Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]2[C:26]([C:27]([OH:29])=[O:28])=[C:25]([CH2:30][CH3:31])[N:24]=[CH:23][N:22]=2)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10].CI>CC(CC)=O>[CH2:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]2[C:26]([C:27]([O:29][CH3:1])=[O:28])=[C:25]([CH2:30][CH3:31])[N:24]=[CH:23][N:22]=2)=[CH:16][CH:17]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1ccc(CCNc2ncnc(CC)c2C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CCCCOc1ccc(CCNc2ncnc(CC)c2C(=O)OC)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
Potassium carbonate (0.27 g, 1.95 mmol) was added to a solution of 4-(2-(4-butoxyphenyl)ethylamino)-6-ethylpyrimidine-5-carboxylic acid (0.34 g, 0.99 mmol) in ethyl methyl ketone (20 ml), and methyl iodide (0.42 g, 2.96 mmol) was added. After stirring at 65° C. for 3 hours, the mixture was cooled to room temperature. The resulting solid was filtered off and the solvent was evaporated. The residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired methyl 4-(2-(4-butoxyphenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.26 g, 73%).
Reaction SMILES: O.[C:2]1([CH3:19])[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.C[O:22][C:23](=[O:37])[C@H:24]([CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)[NH2:25].[Li+].[OH-]>C1COCC1.O>[C:2]1([CH3:19])[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:25][C@H:24]([C:23]([OH:37])=[O:22])[CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1cccc2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2cccc3ccccc23)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to β-(1-naphthyl)alanine methyl ester hydrochloride using the procedure described in Method 3. The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:38])[C@H:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[CH:20][C:19]=1[CH3:27])(=[O:17])=[O:16])[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>N1C=CC=CC=1>[CH2:1]([O:8][NH:9][C:10](=[O:38])[C@H:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[CH:20][C:19]=1[CH3:27])(=[O:17])=[O:16])[CH2:12][O:13][C:39](=[O:41])[CH3:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CO)C(=O)NOCc2ccccc2)c(C)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](COC(C)=O)C(=O)NOCc2ccccc2)c(C)c1
Temperature: 25 °C

Procedure:
To a solution of N-benzyloxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-hydroxypropionamide (450 mg, 0.82 mmol) in pyridine (2 mL) at 0° C. was added acetic anhydride (0.09 mL, 0.98 mmol). The reaction mixture was allowed to warm to room temperature over 12 h and then partitioned between 2 N aqueous hydrochloric acid and methylene chloride (100 mL). The methylene chloride layer was separated, dried over magnesium sulfate, and concentrated. Purification of the residue by preparative TLC (30% ethyl acetate-hexanes) gave N-benzyloxy-2(R)-[(3,4-methylenedioxy-benzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-acetoxypropionamide.
Reaction SMILES: [C:1]([C:4]1[S:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=1)(=O)[CH3:2].[CH3:19]I.[Mg].Cl>CCOCC>[C:1]([C:4]1[S:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([CH3:19])=[CH2:2]
Reactant: CI
Reactant: CC(=O)c1cc2c(s1)Oc1ccccc1NC2=O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: C=C(C)c1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Acetylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (1.8 g) was suspended in ether (15 ml) and 20 equivalent amounts of magnesium methyl iodide was added under ice-cooling. The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into 1M hydrochloric acid under ice-cooling and insoluble matter was filtered off. The resulting mixture was extracted twice with chloroform. The chloroform layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue was suspended in toluene and a catalytic amount of p-toluenesulfonic acid was added. The mixture was stirred under reflux with heating for 20 minutes. The reaction system was cooled to room temperature and the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The solvent was evaporated under reduced pressure and diisopropyl ether was added to the residue. The precipitated crystals were collected by filtration to give 2-isopropenylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (800 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[C:25]1([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:37]([C:34]5([C:32]([NH:31][C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)=[O:33])[CH2:36][CH2:35]5)=[O:38])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cn2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)cc3F)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
To a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (400 mg, 1.23 mmol) in N,N-dimethylacetamide (4.0 mL) were added 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (352 mg, 1.72 mmol), HATU (699 mg, 1.84 mmol) and N,N-diisopropylethylamine (320 μL, 1.84 mmol), and the mixture was stirred at room temperature for 3 hr. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60→0/100). The obtained powder was recrystallized from methyl ethyl ketone/water (=20/1) to give the title compound (294 mg, 47%) as white crystals.
Reaction SMILES: CC([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[OH-].[Na+].Cl>O>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][OH:4])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Yield: 63.9 %

