Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:25])[CH:3]=1.[CH:26](=O)[CH3:27].Cl.[BH4-].[Na+]>CO.O>[ClH:22].[CH2:26]([NH:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[O:7])=[C:4]([Cl:25])[CH:3]=1)[CH3:27]
Reactant: CC=O
Reactant: Nc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.5 g of 1-(4-amino-2-chlorobenzoyl)-4-[2-(4-chlorophenyl)ethyl]-piperazine (see Example 7) are dissolved together with 0.26 g of acetaldehyde and 0.8 ml of 5N alcoholic hydrochloric acid in 15 ml of methanol. 0.41 g of 85% NaBH4 is added thereto and the reaction solution is stirred at room temperature for 24 hours. Water is added to the reaction solution, which is then decanted off and taken up in methylene chloride, dried and concentrated by evaporation. The oily material is chromatographed on silica gel and converted into the hydrochloride, yielding 1-[4-(N-ethylamino)-2-chlorobenzoyl]-4-[2-(4-chlorophenyl)ethyl]-piperazine hydrochloride having a melting point of 230°.
Reaction SMILES: [C:1]([S:9][CH2:10][C@@H:11]([CH3:22])[C:12]([N:14]1[C@H:18]([C:19]([OH:21])=[O:20])[CH2:17][S:16][CH2:15]1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:29][CH2:30]Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>CN(C)C=O.C(N(CC)CC)C>[C:1]([S:9][CH2:10][C@@H:11]([CH3:22])[C:12]([N:14]1[C@H:18]([C:19]([O:21][CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:17][S:16][CH2:15]1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)N1CSC[C@H]1C(=O)O
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1CSC[C@H]1C(=O)OCOC(=O)C(C)(C)C
Temperature: 90 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere, to the solution of 3.4 g of (4R)-3-[(2S)-S-benzoyl-3-mercapto-2-methylpropanoyl]-4-thiazoldinecarboxylic acid in 11 ml of dry N,N-dimethylformamide, 1.4 ml of triethylamine and 1.5 g of chloromethyl pivalate are added, and stirred at 90° C. for 6 hours. The reaction mixture is poured into 100 ml of ice-water, and extracted with ether. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 4.8 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 4.1 g (91%), mp. 69°-69.5° C. (benzene-n-hexane), [α]D25 -153.8° (c=1.0, methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].CI.[C:16](=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:16])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [Cs+]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 5-fluoro-2-nitro-phenol (369 mg, 2.35 mmol) in 5 mL THF, sodium hydride (96 mg, 2.46 mmol) was added at room temperature, followed by methyl iodide (0.88 ml, 14 mmol). The mixture was stirred at room temperature for 10 hours, and then cesium carbonate (744 mg, 2.35 mmol) was added. The mixture was stirred at room temperature for additional 4 hours, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give pure 4-fluoro-2-methoxy-1-nitro-benzene.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([C:16]([C:18]2[NH:19][C:20]3[C:25]([C:26]=2[NH:27][C:28](=[O:31])[CH2:29][CH3:30])=[CH:24][CH:23]=[C:22]([Cl:32])[CH:21]=3)=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([NH3+])CCC.C([NH3+])CCC.C([NH3+])CCC.C([NH3+])CCC.[F-].[F-].[F-]>C1COCC1.C(OCC)C>[Cl:32][C:22]1[CH:21]=[C:20]2[C:25]([C:26]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])=[C:18]([C:16]([C:11]3[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][N:12]=3)=[O:17])[NH:19]2)=[CH:24][CH:23]=1
Reactant: CCC(=O)Nc1c(C(=O)c2ncccc2CO[Si](C)(C)C(C)(C)C)[nH]c2cc(Cl)ccc12
Agent: CCCC[NH3+]
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(=O)Nc1c(C(=O)c2ncccc2CO)[nH]c2cc(Cl)ccc12
Reaction time: 4.5 h
Yield: 87.7 %

