Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[CH:14][N:13]=1>CO>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[CH:14][N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: CO
Product: O=[N+]([O-])c1cnc(Nc2ccc3c(c2)OCO3)c([N+](=O)[O-])c1

Procedure:
To a stirred solution of 12.0 g. (0.0875 mole) of 3,4-methylenedioxyaniline in 100 ml. of methanol, was added with stirring 8.0 g. (0.04 mole) of 2-chloro-3,5-dinitropyridine. Within one minute the mixture had crystallized. To complete the reaction, the mixture was heated on a steam bath for 15 minutes, then cooled and filtered to give 11.0 g. of product. A small amount recrystallized from methanol melted at 187°-188° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.CC1(C)COB([C:26]2[CH:27]=[C:28]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)[C:29]([O:31][CH3:32])=[O:30])OC1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(Cl)Cl>[CH3:17][CH:16]([S:13]([NH:12][C@@H:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][C:26]3[CH:27]=[C:28]([CH:33]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:35]=3)[C:29]([O:31][CH3:32])=[O:30])[CH:4]=2)[CH2:8]1)(=[O:15])=[O:14])[CH3:18]
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CCl)cc2C1
Reactant: COC(=O)c1cc(B2OCC(C)(C)CO2)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 31.8 %

Procedure:
To (S)-N-(5-(chloromethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.160 mmol, 46 mg) in THF (1 mL) was added methyl 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-(trifluoromethyl)benzoate (0.160 mmol, 50.5 mg), Bromo(N-succinimidyl)bis-(triphenylphosphine)palladium(II) (7.99 μmol, 6.46 mg) and sodium carbonate (1.000 mmol, 0.5 mL). The reaction was heated to 100° C. for 10 minutes by microwave irradiation before diluting with DCM and filtering through a hydrophobic frit. The solvent was removed in vacuo before redissolving in MeCN (500 μL) and purifying by reverse phase preparative chromatography to give (S)-methyl 3-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)benzoate (23.2 mg, 31.9%). MS (ESI): m/z [M+H]+ 456.0
Reaction SMILES: C([C:4]1[CH:5]=[N:6][C:7]2[N:8]([N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:16][CH:15]=2)[C:9]=1[OH:10])(O)=O.NC1C=CC=CC=1>>[OH:10][C:9]1[N:8]2[N:11]=[CH:12][C:13]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[CH:18][CH:19]=3)=[C:7]2[N:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(Cc2ccc(-c3cnn4c(O)c(C(=O)O)cnc34)cc2)c1
Solvent: Nc1ccccc1
Product: Cc1cccc(Cc2ccc(-c3cnn4c(O)ccnc34)cc2)c1
Temperature: 0 °C
Yield: 39.6 %

Procedure:
A mixture of 6-carboxy-7-hydroxy-3-[4-(3-methylphenylmethyl)phenyl]pyrazolo[1,5-a]pyrimidine (1.44 g) and aniline (10 ml) was heated at 100° C. to 110° C. with stirring, and reacted with each other for 1 hour. After completion of reaction, ice-water (100 ml) was poured into the mixture, and the precipitate was filtrated, washed with water and 30% methol, dried, and separated and purified by using a silica-gel column chromatography (chloroform:methanol=30:1) to give the title compound (0.50 g).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(OC([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][Cl:25])[CH2:19][CH2:18]1)=O)(C)(C)C.C(=O)([O-])O.[Cs+].Cl>CN1C(=O)CCC1.O1CCOCC1>[ClH:25].[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH2:24][C:23](=[O:26])[N:20]1[CH2:19][CH2:18][NH:17][CH2:22][CH2:21]1)=[O:5]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: COC(=O)/C=C/C(=O)OCC(=O)N1CCNCC1
Yield: 41.4 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (MHF) (1.00 g, 7.68 mmol) dissolved in NMP was reacted at ca. 55° C. with 1-(tert-butyloxycarbonyl)-4-chloroacetyl piperazine (2.42 g, 9.22 mmol) in the presence of CsHCO3 (1.78 g, 9.22 mmol). After work-up and removal of the solvent, the crude material was obtained as a white solid. The solid was reacted at room temperature with 15 mL of a 4 molar (4 M) solution of hydrogen chloride (HCl) in 1,4-dioxane. After removal of the solvents, the solid hydrochloride salt was further purified by mass-guided preparative HPLC to provide 0.93 g (41% yield) of the title compound (14) as a white solid after lyophilization of the solvents in the presence of an excess of aqueous 1 normal (1 N) hydrochloric acid. 1H NMR (D2O, 400 MHz): δ 6.93-6.86 (m, 2H), 4.92 (s, 2H), 3.70-3.63 (m, 7H), 3.23 (t, J=5.2 Hz, 2H), 3.17 (t, J=6 Hz, 2H). MS (ESI): m/z 257.13 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5]O)[CH:3]=[O:4].[C:8]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:10][CH2:11][CH3:12])=[O:9]>ClCCl>[CH3:7][C:2]([CH3:1])([CH2:3][OH:4])/[CH:5]=[CH:13]/[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C=O)CO
Solvent: ClCCl
Product: CCOC(=O)/C=C/C(C)(C)CO
Yield: 58.9 %

