Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)CC)C.Cl.[OH:28][CH2:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[NH2:36].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:36][C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]1[CH2:29][OH:28])=[O:9]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reactant: N[C@@H]1CCCC[C@@H]1CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@@H]2CCCC[C@@H]2CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.6 %

Procedure:
5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200 mg, 0.716 mmol) was dissolved in dimethylformamide (3 ml) and triethylamine (300 μl, 2.14 mmol) was added followed by cis-2-hydroxymethyl-1-cyclohexylamine hydrochloride (125 mg, 0.755 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (151 mg, 0.788 mmol) and 1-hydroxybenzotriazole(106 mg, 0.785 mmol). The reaction was stirred at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (30 ml) and ethyl acetate (30 ml). The organic phase dried over Na2SO4, the solvent removed under reduced pressure, and the residue purified by column chromatography on silica gel using dichloromethane:methanol (95:5) as eluent to afford an oil which crystallized from n-pentane to give the title compound as a white solid (136 mg).
Reaction SMILES: Br.[NH2:2][C:3]1([C:14]([OH:16])=[O:15])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:13])[CH:9]=2)[CH2:4]1.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[NH2:2][C:3]1([C:14]([O:16][CH2:22][CH3:23])=[O:15])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:13])[CH:9]=2)[CH2:4]1
Reactant: CCO
Reactant: NC1(C(=O)O)CCc2cc(O)ccc2C1
Agent: Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(N)CCc2cc(O)ccc2C1
Reaction time: 24 h

Procedure:
2-Amino-6-hydroxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid hydrobromide (580 mg., 2.0 mM) was suspended in dry ethanol (15 ml.). Concentrated sulphuric acid (0.05 ml.) was added and the mixture was stirred under reflux. After 24 hr. reflux, more sulphuric acid (0.05 ml.) was added and the reflux was continued for 48 hr. The mixture was evaporated in vacuo. Ether (15 ml.) and ethyl acetate (20 ml.) were added to the residue, followed by water (10 ml.). The mixture was basified with dilute sodium bicarbonate solution, and then separated. The organic phase was washed successively with water (15 ml.) and saturated brine (15 ml.). The solution was dried (Na2SO4) and evaporated in vacuo, giving ethyl 2-amino-6-hydroxy-1,2,3,4-tetrahydronapthalene-2-carboxylate, Rf 0.54 [kieselgel 60, 5:1 v/v dichloromethane/methanol].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20][CH3:21])[C:3]=1[CH3:22].[NH2:23][C:24]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:35])[NH:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:34][C:31]1[CH:32]=[CH:33][C:24]([N:23]=[CH:11][C@@:10]([OH:17])([C:13]([F:16])([F:14])[F:15])[CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:22])[C:4]=2[O:20][CH3:21])[CH2:18][CH3:19])=[C:25]2[C:30]=1[NH:29][C:28](=[O:35])[CH:27]=[CH:26]2
Reactant: Nc1ccc(F)c2[nH]c(=O)ccc12
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(C)c1OC
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1ccc(F)c2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(C)c1OC