Procedure:
In 100 ml of water was suspended 10 g of 7-aminocephalosporanic acid (hereinafter abbreviated as "7-ACA"). The pH of the suspension was maintained at 12.5 to 13.4 by gradual addition of 2N-sodium hydroxide solution under ice-cooling and stirring. The mixture was further stirred for 2 hours, and adjusted to pH 3.4 with 4N-hydrochloric acid after confirming the disappearance of the starting material (7-ACA) by TLC. The precipitating crystals were collected by filtration, washed with water and acetone and dried over phosphorus pentoxide under reduced pressure to give 5.4 g of 7β-amino-3-hydroxymethyl -3-cephem-4-carboxylic acid as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][CH2:8][CH:9](O)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([CH:9]2[C:21]3[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:22]=3)[CH2:6][NH:7][CH2:8]2)[CH:15]=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: COc1ccc(C(O)CNCc2ccc(C)cc2)cc1OC
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CNCc3ccc(C)cc32)cc1OC
Yield: 98.3 %

Procedure:
530 mg of α-[[(4-methylbenzyl)amino]methyl]-3,4dimethoxybenzyl alcohol was dissolved in 4 ml of trifluoroacetic acid, and after adding thereto 0.12 ml of conc. sulfuric acid under ice cooling, the mixture was allowed to react for 30 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with toluene 2 times. After adding chloroform, the mixture was basified by addition of 28% aqueous ammonia. By a separating procedure, the chloroform layer was collected, was washed with water once, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 490 mg of 4-(3,4-dimethoxyphenyl)-6-methyl-1,2,3,4-tetrahydroisoquinoline (melting point: 94°-96° C.).
Reaction SMILES: N#N.[NH2:3][C:4]1[C:8]([Br:9])=[CH:7][NH:6][N:5]=1.CN(/[CH:13]=[C:14](\[Cl:19])/[CH:15]=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(O)C>C(O)(=O)C>[Br:9][C:8]1[CH:7]=[N:6][N:5]2[CH:15]=[C:14]([Cl:19])[CH:13]=[N:3][C:4]=12
Reactant: CN(C)/C=C(\Cl)C=[N+](C)C
Reactant: Nc1n[nH]cc1Br
Agent: F[P-](F)(F)(F)(F)F
Agent: N#N
Solvent: CCO
Solvent: CC(=O)O
Product: Clc1cnc2c(Br)cnn2c1
Temperature: 70 °C
Yield: 80.8 %

Procedure:
A 5 L 4-neck round bottom flask equipped with mechanical stirrer, thermocouple, condenser and N2 bubbler was charged with 3-amino-4-bromopyrazole (40.0 g, 240 mmol), 2-Chloro-1,3-bis(dimethylamino)trimethinium hexafluorophosphate (77.0 g, 252 mmol) in acetic acid (390 ml)/ethanol (580 ml). The reaction mixture was heated to 70° C. for 8 hrs. Cool to 0° C. Filter off solids. Wash solids with 500 ml water then 500 ml MeOH and dried under high vac to afford the title compound (45.1 g, 194 mmol). LRMS (APCI) calc'd for (C6H3BrClN3) [M+H]+, 231.9; found 231.9. 1H NMR (CDCl3, 500 MHz) δ 8.74 (s, 1H), 8.52 (s, 1H), 8.14 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:25]=[CH:24][C:13]([CH2:14][CH:15]([C:20]([O:22]C)=[O:21])[C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)[C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[S:3]1.[OH-].[K+]>CO>[CH3:19][O:18][C:16](=[O:17])[CH:15]([CH2:14][C:13]1[CH:24]=[CH:25][C:10]([O:9][CH2:8][CH2:7][N:6]2[C:5]3[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=3[S:3][C:2]2=[O:1])=[CH:11][CH:12]=1)[C:20]([OH:22])=[O:21]
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3ccccc32)cc1)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3ccccc32)cc1)C(=O)O

Procedure:
Dissolve the compound obtained in Example 8 (0.5 g) in methanol (30 ml) and add potassium hydroxide (0.07 g) that has previously been dissolved in methanol. Leave for one week at ambient temperature with magnetic stirring. Remove the methanol by evaporation under reduced pressure and acidify the resulting residue with a 6N hydrochloric acid solution until a pH of 1 is obtained. Extract twice with 30 ml of ether each time and then evaporate the organic phase under reduced pressure after having dried it over magnesium sulphate. Precipitate the resulting residue in ether and filter off the precipitate which forms.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: BrCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCBr)cc2)cc1
Yield: 67 %

