Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:40])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:23]3=[O:36])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=O.Cl.[NH2:42][OH:43].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CO>[OH:1][C:2]1[C:3]([CH3:40])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:38]=[CH:37][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([CH2:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[C:23]3=[O:36])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=[N:42][OH:43]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)C(=NO)CC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Reaction time: 48 h

Procedure:
A mixture of 0.5 g of t-butyl α-{5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3yl}acetate (prepared as described in Example 49), 0.25 g of hydroxylamine hydrochloride, 0.25 g of pyridine and 5 ml of methanol was allowed to stand t 25°-30° C. for 2 days. Ethyl acetate and an aqueous solution of potassium carbonate were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (eluted with a 9:1 by volume mixture of benzene and ethyl acetate) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([O:23][CH3:24])[CH:21]=3)[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][C@@H:14]([OH:28])[CH2:15]3)[N:10]=2)=[CH:7][CH:6]=[C:5]([O:29][CH3:30])[N:4]=1.[CH2:31]([S:33](O)(=[O:35])=[O:34])[CH3:32]>CC(C)CC(=O)C>[CH2:31]([S:33]([O:28][C@@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([C:17]3[C:22]([C:9]([C:8]4[C:3]([O:2][CH3:1])=[N:4][C:5]([O:29][CH3:30])=[CH:6][CH:7]=4)=[N:10]2)=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=3)[CH2:15]1)(=[O:35])=[O:34])[CH3:32]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](O)C[C@H]21
Reactant: CCS(=O)(=O)O
Solvent: CC(=O)CC(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](OS(=O)(=O)CC)C[C@H]21
Temperature: 50 °C
Yield: 96.9 %

Procedure:
(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a,10b-hexahydro-phenanthridin-2-ol (1.5 g; 3.64 mmol) is dissolved in 9 ml of 4-methyl-2-pentanone. The solution is heated up to 50° C. 312 μl (3.82 mmol) of ethansulfonic acid are added. After crystallisation 3 ml 4-methyl-2-pentanon is added and the suspension is stirred over night. The crystals are filtered off and dried to obtain 1.78 g (94%) of the title compound (m.p.: 216° C.).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH2:18][CH3:19])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([CH2:20][CH2:21][C:22]([OH:24])=O)[C:7]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][NH:27][CH3:28].C(N(CC)CC)C>CN(C=O)C>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH2:18][CH3:19])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([CH2:20][CH2:21][C:22]([N:27]([CH3:28])[CH3:26])=[O:24])[C:7]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCNc1nc(C)c2cc(CCC(=O)O)c(=O)n(C3CCCC3)c2n1
Reactant: CNC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNc1nc(C)c2cc(CCC(=O)N(C)C)c(=O)n(C3CCCC3)c2n1
Temperature: 50 °C
Yield: 54.8 %

Procedure:
3-(8-cyclopentyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)propanoic acid (94 mg, 0.27 mmole), dimethylamine (1.09 mmole, 0.55 ml of 2.0 M solution in THF), triethylamine (27.6 mg, 0.27 mmole), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU, 104 mg, 0.27 mmole) and DMF (3.0 ml) were added to a reaction vial equipped with a stir bar. The reaction mixture was heated at 50° C. for 26 h. The reaction was quenched with water (2 ml), and the volatiles were removed under reduced pressure to a residue. Ethyl acetate (70 ml) and water (30 ml) were added and shaken well. The organic layer was separated, washed with water (2×30 ml), brine (30 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure to a residue, which was purified using silica (100% petroleum ether to 100% ethyl acetate). The fractions were combined, and the volatiles were removed to a colorless oil as the title compound (55 mg, 54% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:17][C:18]([O:20][C:21](C)(C)[CH3:22])=[O:19])[N:15]=[CH:16][C:10]=2[CH2:9]1)=O)(C)(C)C.S(Cl)([Cl:27])=O>C(O)C>[ClH:27].[ClH:27].[N:14]1([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[CH:16]=[N:15]1
Reactant: CC(C)(C)OC(=O)Cn1ncc2c1CCN(C(=O)OC(C)(C)C)C2
Reactant: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)Cn1ncc2c1CCNC2
Product: Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 181.8 %

