Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH:4]=[CH:3]1.[C:13](Cl)(=[O:17])[C:14]([Cl:16])=[O:15]>C(OCC)C>[C:11]([C:8]1[CH:9]=[C:10]2[C:5]([C:4]([C:13](=[O:17])[C:14]([Cl:16])=[O:15])=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1)#[N:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ccc2ccc(C#N)cc21
Solvent: CCOCC
Product: Cn1cc(C(=O)C(=O)Cl)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
1-methyl-1H-indole-6-carbonitrile (1.0 g, 6.4 mmole), a known compound, was dissolved in ethyl ether (Et2O) (25 mL), chilled in an ice bath and treated with oxalyl chloride (0.95 mL, 10.9 mmole, 1.7 equiv.). After removal of the ice bath, yellow solids soon precipitated. This mixture was stirred at room temperature overnight, the solids were then collected and washed with ethyl ether and dried under vacuum for 30 minutes to provide 1.53 g (96%) of (6-cyano-1-methyl-1H-indol-3-yl)oxo-acetyl chloride. This material (1.53 g, 6.2 mmole) along with 2-(1-methyl-1H-indol-3yl)-acetimidic acid isopropyl ester hydrochloride (1.66 g, 6.2 mmole, 1 equiv.) was suspended in CH2Cl2 (100 mL) and cooled in an ice bath. The mixture was treated with Et3N (3.5 mL, 24.8 mmole, 4 equiv.), stirred at 0° for 30 minutes, then at room temperature for an additional 3 hours. The reaction mixture was then diluted with CH2Cl2 (150 mL), washed with H2O (50 mL), and then 0.5N HCl (50 mL). The organic fractions were dried over MgSO4, filtered and evaporated to give a dark oil. The residue was taken up in toluene (30 mL), chilled in an ice bath, then treated with pTsOH(1.3 g, 6.8 mmole, 1.1 equiv.), then stirred at room temperature for 2 hours. The red solids which precipitated were collected, washed with a small volume of toluene, hexane, the H2O, then partitioned between 500 mL CH2Cl2 and 75 mL saturated NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated to provide 2 g of a red solid. The solid was washed with cold CH2Cl2, then recrystallized from acetone/hexane to give 938 mg of 1-methyl-3-[4-(1-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-1H-indole-6-carbonitrile.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH3:12][N:13]([CH3:21])[CH:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[C:10]2[C:9]([NH:20][CH:17]3[CH2:18][CH2:19][CH:14]([N:13]([CH3:21])[CH3:12])[CH2:15][CH2:16]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: CN(C)C1CCC(N)CC1
Reactant: Clc1ncnc2scc(Br)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCC(Nc2ncnc3scc(Br)c23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 50-mL round-bottom flask was charged with commercially available 5-bromo-4-chlorothieno[2,3-d]pyrimidine (300 mg, 1.20 mmol, 1.00 equiv), 1-N,1-N-dimethylcyclohexane-1,4-diamine (205 mg, 1.44 mmol, 1.20 equiv), potassium carbonate (497 mg, 3.60 mmol, 3.00 equiv) in N,N-dimethylformamide (10 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 250 mg (59%) of 4-N-[5-bromothieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:22]=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[C:23]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])=[C:12]([NH:11][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1NC(=O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
0.055 mL of triethylamine and 0.036 mL of 4-fluorobenzoyl chloride were added to 3.5 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-(2,4-difluorophenyl)benzoate at room temperature sequentially and stirred at the same temperature for 1 hour. 0.014 mL of triethylamine and 0.012 mL of 4-fluorobenzoyl chloride were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane: ethyl acetate=4:1] to obtain tert-butyl 4-(2,4-difluorophenyl)-2-(4-fluorobenzamido)benzoate.
Reaction SMILES: [CH2:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20]>>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:21][CH2:18][CH2:19][CH3:20])=[O:15])=[CH:16][CH:17]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCN
Reactant: O=C(O)c1ccc(CCc2ccccc2)cc1
Product: CCCNC(=O)c1ccc(CCc2ccccc2)cc1