Procedure:
To a solution of 2-[(3-tert-butyldimethylsilyloxymethyl)pyridine-2-carbonyl]-6-chloro-3-(propionylamino)indole (step 5, 544 mg, 1.15 mmol) and acetic acid (0.20 ml, 3.50 mmol) in THF (30 ml) was added tetra(n-butylammonium)fluoride (1M in THF, 3.5 ml, 3.50 mmol) at 0° C. The mixture was stirred for 4.5 h at the same temperature and diluted with diethyl ether (200 ml). This solution was washed with saturated aqueous sodium bicarbonate (50 ml), water (50 ml×2), and dried (MgSO4). Removal of solvent gave a crystalline residue. Recrystallization from ethyl acetate afforded 361 mg (88%) of the title compound. m.p.: 198-199° C. IR (KBr) ν: 3250, 1663, 1624, 1607, 1578, 1541, 1472, 1352, 1211, 1178, 1153, 1074, 1045, 1013, 833, 808, 716 cm−1 1H-NMR (CDCl3) δ: 11.33 (1 H, br s), 10.74 (1 H, br s), 8.75 (1 H, dd, J=1.6, 4.8 Hz), 8.47 (1 H, d, J=9.1 Hz), 8.00 (1 H, dd, J=1.5, 7.7 Hz), 7.57 (1 H, dd, J=4.8, 7.7 Hz), 7.36 (1 H, d, J=1.8 Hz), 7.05 (1 H, dd, J=1.8 and 9.1 Hz), 4.87 (2 H, d, J=7.3 Hz), 4.00 (1 H, t, J=7.1 Hz), 2.62 (2 H, q, J=7.6 Hz), 1.36 (3 H, t, J=7.6 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][O:10][C:11](=[O:33])[C@H:12]([CH2:29][CH2:30][S:31][CH3:32])[NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18](N)=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH3-]C#[N:36].[Na+].C([O-])(O)=O.[Na+]>CO.C(O)(=O)C>[CH3:9][O:10][C:11](=[O:33])[C@H:12]([CH2:29][CH2:30][S:31][CH3:32])[NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[C:3]([CH2:7][NH2:36])=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [BH3-]C#N
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: O=Cc1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(-c2ncccc2CN)cc1-c1ccccc1

Procedure:
A mixture of 3-pyridinecarboxaldehyde (1.0 equivalent), 4-amino-2-phenylbenzoyl methionine methyl ester (1.0 equivalent) and NaCNBH3 (1.0 equivalent) in methanol/acetic acid is stirred until the reaction is judged complete by TLC analysis. The mixture is poured into aqueous NaHCO3 and extracted into ethyl acetate which is dried and evaporated. Chromatography of the residue on silica gel affords the title compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH:7]=C[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([N:19](CC)CC)C.[I-].[K+].ClCCCN1C(C)(C)C2C=CC=CC=2S1(=O)=O>CN(C=O)C>[N:11]1([C:6]2[C:5]3[C:10](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:9]=[N:19][CH:7]=2)[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: c1cc2c(c(N3CCNCC3)c1)CCCC2
Reactant: CCN(CC)CC
Agent: CC1(C)c2ccccc2S(=O)(=O)N1CCCCl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc2c(N3CCNCC3)cncc2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
1.1 g (5.2 mmol) of 1-(5-tetralinyl)piperazine, 1.5 ml of triethylamine and a trace of potassium iodide were added to a solution of 1.64 g (6.0 mmol) of 2-(3-chloroprop-1-yl)-3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide in 40 ml of DMF. The reaction mixture was stirred at 100° C. for four hours and then poured in ice-water, and the resulting precipitate was filtered off with suction. Purification took place by recrystallization from isopropanol to result in 1 g (43%) of the product (melting point 140° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[C:12]1([CH3:19])[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:19][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[O:18][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1OCc1ccccc1[N+](=O)[O-]

Procedure:
75 g (0.347 mol) of 2-nitrobenzyl bromide, 37 g (0.342 mol) of o-cresol and 56 g (0.405 mol) of potassium carbonate in 500 ml of dimethylformamide are stirred for 5 hours at room temperature. The reaction mixture is then diluted with water and the aqueous phase is extracted three times with ether. The ether phase is dried and evaporated down. The crystalline residue is stirred with methanol and filtered off under suction. 73 g (0.300 mol=88%) of the title compound are obtained as a colorless solid.
Reaction SMILES: O[CH:2]=[C:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[CH:9]=2)[C:4]1=O.Cl.[NH2:16][CH:17]([CH3:21])[CH2:18][NH:19][NH2:20].C([O-])(O)=O.[Na+]>C(O)C.CO>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]1[N:19]([CH2:18][CH:17]([NH2:16])[CH3:21])[N:20]=[CH:2][C:3]=1[CH2:11]2
Reactant: COc1ccc2c(c1)CC(=CO)C2=O
Reactant: CC(N)CNN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COc1ccc2c(c1)Cc1cnn(CC(C)N)c1-2
Yield: 19.7 %