Procedure:
In 20 ml of ethanol was dissolved 1.01 g (3.00 mmol) of (t-butyl) 5-t-butoxycarbonyl-4,5,6,7-tetrahydropyrazolo[4,5-c]pyridin-1-acetate, and under ice-cooling, 0.39 g (3.30 mmol) of thionyl chloride was added to the solution and the resulting mixture was stirred at 80° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, the residue was washed with ethyl acetate and dried to obtain 0.90 g (3.00 mmol) of the title compound as pale yellowish powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:9](=[O:28])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][CH2:13][C:12](=[O:23])[N:11]3[CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:5]2=[CH:4][CH:3]=1.[Li+].[CH3:38][CH:39]([N-]C(C)C)[CH3:40].C(Br)C=C>C1COCC1>[CH2:40]([C@@H:13]1[C:12](=[O:23])[N:11]([CH2:24][CH:25]2[CH2:26][CH2:27]2)[C@:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:8]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:9]2=[O:28])[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH2:14]1)[CH:39]=[CH2:38]
Reactant: CC(C)[N-]C(C)C
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(c3ccc(Cl)cc31)[C@@H](c1cccc(Cl)c1)CCC(=O)N2CC1CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@]2(C(=O)N(COCC[Si](C)(C)C)c3cc(Cl)ccc32)N(CC2CC2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (rac) (2′S,3′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-1′-((2-(trimethylsilyl) ethoxy)methyl)spiro[indoline-3,2′-piperidine]-2,6′-dione (Example 62, Step I) (97 mg, 0.178 mmol) in THF (1 mL) at −78° C. under Ar was added freshly prepared LDA (1.0 M in THF) (178 μL, 0.178 mmol). The reaction color turned yellowish orange. The reaction was stirred at −78° C. for 30 min then distilled allyl bromide (15.39 μL, 0.178 mmol) was added. The reaction was stirred at −78° C. for 10 min then warmed to 0° C. The reaction was quenched with sat. NH4Cl and warmed to room temperature. The mixture was diluted with EtOAc and the layers were separated. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 25% EtOAc in hexanes) to give the title compound.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:22])[C@H:8]([CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:5])([CH3:4])[CH3:3].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCO.C([BH3-])#N.[Na+]>C(Cl)(Cl)Cl>[C:2]([O:6][C:7](=[O:22])[C@H:8]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])([CH3:5])([CH3:3])[CH3:4]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 6 h
Yield: 53.7 %

Procedure:
Nα-BOC-L-lysine t-butyl ester hydrochloride salt (3) (25.97 g, 76.64 mmol) was dissolved in CHCl3 (300 ml) and washed with saturated aqueous Na2CO3 solution (2×100 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. The resultant oil (the free amine) was combined with benzaldehyde (10.42 g, 98.13 mmol), EtOH (150 ml) and activated 3 Å molecular sieves (46.0 g). The mixture was stirred under N2 for 6 hours. Sodium cyanoborohydride (2.41 g, 38.4 mmol) was added, and the mixture was stirred overnight at room temperature. The brown mixture was filtered, and the filtrate was acidified to pH 2 with 1 N HCl (110 ml). The yellow solution was concentrated to dryness, dissolved in CHCl3, and washed with saturated Na2CO3 solution and water. The organic layer was separated, dried (MgSO4) and concentrated. Flash column chromatography (10% EtOH/CHCl3, Rf=0.30) afforded the Nε-benzyl-Nα-BOC-L-lysine t-butyl ester (4) (16.16 g, 54%) as a colorless oil. 1H NMR (CD3OD) δ 7.34-7.20 (m, 5H), 3.91 (dd, 1H, J=9.0, 5.1), 3.72 (s, 2H), 2.58 (t, 2H, J=7.2), 1.82-1.30 (m, 6H), 1.45 (s, 9H), 1.43 (s, 9H); 13C NMR (CDCl3) δ 171.9, 155.3, 140.1, 128.3, 128.1, 126.9, 81.6, 79.5, 53.9, 48.9, 32.7, 29.5, 28.3, 27.9, 22.9. HRMS m/z calcd. for C22H36N2O4 392.2675, found 392.2676. Anal. calcd. for C22H36N2O4: C 67.32, H 9.24, N 7.14. Found: C 67.40, H 9.28, N 7.16. [α]25D=6.9° (c =1.00, CHCl3).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21](C(O)=O)=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:37][N:38](C)[CH:39]=[O:40]>O1CCCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:39]([NH:38][C:37]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)=[O:40])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(O)cc2)CCN3CC(C)C)cc1
Reaction time: 1.5 h