Procedure:
Using preparation method 1, 76C (226 mg, 1 mmol) was reacted with n-propylamine (90 μL, 65 mg, 1.1 mmol). No purification was necessary. White crystals were obtained (103 mg, 39%). NMR 1H (ppm, CDCl3): 7.65 (d, J3=8.1 Hz, 2H), 7.28-7.12 (m, 7H), 6.05 (br. s, 1H), 3.44-3.38 (m, 2H), 3.01-2.92 (m, 4H), 1.63 (sext., J3=7.3 Hz, 2H), 0.98 (t, J3=7.4 Hz, 3H).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]5[C:29](O)=[O:30])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CC[N:34]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]5[C:29]([NH2:34])=[O:30])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCCCC3C(=O)O)cc1OCC2
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCCCC3C(N)=O)cc1OCC2
Reaction time: 18 h
Yield: 7 %

Procedure:
A mixture of 1-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-2-carboxylic acid (1.15 g, 2.73 mmol), EDCI (0.58 g, 3.0 mmol), HOBt (0.41 g, 3.0 mmol) and DIPEA (2.34 mL, 13.65 mmol) in DMF was stirred at RT (2 mL) for 5 min before ammonium chloride (0.44 g, 8.18 mmol) was added and the reaction mixture stirred for 18 h. The reaction mixture was concentrated in vacuo and the resultant residue triturated with water before being subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 459 as a white solid (0.08 g, 6%). LCMS: RT=3.48 min, [M+H]+=422. 1H NMR 400 MHz (DMSO-d6) δ: 8.18 (1H, d, J=9.06 Hz), 7.89 (1H, d, J=0.63 Hz), 7.80 (1H, s), 7.31 (1H, br, s), 7.01 (1H, br, s), 6.72 (1H, dd, J=9.16, 2.60 Hz), 6.40 (1H, d, J=2.54 Hz), 5.92-5.91 (1H, m), 4.44-4.43 (4H, m), 4.39 (1H, m), 3.60 (1H, d, J=12.44 Hz), 3.39-3.32 (1H, m), 2.06 (1H, d, J=13.57 Hz), 1.75 (2H, m), 1.58 (3H, m), 1.48 (6H, dd, J=6.60, 2.59 Hz)
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1/[CH:11]=[CH:10]/[C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:24])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(/C=C/c2c(-c3ccccc3)noc2C)nc1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ccc(C(=O)NC2CCOCC2)cn1
Yield: 77 %

Procedure:
As described in example 2, 6-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (200 mg, 0.62 mmol) instead of 6-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester, and 4-aminotetrahydropyran instead of isopropylamine, was converted to the title compound (188 mg, 77%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol 100:0 to 95:5). MS: m/e=390.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2=[CH:11][C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=[C:9]2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4.[H-].[Na+].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:40]=[C:39]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:43][CH:42]=3)[N:38]=[C:37](Cl)[N:36]=2)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O.C1COCC1>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:40]=[C:39]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:45][CH:46]=3)[N:38]=[C:37]([N:13]3[C:12]4[CH:11]=[C:10]5[C:2]([CH3:22])([CH3:1])[C:3]6[C:8]([C:9]5=[CH:21][C:20]=4[C:19]4[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:7][CH:6]=[CH:5][CH:4]=6)[N:36]=2)=[CH:33][CH:34]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1ccc(-c2nc(Cl)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccccc13
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-n3c4ccccc4c4cc5c(cc43)C(C)(C)c3ccccc3-5)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.5 g (44 mmol) of 12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]-fluorene are dissolved in 200 ml of dimethylformamide under a protective-gas atmosphere, and 2.1 g of 60% NaH in mineral oil (52.7 mmol) are added. After 1 h at room temperature, a solution of 2,4-bis(4-tert-butylphenyl)-6-chloro-1,3,5-triazine (20 g, 52.7 mmol) in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum. Yield: 17 g, 60%. The purity is 99.9%.
Reaction SMILES: ClCCl.C(=O)(O)[O-].[Na+].[NH:9]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10]1.Cl[C:16]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17]>O>[OH:14][C@H:11]1[CH2:12][CH2:13][N:9]([C:16]([O:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])[CH2:10]1
Reactant: O[C@H]1CCNC1
Reactant: CC(C)(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)COC(=O)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of dichloromethane (5 mL) and water (5 mL) was added sodium bicarbonate (0.96 g, 11 mmol), followed by (3S)-pyrrolidin-3-ol (1.00 g, 11.5 mmol). Neopentyl chloroformate (1.71 mL, 11.5 mmol) was then added dropwise, and the resulting suspension was stirred at room temperature for 1.5 hours. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 4.50 (br s, 1H), 3.81-3.77 (m, 2H), 3.59-3.41 (m, 4H), 2.07-1.96 (m, 2H), 1.75-1.72 (m, 1H), 0.97 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([O:22]CC)=O.[CH:25]1([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([CH2:31][NH:32][C:20]([C:3]2[C:4](=[O:19])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[N:10][CH:9]=[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=3)=[O:22])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Reactant: NCC1CCCCC1
Product: O=C(NCC1CCCCC1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2 dihydro-1,5-naphthyridine-3-carboxylate and cyclohexylmethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.80 (1H, br), 8.32 (1H, br s), 7.39 (1H, s), 7.35-7.22 (5H, m), 4.05 (2H, br s), 3.17 (2H, t, J=6 Hz), 1.71-0.79 (11H, m); HRMS calcd for C23H25N3O3+H+: 392.1974. Found: 392.1956.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH:15]([CH2:17][CH3:18])[CH3:16])[CH:11]=[CH:10][C:9]=1[OH:19].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C)C=O>[CH:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]([O:19][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=2)=[C:8]([Cl:7])[CH:13]=1)([CH2:17][CH3:18])[CH3:16]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCC(C)Oc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCc2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
A mixture of 0.30 g of potassium carbonate, 0.40 g of 2-chloro-4-sec-butoxyphenol, 0.32 g of p-chlorobenzyl chloride and 15 ml of N,N-dimethylformamide was stirred at room temperature overnight. The reaction mixture was poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.51 g of 1-sec-butoxy-3-chloro-4-(4-chlorobenzyloxy)benzene. Yield, 78%. nD20.6 1.5630.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([N:26]1[C:27]2[C:23](=[C:22]([CH3:21])[CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:25]1)=[O:18]
Reactant: Cc1cccc2c1CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)n1C
Yield: 25.3 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 339 mg of 4-methylindoline hydrochloride and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 240 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 93 mg of 3-methyl-2-[2-(4-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: CO.CC(OC[C:8]1[CH2:17][S:16][C@@H:11]2[C@H:12](N)[C:13](=[O:14])N2[C:9]=1C(O)=O)=O.CC(OCC1CS[C@@H]2[C@H](NC(CC3SC=CC=3)=O)C(=O)N2C=1C(O)=O)=[O:23]>O1CCOCC1>[S:16]1[CH:17]=[CH:8][CH:9]=[C:11]1[CH2:12][C:13]([OH:14])=[O:23]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)Cc1cccs1