Procedure:
A solution of 2,2-dimethyl-3-hydroxypropanal (22 g, 0.22 mol) and (carboethoxymethylene)triphenylphosphorane (75 g, 0.22 mol) in dry dichloromethane (150 ml) was refluxed for 46 h. The solvent was then evaporated and the crude product was distilled at 15 Torr through a very short column. The distillate was separated into two fractions by redistillation through a 40-cm Widmer column. The first fraction gave 22.3 g (60%) of ethyl trans-4,4-dimethyl-5-hydroxypent-2-enoate, b.p. 133 136° C./15 Torr, nD23 1.4641. 1H NMR (CDCl3): (=1.10 [s, 6H, C(CH3)2], 1.25 (t, 3H, CH3CH2), 3.40 (s, 2H, CH2), 3.80 (br. s, 1H, OH), 4.15 (q, 2H, CH2CH3), 5.80 (d, 1H, J=16 Hz, 3-H). Anal. Calad. for C9H16O3: C, 62.76; H, 9.36. Found: C, 62.92; H 9.50.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[N:10]3[C:11](=[N:16][C:17]([CH3:18])=[C:9]3[C:8]1=[O:19])[CH:12]=[CH:13][CH:14]=2.C(N(CC)CC)C.[F:27][C:28]([F:35])([F:34])[CH2:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:18][C:17]1[N:16]=[C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[N:10]2[C:9]=1[C:8](=[O:19])[N:7]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:30]([CH2:29][C:28]([F:35])([F:34])[F:27])(=[O:32])=[O:31]
Reactant: Cc1nc2cccc3n(CCCCCN)c(=O)c1n23
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3n(CCCCCNS(=O)(=O)CC(F)(F)F)c(=O)c1n23
Yield: 65.4 %

Procedure:
To a solution of 1.630 g (6.31 mmol) of 1-[5-(amino)pentyl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 1.32 ml (9.47 mmol) of triethylamine in 30 ml of methylene chloride was added, while stirring under ice-cooling, 1.38 g (7.56 mmol) of 2,2,2-trifluoroethanesulfonylchloride. The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 1.669 g of the desired compound (65.4%, pale brown solid substance).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([O:6][CH:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][C:16]=2[CH3:31])[C:9]2[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:8]1=2)=[O:5].[C:38](=O)([O:48]C1C=CC([N+]([O-])=O)=CC=1)[O:39][CH2:40][CH:41]1[CH:45]([CH3:46])[O:44][C:43](=[O:47])[O:42]1.O>CN(C=O)C>[CH3:1][N:2]([CH2:3][C:4]([O:6][CH:7]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](=[O:32])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])=[CH:17][C:16]=2[CH3:31])[C:9]2[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:8]1=2)=[O:5])[C:38]([O:39][CH2:40][C:41]1[O:42][C:43](=[O:47])[O:44][C:45]=1[CH3:46])=[O:48]
Reactant: CC1OC(=O)OC1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNCC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CN(C)C(=O)OCc3oc(=O)oc3C)c3cc(Cl)ccc32)c(C)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl methylaminoacetate (0.34 g, 0.65 mmol), and (5-methyl-1,3-dioxolane-2-one-4-yl)-methyl 4-nitrophenyl carbonate (0.22 g, 0.74 mmol) were dissolved in DMF (5 ml), and the mixture was stirred at room temperature over night. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, an aqueous saturated sodium chloride solution, and then dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel chromatography (n-hexane:ethyl acetate) to obtain 0.44 g (43%) of {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl} [methyl-(5-methyl-2-oxo-1,3-dioxol-4-yl-methoxycarbonyl)-amino]acetate as amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([CH:18]=O)[N:15]=[N:14]1.[NH2:20]/[C:21](/[C:26]#[N:27])=[C:22](\[NH2:25])/[C:23]#[N:24]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([CH:18]=[N:20][C:21]([C:26]#[N:27])=[C:22]([NH2:25])[C:23]#[N:24])[N:15]=[N:14]1
Reactant: O=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1
Reactant: N#C/C(N)=C(/N)C#N
Solvent: CO
Product: N#CC(N)=C(C#N)N=Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1
Reaction time: 60 h