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (2 g) was dissolved in tetrahydrofuran (25 ml), and to the solution were added thionyl chloride (0.5 ml) and N,N-dimethylformamide (catalytic amount) at room temperature under ice-cooling, and the mixture was stirred for 1.5 hours. The solvent was distilled off, the residue was dissolved in tetrahydrofuran (50 ml), and the solution was added dropwise to a solution of p-aminophenol (0.55 g) and triethylamine (2 ml) in tetrahydrofuran (25 ml) under ice-cooling. The mixture was stirred for 3 hours under nitrogen atmosphere at room temperature, and the solvent was distilled off. To the residue was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-(4-hydroxyphenyl)-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (2 g) as pale yellow crystals.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2.[CH3:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH3:18][N:19]([CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNCc1ccccc1
Reactant: O=c1ccc2cc(OCC(O)CCl)ccc2[nH]1
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)CC(O)COc1ccc2[nH]c(=O)ccc2c1
Reaction time: 5 h
Yield: 37.1 %

Procedure:
A solution of 6-(3-chloro-2-hydroxypropoxy)carbostyril (5.05 g) and N-methylbenzylamine (6.0 g) in dimethylformamide (50 ml) is heated with stirring at 50°-60° C. for 5 hours. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (solvent; methanol:chloroform=1:100-1:25) and recrystallized from ethanol to give 6-[3-(N-methyl-N-benzylamino)-2-hydroxypropoxy]carbostyril (2.5 g), as white powder, m.p. 129°-132° C.
Reaction SMILES: [Na].Br[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:13])[CH:11]=2)[C:6]([CH3:15])([CH3:14])[CH2:5][CH2:4]1.[CH:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]([CH3:15])([CH3:14])[CH2:5][CH2:4][CH:3]2[O:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC1(C)CCC(Br)c2cc(Br)ccc21
Reactant: OC1CCCCC1
Agent: [Na]
Product: CC1(C)CCC(OC2CCCCC2)c2cc(Br)ccc21
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To 9 g (89.9 mmol) of cyclohexanol was added 160 mg (7.0 mmol) of sodium metal and the mixture was stirred at 70° C. for 12 hours. After all of the sodium dissolved the reaction mixture was cooled to ambient temperature and then a solution of 1 g (3.2 mmol) of 4,6-dibromo-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (Compound I) in 1 ml of cyclohexanol was added. The mixture was heated at 120° C. for 4 hours and thereafter the excess solvent distilled off under reduced pressure. The product was dissolved in Et2O (75 ml), washed with water (5 ml) and brine (5 ml), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 5% EtOAc-hexane) yielded the title compound as a colorless oil.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)(C)(C)C.[CH3:31][CH2:32]N(CC)CC.C(Cl)(=O)C=C>C(Cl)Cl.Cl.O1CCOCC1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][O:24][C:18]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=1[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][N:8]1[C:6](=[O:5])[CH:31]=[CH2:32])[CH3:30]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CN1C(=O)OC(C)(C)C
Agent: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=CC(=O)N1Cc2ccccc2C1c1cc(Cl)ccc1OCC(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice-cooled solution of (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (2.16 g, 5.0 mmol, 1.0 eq.) in DCM (100 mL), 4M HCl in dioxane (25 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. To a solution of the residue and NEt3 (3.48 mL, 25 mmol, 5.0 eq.) in DCM (100 mL), acryloyl chloride (0.45 mL, 5.5 mmol, 1.1 eq.) was added. The resulting solution was stirred at r.t. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by flash master (column: 100 g, flow: 45 mL/min, Heptane+20% AcOEt to Heptane+70% AcOEt) to give the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:13])=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3]>C1(C)C=CC=CC=1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[OH:13][C:5]1[C:4](/[CH:1]=[CH:2]/[CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=1[C:10](=[O:12])[CH3:11]
Reactant: C=CCc1cccc(C(C)=O)c1O
Agent: Cl[Pd]Cl
Solvent: N#Cc1ccccc1
Solvent: Cc1ccccc1
Product: C/C=C/c1cccc(C(C)=O)c1O
Temperature: 120 °C