Procedure:
A solution of 15 mM of 7 ACA and 400 mM of thienylactic acid in 50% dioxane/50% acetate 50 mM is prepared at a ph 6. The column is thermostatized at 25° C., the flow and volume of the derivative are the same as in example 1. The moveable phase that we use for HPLC is 30% methanol/70% phosphate, 0.067M at a pH of 4.7, the rest of the conditions are maintained like those in example 1. After attaining the balance, the degree of conversion of 7-ACA into cephalothin is above 95%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(OO)(=[O:27])C>CO>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([S:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:27])[CH:8]=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC(=O)OO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)Nc1cc(S(=O)c2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
3.5 G. of 2-acetamido-4-phenylthio-1-nitrobenzene is dissolved in 35 ml. chloroform and treated at -25° C to -20° C with 2.5 g. 40% peracetic acid in 5 ml. methanol. The reaction mixture is allowed to warm slowly to 20°-25° C where it is held for four hours, then washed with sodium bisulfate solution and then with sodium bicarbonate solution. Evaporation of the solvent leaves 2-acetamido-4-phenylsulfinyl-1-nitrobenzene as a gum. This is treated with 20 ml. methanol and 10 ml. 5N aqueous sodium hydroxide at 20°-25° C for one hour. The mixture is diluted with water and the crude product filtered off. Recrystallization from benzene yields pure 2-amino-1-nitro-4-phenylsulfinylbenzene. 2.7 G. of 2-amino-1-nitro-4-phenylsulfinylbenzene is hydrogenated in 270 ml. methanol in the presence of 2.7 g. 5% palladized charcoal at one atmosphere pressure, until the theoretical uptake of hydrogen has occurred. The catalyst is removed by filtration and the filtrate concentrated to dryness. The residue is triturated with hot benzene, affording pure 1,2-diamino-4-phenylsulfinylbenzene.
Reaction SMILES: ClC(OCC)=O.[C:7]([C@@H:10]1[N:13]([C:14](=[O:16])[CH3:15])[C:12](=[O:17])[C@H:11]1[CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[N:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])([OH:9])=O.C(N(CC)CC)C.Cl.[CH2:53]([O:60][C:61](=[O:64])[CH2:62][NH2:63])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C(Cl)Cl>[O:64]=[C:61]([O:60][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH2:62][NH:63][C:7]([C@@H:10]1[N:13]([C:14](=[O:16])[CH3:15])[C:12](=[O:17])[C@H:11]1[CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:34][C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])=[N:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:9]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 47.4 %