Procedure:
A mixture of this alcohol (1.7 g) and manganese dioxide (6.9 g) in chloroform (40 ml) was stirred at room temperature for 24 hours. This mixture was then filtered through Kieselguhr and the solvent evaporated to give crude material, which was purified by flash column chromatography (silica) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazole-4-carboxaldehyde, m.p 143°-144.5°. The aldehyde (2.32 g) and diaminomaleonitrile (0.85 g) were heated under reflux in methanol (40 ml) for 6 hours and then left to stand for 60 hours at room temperature. The solvent was evaporated and the residue was purified by column chromatography and recrystallisation from ethyl acetate/light petroleum (bp 60°-80°) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(2-amino-1,2-dicyanoethenylimino)methyl]-1H-1,2,3-triazole, m.p.184°-186°(dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[F:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH:33]=[O:34])=[C:21]([CH3:32])[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:23]2)=[CH:18][CH:17]=1>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([CH:33]([C:20]2[C:19]3[C:24](=[CH:25][C:16]([F:15])=[CH:17][CH:18]=3)[N:23]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:21]=2[CH3:32])[OH:34])[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:5]=1
Reactant: Clc1cc(Br)cc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1C=O
Solvent: C1CCOC1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1C(O)c1cc(Cl)cc(N2CCOCC2)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
An oven-dried conical flask was charged with 4-(3-bromo-5-chlorophenyl)-morpholine (0.384 g, 1.390 mmol) and 1.0 mL THF. While this solution was stirring at −78° C. under nitrogen, 2.5M butyllithium hexanes (0.556 mL, 1.390 mmol) was added via syringe. This solution was stirred at −78° C. for 30 minutes. After this time a solution of 7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline-4-carbaldehyde (0.074 g, 0.278 mmol) in 2.0 mL THF was added, and the reaction continued at −78° C. for 45 minutes. Upon completion, the reaction was quenched with satd aqueous ammonium chloride and concd. The resulting material was partitioned between EtOAc and water, and the organic phase was dried over magnesium sulfate and concd. The afforded crude product was purified by column chromatography (silica; 0-50% EtOAc in hexanes) to yield (3-chloro-5-(4-morpholinyl)phenyl)(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)methanol as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (1H, d), 8.35 (1H, m), 8.01 (1H, t), 7.83 (1H, s), 7.71 (1H, d), 7.51 (1H, m), 7.42 (1H, m), 6.97 (1H, s), 6.83 (1H, s), 6.64 (1H, d, J=4.5 Hz), 6.55 (1H, d), 6.51 (1H, s), 3.69 (4H, t, J=4.8 Hz), 3.08 (4H, d, J=3.9 Hz), 2.46 (3H, s). Mass Spectrum (ESI) m/e=464.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=3Br)[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.[CH:32](=[O:34])[CH3:33].C(=O)([O-])O.[Na+]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=3[CH:32]([OH:34])[CH3:33])[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC=O
Reactant: COc1cccc(CCN2CCC(Cc3cc(OC)ccc3Br)CC2)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(CCN2CCC(Cc3cc(OC)ccc3C(C)O)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of N-(2-(3-methoxyphenyl)ethyl)-4-(2-bromo-5-methoxybenzyl)piperidine (the compound of Example 64) (500 mg, 1.2 mmol) in tetrahydrofuran (5 ml) was cooled to −78° C., and n-butyllithium (a 1.57M hexane solution, 910 μl, 1.4 mmol) was added dropwise thereto. After the resulting solution was stirred at the same temperature for 30 minutes, acetaldehyde (135 μl, 2.4 mmol) was added dropwise thereto, and the reaction mixture was stirred at the same temperature for another 1 hour. A saturated aqueous sodium hydrogencarbonate solution was added thereto and the resulting mixture was slowly heated to room temperature. Then, the mixture was extracted with ethyl acetate and the combined extract layer was washed with a saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column chromatography (chloroform/methanol=30/1 to 10/1) to obtain the title compound (386 mg, 84%) as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH:10]([O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1)[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([O:8][C:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH:10]([O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[N:17]=1)[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(OCc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)nc(OC(C(=O)O)C(C)(OCc2ccccc2)c2ccccc2)n1
Reaction time: 12 h