Procedure:
To a solution of the product from Step A (1.9 g, 10 mmol) in ethanol (20 mL) was added a 1 N solution of HCl in a 1:1 mixture of methanol and ethanol followed by 2-aminopropylhydrazine (0.9 g, 10 mmol) and the solution was heated to reflux for 16 h. The solution was allowed to cool, poured into aqueous NaHCO3, extracted with ethyl acetate (2×20 mL), dried (Na2SO4) and concentrated. The crude material was taken up in 0.1 N HCl and washed with ether (2×20 mL), basified by the addition of NaHCO3 and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated to a residue, which was purified by chromatography (silica, 10% methanol in dichloromethane) to furnish an oil (0.48 g, 20%); MS m/z 244 [M+H]+.
Reaction SMILES: O.[NH:2]1[C:10](=[O:11])[C:8](=[O:9])[C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>C(O)C>[OH:9][C:8]1([C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]([CH3:12])[CH:14]=2)[C:6](=[O:7])[NH:5][C:3](=[O:4])[NH:2][C:10]1=[O:11]
Reactant: Cn1ccc2ccccc21
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Solvent: O
Solvent: CCO
Product: Cn1cc(C2(O)C(=O)NC(=O)NC2=O)c2ccccc21

Procedure:
Alloxan hydrate (1.6 g., 0.01 mole) 1-methylindole (1.3 g., 0.01 mole) and ethanol (50 ml.) was combined and the mixture refluxed for 0.5 hour, then concentrated to half-volume, diluted with water and the resulting product recovered by filtration [2.7 g., Rf 0.5 (1:1 ethyl acetate:hexane/5% acetic acid)].
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)=[CH:19][CH:18]=2)=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.ClC1C=C(CO)C=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:32][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([Cl:31])[CH:28]=1)[CH2:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:22][CH:21]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3cc(Cl)cc(Cl)c3)cc2)c2c1CCC2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: OCc1cc(Cl)cc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(SCc2ccc(OCc3cc(Cl)cc(Cl)c3)cc2)c2c1CCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Preparation of {7-[4(3,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (compound 77A) The product from Example 75C (0.42 g, 1 mmoles), (3,5-dichlorophenyl)-methanol (0.24 g, 1.3 mmoles), triphenyl phosphine (0.38 g, 1.5 mmoles) and 0.23 mL of diethyl azodicarboxylate (0.25 g, 1.5 mmoles) were dissolved in 9 mL of tetrahydrofuran. The reaction mixture was stirred at room temperature under nitrogen for 18 hrs. The reaction mixture was evaporated to give a residue, which was flash chromatographed (silica gel, 20% ethyl acetate in hexane) to afford the title compound in good purity. MS m/z 265 Step 2. Preparation of {7-[4-(3,5-Dichloro-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid (compound 77) The title compound was prepared in the manner analogous to Example 1 using 77A. mp 134-135° C.; IR (KBr) cm−1: 3070, 1747, 1708, 1572, 1432, 1244; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 7.51-7.53 (m, 1H), 7.42-7.45 (m, 2H), 7.07-7.13 (m, 2H), 7.04 (d, 1H, J=8.6 Hz), 6.83-6.90 (m, 2H), 6.56 (d, 1H, J=8.6 Hz), 5.05 (s, 2H), 4.61 (s, 2H), 3.93 (s, 2H), 2.75 (t, 2H, J=7.5 Hz), 2.66 (t, 2H, 7.5 Hz), 1.88 (pentet, 2H); MS m/z 487 (M−1). Anal. Calc'd for C25H22Cl2O4S: C, 61.35; H, 4.53; found: C, 61.01; H, 436.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[CH:7]1[C:12]([CH:13]=O)=[CH:11][C:10]2[O:15][CH2:16][O:17][C:9]=2[CH:8]=1>>[CH:4]1([C:2]([CH:1]=[CH:13][C:12]2[CH:7]=[CH:8][C:9]3[O:17][CH2:16][O:15][C:10]=3[CH:11]=2)=[O:3])[CH2:6][CH2:5]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)C1CC1
Product: O=C(C=Cc1ccc2c(c1)OCO2)C1CC1

Procedure:
2-(3,4-Methylenedioxyphenyl)vinyl cyclopropyl ketone [III; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 8.4 g. of cyclopropyl methyl ketone and 15 g. of piperonal according to the procedure described above in Preparation A1 affording 21.5 g., m.p. 85°-87° C. when crystallized from ethanol.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-:25])=[O:24])[CH2:9]2)[CH2:5][CH2:4]1)#N.[OH-].[Na+].[ClH:28]>C(O)(=O)C>[ClH:28].[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2([CH2:5][CH2:4][NH:3][CH2:8][CH2:7]2)[CH2:9]1)([O-:25])=[O:24]
Reactant: N#CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1N1CC2(CCNCC2)c2ccccc21