Procedure:
To a -10° C. methylene chloride (2 mL) solution of ethyl chloroformate (57 mg, 0.53 mmol) was added a methylene chloride (2 mL) solution of compound 29 (220 mg, 0.44 mmol) and triethylamine (530 mg, 0.13 mmol). The resultant solution was stirred between -5° C. and 5° C. for 1 h. Glycine benzyl ester hydrochloride (0.11 g, 0.64) was added, followed by triethylamine (0.53 g, 0.13 mmol). The resulting suspension was stirred at room temperature for 21 h and filtered through a sintered glass funnel. The solid was washed with methylene chloride. The filtrate and the washing portion were combined and washed with 1N HCl, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography (Et2O:EtOAc/9:1) to afford 140 mg (47%) of the title product.
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][C@@H:9]1[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1>[Pd].CC(O)=O.[H][H]>[CH2:27]([O:26][CH2:25][C@H:9]1[CH2:10][N:11]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C@H:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:13][NH:8]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)C[C@@H]1CN(Cc2ccccc2)[C@@H](COCc2ccccc2)CN1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)C[C@@H]1CN[C@@H](COCc2ccccc2)CN1C(=O)OC(C)(C)C
Yield: 89.4 %

Procedure:
10% Palladium on carbon (0.8 g) was added to a solution of (2R,5R)-1-benzyl-2-benzyloxymethyl-4-(tert-butoxycarbonyl)-5-(2-methylpropyl)piperazine (8.1 g) in AcOH (80 ml), and the mixture was hydrogenated in hydrogen at 3 atm for 4 hours at ambient temperature. The catalyst was removed by filtration through a celite pad and the filtrate was washed with AcOH. The filtrate and combined washings were concentrated in vacuo, and the residue was partitioned by dissolving same in saturated aqueous NaHCO3 solution and AcOEt. The organic layer was washed with NaCl solution, dried over MgSO4, and concentrated in vacuo to give 5.8 g of (2R,5R)-2-benzyloxymethyl-4-(tert-butoxycarbonyl)-5-(2-methylpropyl)piperazine as an oil.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:19][C@H:20]1[O:22][CH2:21]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:19]([O:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C@H:20]1[O:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: COC(=O)c1cc2c(O)cccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(OC[C@@H]3CO3)cccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution (60 ml) of methyl 4-hydroxybenzo(b)furan-2-carboxylate (3.6 g) in DMF were added (S)-glycidyl nosylate (5.1 g) and potassium carbonate (6.5 g) and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (4.1 g) as a yellow crystalline compound.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31](=[O:39])[NH:32][S:33]([CH:36]4[CH2:38][CH2:37]4)(=[O:35])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][C:17]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.C1COCC1>CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31](=[O:39])[NH:32][S:33]([CH:36]4[CH2:37][CH2:38]4)(=[O:35])=[O:34])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][C:17]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)NS(=O)(=O)C4CC4)cc3n2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 60 °C
Yield: 94.4 %

Procedure:
Methyl 13-cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylate (1.0 g, 1.8 mmol) was dissolved into MeOH//THF (1:1, 24 mL) and treated with 1M aqueous NaOH (5 mL). The reaction mixture was stirred and heated at 60° C. for 1.5 h and cooled to rt. The clear solution was neutralized with 1M aqueous HCl (5 mL) and concentrated to remove organic solvents. The resultant solids were collected by filtration, washed with H2O and dried under vacuum to yield 13-cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (1.0 g, 1.7 mmol, 94%) as a bright yellow solid (with 0.75 equiv. of THF) which was used without further purification. 1HNMR (300 MHz, CD3OD) δ 1.11-2.24 (m, 17H, 3H from THF), 2.81-2.96 (m, 1H), 3.17-3.28 (m, 1H), 3.69-3.79 (m, 3H, from THF), 3.94 (s, 3H), 4.07-4.33 (m, 1H), 5.55-5.81 (m, 1H), 7.14-7.24 (m, 2H), 7.55-7.64 (m, 2H), 7.88-7.94 (m, 2H), 8.20 (br s, 1H). LCMS: m/e 535 (M+H)+, ret time 3.73 min, column B, 4 minute gradient.