Procedure:
1.4 g (3 mmol) of methyl 3-benzyloxy-3-phenyl-2-(4,6-dimethoxypyrimidin-2-yloxy)butyrate (Example 3) are dissolved in 20 ml of methanol and 20 ml of tetrahydrofuran, and 3.7 g of 10% strength NaOH solution are added. Stirring is carried out for 6 hours at 60° C. and for 12 hours at room temperature, the solvent is distilled off under reduced pressure and the residue is taken up in 100 ml of water. Extraction is now carried out with ethyl acetate to remove unconverted ester. The aqueous phase is then brought to pH 1-2 with dilute hydrochloric acid and is extracted with ethyl acetate. After drying has been carried out over magnesium sulfate and the solvent has been distilled off, a little acetone is added to the residue and the precipitate formed is filtered off with suction. After drying, 1.2 g of a white powder remain.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:23]([NH:24]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22](=[O:44])[N:13]3[C:14]=2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:1]1([CH2:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:23]([NH2:24])[C:22](=[O:44])[N:13]3[C:14]=2[C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1=C(CCc2ccccc2)CS[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)C1=C(CCc2ccccc2)CS[C@@H]2C(N)C(=O)N12
Reaction time: 1 h

Procedure:
The cephem (XX111) (77 mg) was dissolved in acetone (1 ml) and cooled to 0°C. p-Toluene sulphonic acid monohydrate (24 mg) was added and the mixture was stood at 0°C for 1 hour. The mixture was then allowed to attain room temperature and was stood at room temperature for 6 hours. The mixture was evaporated. The residue was suspended in ethyl acetate (20 ml) and shaken with saturated sodium bicarbonate solution (5 ml). The organic layer was separated and washed with brine. The dried (MgSO4) organic layer was evaporated to give t-butyl 3-β-phenylethyl-7-amino-3-cephem-4-carboxylate (XXV) contaminated with triphenylmethanol as a solid (61 mg). ##SPC6##
Reaction SMILES: [C:1]([N:3]1[CH2:8][C:7]2[C:9]3[C:18]([OH:19])=[CH:17][C:16]([CH:20]([CH3:28])[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][C:10]=3[O:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH2:5][CH2:4]1)#[N:2].Cl.[NH2:30][OH:31].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:13][C:12]1([CH3:14])[C:6]2[CH2:5][CH2:4][N:3]([C:1](=[N:30][OH:31])[NH2:2])[CH2:8][C:7]=2[C:9]2[C:18]([OH:19])=[CH:17][C:16]([CH:20]([CH3:28])[CH:21]([CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][C:10]=2[O:11]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(C#N)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(C(N)=NO)CC1
Yield: 51.4 %

Procedure:
A mixture of 0.5 g (1.31 mmole) of 2-cyano-5,5-dimethyl-8-(1,2-dimethylheptyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, 0.139 g (2.0 mmole) of hydroxylamine hydrochloride and 0.212 g (2.0 mmole) of sodium carbonate in 17 ml of dimethylformamide was heated on a steam bath for 1.5 hours. After cooling, the reaction mixture was partitioned between 50 ml each of chloroform and water. The organic layer was separated, washed with water, dried over Na2SO4 and filtered. After removal of the solvents on a rotary evaporator, the last traces of dimethylformamide were removed in vacuo. Crystallization from chloroform gave 280 mg (56%) of 5,5-dimethyl-8-(1,2-dimethylheptyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine-2-carboxamidoxime as colorless crystals. Recrystallization of the compound from chloroform gave poor recovery (17.5%) of the crystalline material, m.p. 142°-45° C. The assigned structure was confirmed by the ir, nmr and mass spectra (M+ at 415). Thin-layer chromatography (20% methanol/chloroform on silica gel) revealed two spots corresponding to the two stereoisomers.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:18])[C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11])=O)(C)(C)C.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:24][CH:25]=1.O>C(OCC)(=O)C>[C:20]1([CH3:19])[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[NH2:8][C@@H:9]([CH3:18])[C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](N)C(=O)OCC(C)(C)C
Temperature: 65 °C
Yield: 79 %