Procedure:
A slurry of 14.62 g of 1'-cyano-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine] of Example 37 in 100 ml of glacial acetic acid and 190 ml of 3 N aqueous hydrochloric acid is heated at reflux for 18 hours, the mixture becomes homogeneous at 70°-80° C. The mixture is made basic using aqueous sodium hydroxide and extracted with chloroform. The organic portions are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to give a solid comprising the free base of the product. The salt is prepared from the freshly alkali washed and dried free base using chloroform/ethereal hydrochloric acid, to yield the product mp. 222°-224° C. of 1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine]hydrochloride.
Reaction SMILES: C(O)(=O)C1C=CC(C(O)=[O:7])=CC=1.[C:13](OC)(=O)[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.COC(=O)C1C=CC(C=O)=CC=1.[OH2:39]>CC1C=CC(C)=CC=1>[C:14]1([CH3:13])[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1.[O:39]=[O:7]
Reactant: O
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: COC(=O)c1ccc(C=O)cc1
Solvent: Cc1ccc(C)cc1
Product: COC(=O)c1ccc(C)cc1
Product: O=O

Procedure:
In a process for the preparation of fiber-grade terephthalic acid from intermediate stage crude dimethyl terephthalate, the crude dimethyl terephthalate, which has a limited content of intermediate oxidation products including a content of terephthalaldehydic acid methyl ester of up to 0.1% by weight based on the weight of the crude dimethyl terephthalate, is hydrolyzed with water at a weight ratio of the crude dimethyl terephthalate to water of between 3:1 and 0.1:1 and at a temperature between 140° C. and 350° C. and under a pressure required to maintain a liquid phase (e.g., from 6 to 200 bars) to produce a reaction mixture containing crystalline fiber-grade terephtalic acid and thereafter the terephthalic acid is recovered from the reaction mixture. The initial crude dimethyl terephthalate used as a starting material is obtained from a crude ester mixture produced by the oxidation of p-xylene and/or methyl p-toluate with oxygen-containing gases in the presence of heavy metal-containing oxidation catalyst at an elevated temperature and under an elevated pressure and by esterification of the oxidation mixture with methanol at an elevated temperature and elevated pressure followed by separating the resulting crude ester mixture by distillation into a methyl p-toluate enriched fraction, a residual high-boiling fraction and the crude dimethyl terephthalate having the limited content of intermediate oxidation products.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH3:13][N:14]([CH:16]=O)[CH3:15].COS(OC)(=O)=O.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:13][N:14]([CH:16]=[C:3]1[C:4](=[O:12])[O:5][C:6]2=[CH:7][CH:8]=[CH:9][CH2:10][CH:11]2[C:2]1=[O:1])[CH3:15]
Reactant: O=c1cc(O)c2ccccc2o1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: COS(=O)(=O)OC
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C=C1C(=O)OC2=CC=CCC2C1=O
Yield: 44.5 %

Procedure:
This compound was prepared by the method of example 2, by stirring 4-hydroxycoumarin (5.0 g) and DMF-dimethylsulfate (10.0 g) with ethyldiisopropylamine (10 mL) in CH2Cl2 (100 mL) for 0.5 hour. Product was crystallized from ether-CH2Cl2 to obtain 3.01 g of tan crystals, mp 135°-140° with decomposition.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:16](B2OC(C)(C)C(C)(C)O2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[C:34]1[CH2:39][CH2:38][CH:37]([C:40]([F:43])([F:42])[F:41])[CH2:36][CH:35]=1)(=O)=O.C(OC(C1C(C2CCC(C(F)(F)F)CC=2)=C(C)SC=1C)C([O-])=O)(C)(C)C>>[C:1]([O:5][CH:6]([C:12]1[C:16]([C:34]2[CH2:39][CH2:38][CH:37]([C:40]([F:43])([F:42])[F:41])[CH2:36][CH:35]=2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(OC1=CCC(C(F)(F)F)CC1)C(F)(F)F
Agent: Cc1sc(C)c(C(OC(C)(C)C)C(=O)[O-])c1C1=CCC(C(F)(F)F)CC1
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1C1=CCC(C(F)(F)F)CC1