Procedure:
An acetone solution of 90 m moles (21.8 g) of the above 4'-hydroxybiphenyl-4-carboxylic acid ethyl ester, 0.15 mole (49.2 g) of 1,12-dibromododecane, and 0.4 mole (55.3 g) of potassium carbonate was refluxed for four hours. The reaction solution was filtered. The filtrate was concentrated, and then purified by column chromatography, to obtain 29.5 g of 4'-(12-bromododecyloxy)biphenyl-4-carboxylic acid ethyl ester [m.p. 88.6°-90.5° C⟧ (yield: 67%)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12](O)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[C:3]([CH2:12][OH:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1cc2ccccc2cc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc2ccccc2cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-amino-2-naphthoic acid (85%, 1.17 g, 5.34 mmol) in dry THF (20 mL) was added dropwise over 30 min to a stirred solution of lithium aluminum hydride (95%, 0.53 g, 13.4 mmol) in dry THF (20 mL) at 0° C. under N2. The mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture was adjusted to basic pH with 1N NaOH (20 mL). The mixture was filtered and extracted with Et2O (4×100 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford (3-amino-2-naphthyl)methanol. LCMS calc.=174.1; found=174.2 (M+1)+. 1H NMR (500 MHz, CD3OD): δ 7.66 (d, J=8.0 Hz, 1H); 7.61 (s, 1H); 7.55 (d, J=8.2 Hz, 1H); 7.30-7.27 (m, 1H); 7.18-7.14 (m, 1H); 7.08 (s, 1H); 4.74 (s, 2H).
Reaction SMILES: [C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:32]=[CH:31][C:20]([O:21][CH2:22][C:23]3[O:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2].C1C=CC2N(O)N=[N:47]C=2C=1.CCN=C=NCCCN(C)C.[Cl-].[NH4+]>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[C:1]([N:4]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]3[O:27][C:26]([C:28]([NH2:47])=[O:30])=[CH:25][CH:24]=3)=[CH:31][CH:32]=2)=[O:16])[C@@H:7]([CH3:33])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCc3ccc(C(=O)O)o3)cc2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCc3ccc(C(N)=O)o3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 11 h
Yield: 61 %

Procedure:
(2S,4R)-5-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxymethyl)-furan-2-carboxylic acid (0.065 g, 0.12 mmol) was converted to the amide by dissolving in THF (1 mL) at room temperature. HOBt (0.024 g), EDCI (0.033 g), and ammonium chloride (0.013 g, 0.232 mmol) was added along with 2 drops of DMF and stirred at room temperature for 11 h. The reaction was diluted with ethyl acetate, washed with 1N NaOH, 1N HCl and brine. The organics were dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (10 ethyl acetate:1 methanol) to afford the product as a white solid in 61% yield.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH2:30]([NH2:32])[CH3:31].O1CCCC1>C(OCC)(=O)C>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH2:30]([NH-:32])[CH3:31]
Reactant: CCN
Agent: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[NH-]
Temperature: 70 °C

Procedure:
A mixture of lovastatin (5.0 g, 0.012 mol) and 2N solution of ethylamine in tetrahydrofuran (37 ml, 0.074 mol) was heated to gentle reflux at 70° C. for 10 hours. The solution was cooled to ambient temperature and ethyl acetate (100 ml) was added; the mixture was washed with 2N hydrochloric acid (3×50 ml). The combined aqueous layers were washed with ethyl acetate (100 ml) and the combined organic layers with water (2×100 ml). The organic layer was dried over sodium sulphate, filtered and evaporated at reduced pressure to give an orange oil.
Reaction SMILES: CC(C)([O-:4])C.[K+].C(OCC)(=O)C(OCC)=O.[O:17]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.OS(O)(=O)=O>O1CCCC1>[C:30]1(=[O:4])[C:31]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH2:24][CH2:25][C:26]=2[C:27](=[O:28])[O:29]1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CCCOc1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(=O)C(=O)OCC
Solvent: C1CCOC1
Product: O=C1OC(=O)C2=C1CCOc1ccccc12
Reaction time: 8 h

Procedure:
To potassium tert-butoxide (1.35 g, 12 mmol) in tetrahydrofuran (30 mL) was added diethyl oxalate (2.2 g, 15 mmol) and ethyl 4-phenoxybutanoate (2.08 g, 10 mmol) in tetrahydrofuran (30 mL) at 0° C. dropwise. The mixture was allowed to stir overnight, concentrated, quenched with 1 N HCl(aq), extracted with ethyl acetate, and concentrated. A fraction of this material (308 mg, 1 mmol) was added to concentrated H2SO4 at 0° C. The mixture was stirred for 1.5 hours and was poured onto ice chips. The precipitate was collected to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (dd, J=1.5, 8.1 Hz, 1H), 7.48 (t, J=8.1 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 4.28 (t, J=5.1 Hz, 2H), and 3.02 (t, J=5.1 Hz, 2H).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[OH-].[Na+].[N+:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)([O-:9])=[O:8].O>CC(C)=O>[CH:1]([NH:4][C:14](=[O:15])[C:13]1[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:18][CH:17]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 74 %