Procedure:
The conversion was carried out using a 22 L 3-neck open head flask equipped with a mechanical stirrer and an internal thermocouple. To a stirred solution of (S)-neopentyl 2-(tert-butoxycarbonylamino)propanoate (900 g, 3.47 mol) in 14 L of ethyl acetate was added PTSA.H2O (660 g, 3.47 mol, 98% reagent grade, Product No 161993, Aldrich) and heated at 65° C. for 10 h. The mixture was cooled to give white solid at room temperature and cooled at ice bath for 30 min prior to filtration. The mixture solution was filtered and dried in a vacuum oven (40° C., Welch Model 2034, ca. 10 mmHg) for 15 hr to yield 907 g (2.74 mol, 79%) of desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:31])[C@H:26]([C@@H:28]([CH3:30])[OH:29])[NH2:27])[CH3:23].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:22]([O:24][C:25](=[O:31])[CH:26]([NH:27][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH:28]([OH:29])[CH3:30])[CH3:23]
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C(NC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)C(C)O

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.736 g (10 mmol) of L-threonine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[C:5]([CH2:11][CH3:12])=[C:4]([I:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1.S(Cl)([Cl:28])=O>>[I:1][C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([I:10])[C:5]([CH2:11][CH3:12])=[C:4]([I:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([Cl:28])=[O:21])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=1
Reactant: CCc1c(I)c(CC)c(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I
Reactant: O=S(Cl)Cl
Product: CCc1c(I)c(CC)c(I)c(-c2ccc(C(=O)Cl)c([N+](=O)[O-])c2)c1I

Procedure:
2′,4′,6′-triiodo-3′,5′-bis(ethyl)-3-nitrobiphenyl-4-carboxylic acid (18) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3′,5′-bis(ethyl)-3-nitrobiphenyl-4-carbonyl chloride (19).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]#[N:17])[CH:12]=[CH:11][C:10]=1[N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1)(C)(C)C.[ClH:24].[CH2:25]([OH:27])[CH3:26]>>[ClH:24].[ClH:24].[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][C:16](=[NH:17])[O:27][CH2:25][CH3:26])[CH:12]=[CH:11][C:10]=1[N:18]1[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: CCO
Reactant: CC(C)(C)OC(=O)NCc1cc(NC#N)ccc1-n1cccn1
Agent: Cl
Product: CCOC(=N)Nc1ccc(-n2cccn2)c(CN)c1
Temperature: 25 °C
Reaction time: 29 h
Yield: 61 %

Procedure:
A mixture of the compound (243 mg) obtained in Example 4a and saturated HCl-ethanol (10 ml) was stirred at room temperature for 29 hours. The reaction mixture was concentrated at reduced pressure and the resulting residue was recrystallized from ethanol-ethyl acetate to give the titled compound (yield, 61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]([N:13]=[N+]=[N-])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]([NH2:13])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: [H][H]
Reactant: COc1cnc2c(c1)CCCC2N=[N+]=[N-]
Agent: [Pd]
Solvent: CO
Product: COc1cnc2c(c1)CCCC2N
Yield: 98.2 %

Procedure:
To a solution of (3-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)-azide (0.33 g, 1.6 mmol) in MeOH (16 mL) was added palladium on activated carbon, (10%, 50 mg) and the reaction mixture stirred under 1 atmosphere of hydrogen for 4 h. The mixture was filtered through celite, the cake washed with methanol and the solvent from the eluent removed in vacuo to give crude (3-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)-amine as a yellow oil (0.28 g, 96%). 1H NMR (CDCl3) δ 1.75 (m, 2H), 1.97 (m, 1H), 2.17 (m, 1H), 2.77 (m, 2H), 3.81 (s, 3H), 3.98 (t, 1H, J=4.5 Hz), 6.88 (d, 1H, J=1.5 Hz), 8.12 (d, 1H, J=1.5 Hz).