CH:1]=[C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:20]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:21]2=[O:29])[C:12]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:5][CH:4]=1
Reactant: O=C1Cc2ccccc2N1Cc1ccccc1
Reactant: O=Cc1ccc2cccccc1-2
Solvent: C1CCNC1
Solvent: CCO
Product: O=C1C(=Cc2ccc3cccccc2-3)c2ccccc2N1Cc1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
1-Formylazulene (1 mmol) was dissolved in 20 mL ethanol. 223 mg 1-benzylindolin-2-one (1 mmol) and 20 mL ethanol were then added. Next, a 2 mL solution (1 mmol) containing 1M pyrrolidine and ethanol was added to react at room temperature for three days. After removal of solvent, the resulting solution was extracted by 150 mL ethyl acetate and 50 mL water. The resulting solution was extracted again by 50 mL citric acid aqueous solution and ethyl acetate. The ethyl acetate layer was collected, dried with anhydrous magnesium sulfate, filtered, and concentrated under vacuum. Next, methanol was added and ultrasonically shaken at 40° C. for 1 hour. After filtration, washing by methanol, and drying, Compound 002 (315 mg, 87%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:10])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: OCc1ccc(Cl)nc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of (2,6-dichloropyridin-3-yl)methanol (1.0 g, 5.62 mmol) in CH2Cl2 (10 ml) was added Dess-Martin reagent (4.8 g, 11.24 mmol) at 26° C. After addition the mixture was stirred at room temperature for 2 h. Once the reaction was complete, the mixture was then quenched by adding 5% aqueous Na2S2O3 and stirred for 30 min. The resulting mixture was extracted with CH2Cl2 (2×30 ml). The combined organic layers were washed with saturated Na2S2O3 solution (50 ml), brine (30 ml), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification. (800 mg, Yield 80%). 1H NMR (400 MHz, CDCl3): 10.38 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][NH:24]1>O>[F:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([N:24]2[CH2:25][CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23]2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)cnc1N1CCc2ccccc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
2-chloro-5-fluoro-3-nitropyridine (1.00 g, 5.66 mmol) prepared in Step 4 and sodium carbonate (1.25 g, 9.06 mmol) were added to anhydrous N,N-dimethylformamide (50 ml). 1,2,3,4-tetrahydroisoquinoline (712 μg, 5.66 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 hour at 100° C. and then cooled to room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a sodium chloride solution three times, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 1.34 g of the titled compound as yellow solid. (Yield: 86%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:17]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(O)cc(O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)cc(O)c1
Yield: 91.9 %

Procedure:
To a solution of 3,5-dihydroxybenzoic acid (50.0 g, 320 mmol) in methanol (310 ml) was added concentrated sulfuric acid (7.7 ml) and the resultant solution heated at reflux for 16 hrs. It was then cooled and approximately 200 ml of methanol removed under reduced pressure. To the remaining solution was added water (300 ml) and the mixture extracted with ether (4×50 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate (50 ml), dried, and evaporated to dryness. The resultant solid was recrystallized from 50 ml of methanol/125 ml of water to give methyl 3,5-dihydroxybenzoate as off-white crystals (50.1 g, 91.9%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][C:31]=1[F:32])[NH:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([OH:22])=O.Cl.[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:29]=[CH:30][C:31]=1[F:32])[NH:17][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([NH:42][O:41][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:22]
Reactant: NOCc1ccccc1
Reactant: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(F)c(Cl)c1
Yield: 104.9 %

Procedure:
Using General Method 2, the reaction of carbonyldiimidazole (2.60 g, 15.7 mmol), 2-(3-chloro-4-fluoro-anilino)-4,5-difluorobenzoic acid (Example P, 4.32 g, 14.3 mmol), O-benzylhydroxylamine hydrochloride (2.3 g, 14.3 mmol), and triethylamine (2.2 mL, 15.7 mmol) provided 6.1 g of the crude title compound.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]#[N:20])[N:4]=1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[OH:25][NH:24][C:19]([C:5]1[N:4]=[C:3]([C:2]([F:21])([F:22])[F:1])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][CH:10]=2)[N:6]=1)=[NH:20]
Reactant: N#Cc1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
A stirred mixture of 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (example B.2) (1.0 g, 3.15 mmol), hydroxylamine hydrochloride (0.81 g, 11.7 mol) and sodium carbonate (0.67 g, 6.32 mol) in water (15 mL) and ethanol (15 mL) was heated under reflux conditions for 2 h. The ethanol was removed partly and the mixture stirred at room temperature for 0.5 h. The precipitate was collected by filtration, washed with water and dried to yield the title compound (1.08 g, 98%) as a light brown solid. MS (ISP) 351.1 [(M+H)+]; mp 224° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11]1[C:12](=O)[C:13](=[O:18])[C:14]=1[O:15]CC)[CH3:9]>C(O)C>[NH:1]([C:12]1[C:13](=[O:18])[C:14](=[O:15])[C:11]=1[O:10][CH2:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1ccccc1
Solvent: CCO
Product: CCOc1c(Nc2ccccc2)c(=O)c1=O