Procedure:
40 g (227 mmol) of 1-(3-allyl-2-hydroxyphenyl)ethanone are dissolved in 120 ml of toluene, and 2.17 g (5.6 mmol) of bis(benzonitrile)dichloropalladium(II) are added. The reaction mixture is heated at 120° C. ovemight. Cooling to room temperature is followed by filtration through kieselguhr, and the solvent is removed in vacuo. 20.9 g (95% of theory) of the title compound are obtained and are reacted without further purification in the next stage.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:22](Cl)(=[O:25])[CH2:23][CH3:24].CO>C1COCC1>[CH3:20][C:12]1([N:5]2[C:4](=[O:21])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22](=[O:25])[CH2:23][CH3:24])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CCC(=O)Cl
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Solvent: CO
Solvent: C1CCOC1
Product: CCC(=O)Nc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added propionyl chloride (0.07 g, 0.70 mmol). The mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.07 g (63%) of product as an off-white solid: mp 222–224° C.; 1H NMR (DMSO-d6) 11.03 (s, 1H), 9.63 (s, 1H), 8.51 (d, J=8.3 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.51 (d, J=7.3 Hz, 1H), 2.76–2.45 (m, 5H), 2.10–2.03 (m, 1H), 1.90 (s, 3H), 1.12 (t, J=7.5 Hz, 3H); 13C NMR (DMSO-d6) 172.70, 172.14, 172.03, 168.80, 167.37, 136.48, 135.94, 131.20, 125.59, 117.67, 116.21, 58.81, 29.71, 29.07, 28.53, 20.97, 14.74, 9.18; Anal. Calcd. For C17H17N3O5: C, 59.47; H, 4.99; N, 12.24 Found: C, 59.24; H, 5.06; N, 11.97.
Reaction SMILES: [NH2:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:6]([S:9][CH2:10][S:11][C:12]3[N:13]=[N:14][NH:15][CH:16]=3)[CH2:7][S:8][C@H:3]12.Cl.CC(C)=O.C(OCC)(=O)C>C(O)=O>[NH2:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([S:9][CH2:10][S:11][C:12]3[N:13]=[N:14][NH:15][CH:16]=3)[CH2:7][S:8][C@H:3]12
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCSc3c[nH]nn3)CS[C@H]12
Agent: Cl
Solvent: O=CO
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(SCSc3c[nH]nn3)CS[C@H]12
Reaction time: 2.5 h
Yield: 81.1 %

Procedure:
To a solution of diphenylmethyl 7β-amino-3-[(1H-1,2,3-triazol-4-yl)thiomethylthio]-3-cephem-4-carboxylate (9.9 g) in formic acid (39.6 ml) was added conc. hydrochloric acid (8.54 ml) at room temperature, and the mixture was stirred at the same temperature for 2.5 hours. The mixture was poured into a mixture of acetone (297 ml) and ethyl acetate (594 ml) under ice-cooling, and the resulting precipitate was collected by filtration. The precipitate was resolved in water, and adjusted to pH 4 with 28% ammonium hydroxide under ice-cooling. The precipitate was collected by filtration to give 7β-amino-3-[(1H-1,2,3-triazol-4-yl)thiomethylthio]-3-cephem-4-carboxylic acid (5.42 g).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:22])([C:12]([F:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[O-:11].CN([S+](N(C)C)N(C)C)C.O>C(#N)C>[F:9][C:10]([O:11][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([F:22])[C:12]([F:21])([C:13]([F:15])([F:14])[F:16])[C:17]([F:20])([F:19])[F:18]
Reactant: BrCc1ccccc1
Reactant: [O-]C(F)(F)C(F)(C(F)(F)F)C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: O
Solvent: CC#N
Product: FC(F)(F)C(F)(C(F)(F)F)C(F)(F)OCc1ccccc1
Reaction time: 2 h

Procedure:
Benzyl bromide, 10.62 g (0.0621 mol), was added dropwise to a solution of 27.5 g (0.069 mol) of tris(dimethylamino)sulfonium 1,1,2,3,3,3-hexafluoro-2-(trifluoromethyl)propoxide (prepared as in Example 7) in 50 mL of acetonitrile at 25°. The reaction mixture was stirred for 2 h and then poured into water. The aqueous mixture was extracted with ether, and the ether extracts were washed with water, dried (MgSO4), and distilled to give benzyl 1,1,2,3,3,3-hexafluoro-2-(trifluoromethyl)propyl ether as a colorless liquid: bp 86°-87° (36 mm); 19F NMR (CDCl3) δ-73.9 ppm (t, d, J=9, 6 Hz, 6F), -79.2 ppm (d, septet, J=9, 9 Hz, 2F), and -187.7 ppm (t, septet, J=9, 6 Hz, 1F). Anal. Calcd. for C11H7F9O: C, 40.50; H, 2.16. Found: C, 40.69; H, 2.29.