Procedure:
32.5 g of isopropylamine dissolved in 250 ml of acetone are added with 71 g of a 30% sodium hydroxide aqueous solution. This mixture, cooled to 0° C., is slowly added with 92.7 g of p-nitrobenzoyl chloride dissolved in 300 ml of acetone, coo ling with an ice bath to keep temperature from 0° to 5° C. Subsequently stirring is continued for 1 more hour allowing temperature to raise to 20°-30° C. Then the reaction mixture is poured into cold water. The formed precipitate is filtered, washed with water, dried and crystallized from isopropanol. 77 g of N-isopropyl-p-nitrobenzamide are obtained as a whitish solid substance with m.p. 152°-154° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[C:17]([C:24]([OH:26])=[O:25])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[C:11]([O:13]C)=[O:12])([O:3]C)=[O:2].Cl>>[C:7]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[C:17]([C:24]([OH:26])=[O:25])[CH:16]=2)[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:5]([C:1]([OH:3])=[O:2])[CH:6]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)O)c(C(=O)O)c2)cc1C(=O)OC
Agent: Cl
Product: O=C(O)c1ccc(-c2ccc(C(=O)O)c(C(=O)O)c2)cc1C(=O)O

Procedure:
The 3,4-dicarbomethoxy-biphenyl-3′,4′-dicarboxylic acid obtained in Example 3-1 was reacted with concentrated hydrochloric acid to obtain 3,4,3′,4′-biphenyltetracarboxylic acid (s-BPTA). Then, the obtained 3,4,3′,4′-biphenyltetracarboxylic acid was reacted in acetic anhydride under heating, to obtain a 3,4,3,4′-biphenyltetracarboxylic acid anhydride (s-BPDA).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[NH:30][N:29]=[C:28]([C:31]([OH:33])=O)[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:67])[C:59]2[CH:64]=[C:63]([Cl:65])[CH:62]=[CH:61][C:60]=2[Cl:66])[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[Cl:66][C:60]1[CH:61]=[CH:62][C:63]([Cl:65])=[CH:64][C:59]=1[C:58]([N:55]1[CH2:54][CH2:53][N:52]([C:50](=[O:51])[CH2:49][NH:48][C:31]([C:28]2[CH:27]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:30][N:29]=2)=[O:33])[CH2:57][CH2:56]1)=[O:67]
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]n1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1)c1cc(-c2ccccc2)[nH]n1
Temperature: 10 °C
Reaction time: 8 h
Yield: 89.47 %

Procedure:
HOBt (24 mg, 0.18 mmol) and DIPEA (74 mg, 0.57 mmol) were added to a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid; hydrochloride (32 mg, 0.14 mmol) in DMF (1.0 mL). The mixture was then cooled to 10° C. and EDCI.HCl (34 mg, 0.18 mmol), followed by 2-amino-1-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-ethanone hydrochloride (50 mg, 0.14 mmol) were added. The reaction mixture was then stirred at room temperature overnight. Water was added, and the resulting precipitate was isolated by filtration and dried under reduced pressure to afford 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a solid in 89.47% Yield. LC-MS purity: 92.226%. 1H-NMR (DMSO): δ 8.6 (s, 1H), 8.1 (t, 1H), 7.8 (m, 2H), 7.6 (m, 3H), 7.45 (m, 4H), 7.1 (s, 1H), 3.9 (m, 2H), 3.4 (m, 6H), 3.2 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])=O)[CH2:3][CH2:2]1.[F:14][C:15]([F:35])([F:34])[O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][CH:29]([O:32][NH2:33])[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[CH:1]1([C:4](=[N:33][O:32][CH:29]2[CH2:28][CH2:27][N:26]([S:23]([C:20]3[CH:19]=[CH:18][C:17]([O:16][C:15]([F:35])([F:14])[F:34])=[CH:22][CH:21]=3)(=[O:24])=[O:25])[CH2:31][CH2:30]2)[C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[CH2:3][CH2:2]1
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reactant: N#Cc1cccc(C(=O)C2CC2)c1
Product: N#Cc1cccc(C(=NOC2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)C2CC2)c1

Procedure:
3-(Cyclopropanecarbonyl)benzonitrile was coupled with O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine to give 3-(cyclopropyl(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxyimino)methyl)benzonitrile as a mixture of stereoisomers.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[OH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6]
Reactant: CC(O)CN
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCC(C)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
19 ml (0.24 mol) 1-amino-2-propanol were added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 29.50 g (0.19 mol, 78% yield) of a colorless oil.