Procedure:
0.01 mol of aniline is added to a solution of 0.01 mol of 3,4-diethoxy-3-cyclobutene-1,2-dione in 30 ml of anhydrous ethanol. The mixture is refluxed for 12 hours and the precipitate that forms is filtered off while hot. The resulting residue is solidified in the presence of ether enabling the expected product to be isolated.
Reaction SMILES: O[N:2]=[C:3]([C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]2[NH:29][C:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)=[CH:30][CH:31]=1)([O-:23])=[O:22]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(C(F)(F)F)cc1
Yield: 30.7 %

Procedure:
Ethyl 2-hydroxyimino-3-oxo-3-(4-trifluoromethylphenyl)-propionate (24.6 g) and 4-nitrobenzylamine (14.0 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2-(4-nitrophenyl)-5-(4-trifluoromethylphenyl)-imidazole-4-carboxylate (10.6 g). 9.0 g therefrom was dissolved in ethyl alcohol. 1 M Sodium hydroxide solution was added and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(4-nitrophenyl)-5-(4-trifluoromethylphenyl)imidazole-4-carboxylic acid (8.2 g), melting point 172-174° C. (decomposition).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2.Cl.N([O-])=O.[Na+].NNC(N)=O.[CH:25](=[O:27])[CH3:26].C([O-])(=O)C.[Na+]>O.S([O-])([O-])(=O)=O.[Cu+2].S([O-])([O-])=O.[Na+].[Na+]>[C:25]([C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2)(=[O:27])[CH3:26]
Reactant: CC=O
Reactant: COc1cc(N)cc2c1NC(=O)CC2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Product: COc1cc(C(C)=O)cc2c1NC(=O)CC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
To a mixture of 6-amino-8-methoxy-3,4-dihydrocarbostyril (12 g), concentrated hydrochloric acid (16 ml) and water (50 ml) was added ice (30 g), and sodium nitrite (5 g) and water (20 ml) were added gradually to the resulting mixture under ice-cooling. After completion of addition, the resulting mixture was reacted at 0° to 5° C. for 1 hour. On the other hand, a heated solution of acetaldehyde semicarbazide (10 g) in water (50 ml) and then sodium sulfite (0.25 g) and copper sulfate (3.2 g) were added to a solution of sodium acetate (34 g) in water (40 ml), and the internal bath was adjusted to a temperature of 10° to 20° C. The solution was stirred and below the surface of the solution was added gradually a solution prepared by adding a solution of sodium acetate (26 g) in water (46 ml) to the above diazonium salt solution. After stirring was continued for 2 hours, the reaction was allowed to stand for one night. Precipitates which formed were collected by filtration and washed with water. They were added in 200 ml of 2 N hydrochloric acid and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was extracted with chloroform (150 ml) twice and the chloroform layer was washed with water. The solution was filtered through a short column charged with silica gel-activated carbon. This column was washed with 500 ml of chloroform. The two chloroform layers were combined and chloroform was evaporated. The residue was recrystallized from benzene to give 5.1 g of 6-acetyl-8-methoxy-3,4-dihydrocarbostyril.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=3)[C:7](=[O:15])[C:6]([C:16]([O:18]CC)=[O:17])=[CH:5]2)[CH2:3][CH2:2]1.O.S(=O)(=O)(O)O>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=3)[C:7](=[O:15])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)ccc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2cc(F)ccc2c1=O
Temperature: 0 °C

Procedure:
2.75 g (0.01 mol) of ethyl 1-cyclopropyl-7-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate are refluxed for four hours in a mixture of 12 ml of acetic acid, 12 ml of water and 1.2 ml of concentrated sulphuric acid. The cooled reaction mixture is poured into ice-water, and the precipitate is filtered off, washed with water and dried at 100° C. in a drying cupboard.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:8][S:9][CH2:10]Cl.C(N(CC)CC)C>>[C:1]([O:7][CH2:8][S:9][CH3:10])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CSCCl
Reactant: CC(C)CC(=O)O
Solvent: CCN(CC)CC
Product: CSCOC(=O)CC(C)C

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting isovaleric acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 78°-79° C./12 mm Hg, nD20 1.4496.
Reaction SMILES: [C:1]([NH:11][C@@H:12]1[C:38](=[O:39])[N:14]2[C:15]([C:35]([OH:37])=[O:36])=[C:16]([CH:19]([S:29][C:30]3[NH:34][N:33]=[N:32][N:31]=3)[CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][S:18][C@H:13]12)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C[O-].[Na+:42]>CO>[Na+:42].[C:1]([NH:11][C@@H:12]1[C:38](=[O:39])[N:14]2[C:15]([C:35]([O-:37])=[O:36])=[C:16]([CH:19]([S:29][C:30]3[NH:34][N:33]=[N:32][N:31]=3)[CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][S:18][C@H:13]12)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: CCOP(=O)(CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](O)c3ccccc3)[C@H]2SC1)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOP(=O)(CC(Sc1nnn[nH]1)C1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)[C@H](O)c3ccccc3)[C@H]2SC1)OCC