Procedure:
Using the procedure described in example 29, step 2, ethyl 2-(tert-butoxy)-2-[2,5-dimethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl]acetate (28f) (60 mg, 0,148 mmol) is converted, by reaction with 4-(trifluoromethyl)cyclohex-1-en-1-yl trifluoromethanesulfonate (41a) and after purification by preparative TLC (cyclohexane/ethyl acetate 90/10), to 2-(tert-butoxy)-2-{2,5-dimethyl-4-[4-(trifluoromethyl)cyclohex-1-en-1-yl]thiophen-3-yl}acetate (41b) (31 mg, 0.07 mmol, 50%).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]#[N:19])C1C=CC=CC=1>C(OCC)(=O)C.O1CCCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]#[N:19]
Reactant: N#C[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 6 h
Yield: 99.8 %

Procedure:
A solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonitrile (XIII) (1 gm, 0.00389 mol) in a mixture of ethyl acetate and tetrahydrofuran (THF) (4:6, 4 ml:6 ml) containing 10% palladium over carbon (0.300 gm, 50% wet) was hydrogenated at 50-55 psi, for 6 hours at 25° C. The resulting mixture was filtered through a celite pad and residue was washed with mixture of ethyl acetate and tetrahydrofuran (4:6, 4 ml:6 ml). The solvent from the combined filtrate was evaporated under reduced pressure to obtain 0.649 gm of the titled compound of Formula (XIIIa) as oil, which was used as such for the next reaction without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])=[CH:16][CH:17]=2)[C:12]([NH:26][C:27]([NH2:29])=[NH:28])=[N:11][CH:10]=1.Cl.NC(N)=N.[C:35](OC(=O)CNC(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)=O)([CH3:38])([CH3:37])[CH3:36].O>CS(C)=O>[C:35]([O:24][C:23](=[O:25])[CH2:22][NH:21][C:19]([C:15]1[CH:14]=[C:13]2[C:18]([C:9]([Cl:8])=[CH:10][N:11]=[C:12]2[NH:26][C:27]([NH2:29])=[NH:28])=[CH:17][CH:16]=1)=[O:20])([CH3:38])([CH3:37])[CH3:36]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NCC(=O)O)cc12
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: N=C(N)N
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CNC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]glycine trifluoroacetate ##STR60## NaH (34 mg, 60% dispersion in mineral oil, 0.85 mmol) was added to a stirred solution of guandine hydrochloride (80 mg, 0.84 mmol) in DMSO (2 mL) at 23° C. After 30 min, N-[(1,4-dichloro-7-isoquinolinyl)carbonyl]glycine t-butyl ester (120 mg, 0.34 mmol) was added and the resultant solution heated at 90° C. for 21 h. After cooling, the mixture was poured into water (30 mL), extracted with EtOAc, and then with CH2Cl2, and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography on silica gel using CH2Cl2 -MeOH-0.880NH3 (90:10:1) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]glycine t-butyl ester (25 mg, 0.07 mmol) as a yellow gum.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:6]([C:7]([OH:9])=[O:8])[N:5]2[C:10](=[O:22])[C@@H:11]([NH:12][C:13](=[O:21])[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@H:4]2[S@:3]1=O.ClC(Cl)(Cl)COP([O-])([O-])=O.N1C=CC=CC=1>O1CCOCC1>[CH3:1][C:2]1[CH2:24][S:3][C@@H:4]2[C@H:11]([NH:12][C:13](=[O:21])[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10](=[O:22])[N:5]2[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC1(C)C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2[S@]1=O
Agent: O=P([O-])([O-])OCC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 244.6 %

Procedure:
The polymer ester of (1S, 5R, 6R)-2,2-dimethyl-6-phenylacetamidopenam-3-carboxylic acid 1-oxide[45.60g, 0.05 mole, from example 29(a)] was refluxed for 24 hours in dioxan (500 ml.) with trichloroethylphosphate (1.15g, 5.0 m.mole) and pyridine (0.41 ml., 0.40g, 0.0051 mole) as in example 16 above to give the polymer ester of (6R, 7R)-3-methyl-7-phenylacetamidoceph-3-em-4-carboxylic acid (40.65g). The IR and NMR spectra were identical with the product obtained in example 8 above.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:13][C:9]1[N:8]=[C:7]([CH:2]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:3]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(Br)c1cccc(Br)n1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(c1cccc(Br)n1)N1CCOCC1

Procedure:
Methyl bromo(6-bromopyridin-2-yl)acetate (1.00 g, 3.24 mmol) was taken up in DMF (10 mL) and morpholine (367 μL, 4.21 mmol) and DIEA (848 μL, 4.86 mmol) were added. After maintaining the reaction at room temperature overnight, the reaction was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated. Silica gel chromatography (0-100% EtOAc/hexanes) afforded the title compound as a yellow oil.