Procedure:
A solution of 7β-D-mandelamido-3-(1-diethoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid in methanol was adjusted to pH 6.5 by addition of 5% aqueous sodium methoxide then filtered. Ether was added to the filtrate and the solid material which formed was collected by filtration to give 7β-D-mandelamido-3-(1-diethoxyphosphinylmethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid sodium salt.
Reaction SMILES: [Cl-].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([I+:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[C:23]12([CH2:33][S:34]([O:37]C)(=[O:36])=[O:35])[C:30]([CH3:32])([CH3:31])[CH:27]([CH2:28][CH2:29]1)[CH2:26][C:24]2=[O:25]>C(OCC)(=O)C>[C:23]12([CH2:33][S:34]([O-:37])(=[O:35])=[O:36])[C:30]([CH3:32])([CH3:31])[CH:27]([CH2:28][CH2:29]1)[CH2:26][C:24]2=[O:25].[C:19]([C:16]1[CH:17]=[CH:18][C:13]([I+:12][C:9]2[CH:8]=[CH:7][C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:11][CH:10]=2)=[CH:14][CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COS(=O)(=O)CC12CCC(CC1=O)C2(C)C
Agent: CC(C)(C)c1ccc([I+]c2ccc(C(C)(C)C)cc2)cc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CC1(C)C2CCC1(CS(=O)(=O)[O-])C(=O)C2

Procedure:
Ethyl acetate (50 ml) was added to bis(p-tert-butylphenyl)iodonium chloride (17.06 g; 39.79 mmol) and methyl camphorsulfonate (10.78 g; 43.76 mmol). The resultant mixture was heated at 77° C.-80° C. and refluxed for 24 hours while being stirred. The reaction mixture was cooled, and formed solid was removed through filteration. The solid was recrystallized from acetone, and dried under vacuum, to thereby yield 20.63 g of bis(p-tert-butylphenyl)iodonium camphorsulfonate (yield: 83%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:22][C:23]([N:25]([CH:32]([CH3:34])[CH3:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>CN(C=O)C>[CH:32]([N:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](=[O:24])[CH2:22][NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH3:34])[CH3:33]
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CNc1ccccc1Nc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 56.1 %

Procedure:
Potassium carbonate (6.9 g) was added to a solution of N-phenylphenylene diamine (9.2 g) in DMF and 2-bromo-N-isopropyl-N-phenyl acetamide (12.7 g) in DMF (200 ml) and the mixture was allowed to stir overnight. The DMF was evaporated in vacuo and the residue was dissolved in ethyl acetate (400 ml) and washed exhaustively with aqueous 1N HC (4×250 ml). The organic layer was washed with water (2×200 ml), dried (Na2SO4) and evaporated to give 17.8 gm of crude alkylated product. The oil was purified by chromatography on silica gel (600 g) using first CHCl3 (8000 mL), then hexane:ethyl acetate (2:1, 8000 ml) as eluents to give the title compound (10 g), as an oil. 1H-NMR (300 MHz, CDCl3): d 7.42-6.8 (m, 14 H), 6.36 (d, 1H), 4.95 (m, 1H), 3.22 (s, 2H), 1.05 (d, 6H); MS (FAB)=360 (MH+); TLC, Rf =0.18 (CHCl3).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13](Cl)(Cl)Cl.CO>C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: ClC(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
p-Nitrobenzoic acid (1.67 g) is suspended into chloroform (20 ml) and thereto are added triethylamine (1.40 ml) under ice-cooling and further 1-(p-chlorobenzenesulfonyoxy)-6-chloro-1,2,3-benzotriazole (3.44 g). When the mixture is stirred at room temperature for 15 minutes, yellow precipitates are produced and the mixture is further stirred for 5 hours. To the mixture are added methanol (0.6 ml) and triethylamine (1.4 ml), whereby the precipitates are dissolved. After stirring for 1 hour, chloroform is distilled off and the residue extracted with ethyl acetate. The extract is washed with water, an aqueous sodium hydrogen carbonate, 1 N hydrochloric acid and water in order and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off. The resulting crystals aare recrystallized from isopropyl alcohol to give yellow crystals of methyl p-nitrobenzoate (1.4 g), melting point: 93°-94° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[N:4]2[C:8]([CH:9]=1)=[N:7][C:6]([CH2:10][CH2:11][CH3:12])=[N:5]2.CC1C=C2N(N=C(CCC)N2)N=1>>[CH3:1][C:2]1[N:3]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[N:4]2[C:8]([CH:9]=1)=[N:7][C:6]([CH2:10][CH2:11][CH3:12])=[N:5]2
Reactant: CCCc1nc2cc(C)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)n2n1
Agent: CCCc1nn2nc(C)cc2[nH]1
Product: CCCc1nc2cc(C)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)n2n1

Procedure:
A 359 mg portion of the mixed product obtained in Example 6 consisting (about 2:1) of 6-methyl-2-propyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole (compound 6c) and 6-methyl-2-propyl-1H-pyrazolo[1,5-b][1,2,4]triazole was treated in the same manner as described in Example 23 to give 126 mg of 6-methyl-2-propyl-5-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole in the form of colorless crystals.