Procedure:
In the same way as in Example 130, 300 mg (0.93 mmol) of (2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 165 mg (0.93 mmol) of 5-amino-8-fluoroquinolin-2(1H)-one and 0.58 ml of titanium tert-butoxide are reacted to give 8-fluoro-5-{[(2R,4R)-4-(4-fluoro-2-methoxy-3-methylphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}quinolin-2(1H)-one. 280 mg of chromatographically purified imine (silica gel, hexane/ethyl acetate 0-75%) are cyclized in the same way as in Example 130 at −30° C. with 4.6 ml (4.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-100%) yields 230 mg of desired product.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][C@@H:13]([CH3:17])[C:14]#[C:15][CH3:16])[CH:3]=1.ClC(OCC)=O.[NH2:24][CH:25]1[CH:30]2[CH2:31][N:32]([CH3:34])[CH2:33][CH:26]1[CH2:27][N:28]([CH3:35])[CH2:29]2.[OH-].[Na+]>ClCCl.O.C(N(CC)CC)C>[CH3:34][N:32]1[CH2:33][CH:26]2[CH:25]([NH:24][C:6](=[O:8])[C:5]3[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=3[O:12][C@@H:13]([CH3:17])[C:14]#[C:15][CH3:16])[CH:30]([CH2:29][N:28]([CH3:35])[CH2:27]2)[CH2:31]1
Reactant: CC#C[C@H](C)Oc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN1CC2CN(C)CC(C1)C2N
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC#C[C@H](C)Oc1cc(N)c(Cl)cc1C(=O)NC1C2CN(C)CC1CN(C)C2
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
A solution of 546 mg of (S)-4-amino-5-chloro-2-[(1-methyl-2-butynyl)oxy]benzoic acid and 0.9 ml of triethylamine in 10 ml of dichloromethane was cooled with ice. followed by the addition thereto of 0.225 ml of ethyl chloroformate. The obtained mixture was stirred for 10 minutes, while the temperature was brought to room temperature. 400 mg of 9-amino-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane was added to the resulting mixture at room temperature. The obtained mixture was stirred for 30 minutes, followed by the addition thereto of 200 mg of 9-amino-3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane at room temperature. The obtained mixture was stirred for one hour, followed by the addition thereto of dichloromethane and water. The pH of the aqueous layer was adjusted to 10 or above with a 2.5N aqueous solution of sodium hydroxide. The organic phase was recovered, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The residue was purified by silica gel column chromatography (with 0 to 10 to 20% methanol/chloroform and then with chloroform/methanol/aqueous ammonia (75/25/1.5) to give 650 mg of the title compound.
Reaction SMILES: CCN(CC)CC.[CH2:8]1[CH:12]2[CH2:13][NH:14][CH2:15][CH:11]2[CH2:10][N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].Cl[C:24]1[N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:27]=[N:26][N:25]=1>O1CCOCC1>[C:29]1([N:28]2[C:24]([N:14]3[CH2:13][CH:12]4[CH2:8][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH:11]4[CH2:15]3)=[N:25][N:26]=[N:27]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC2CN(c3nnnn3-c3ccccc3)CC2C1
Temperature: 115 °C

Procedure:
Et3N (5 mL) was added into a solution of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1 g) and 5-chloro-1-phenyl-1H-tetrazole (1 g) in dioxane (50 mL). The mixture was heated to 115° C. for 24 hours. The reaction was quenched with water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phase was dried over MgSO4 and concentrated to give a residue which was purified by silica gel chromatography to give tert-butyl 5-(1-phenyl-1H-tetrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:26]=[CH:25][C:17]([C:18]([NH:20][CH:21]4[CH2:24][S:23][CH2:22]4)=[O:19])=[C:16]([N+:27]([O-])=O)[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>C(O)(C)C.C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:31])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:26]=[CH:25][C:17]([C:18]([NH:20][CH:21]4[CH2:22][S:23][CH2:24]4)=[O:19])=[C:16]([NH2:27])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NC1CSC1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CSC1
Temperature: 70 °C
Yield: 43.7 %

Procedure:
A suspension of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4H-isoxazol-3-yl]-2-nitro-N-(thietan-3-yl)benzamide (40 mg, 0.07 mmol) and iron powder (26 mg) in isopropanol (10 ml) and acetic acid (1 ml) was heated at 70° C. for 3 hours. Isopropanol was evaporated and the residue was treated with water (10 ml) and extracted with dichloromethane (25 ml). The combined organic layers were dried over sodium sulfate, concentrated, and purified by column chromatography (hexane/ethyl acetate as eluent) to give 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4H-isoxazol-3-yl]-2-amino-N-(thietan-3-yl)benzamide (15 mg). 1H-NMR (400 MHz, CDCl3): 7.49 (2H, d), 7.42 (1H, m), 7.34 (1H, d), 6.92-6.94 (2H, m), 6.48 (1H, d) 5.18-5.20 (1H, m), 4.03 (1H, d), 3.64 (1H, d), 3.31-3.41 (4H, m), 0.82 (3H, m) ppm.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:11]2[CH2:31][CH2:32][N:33]([CH:36]([CH3:38])[CH3:37])[C:34](=[O:35])[C:10]=12)C1C=CC=CC=1.OS(O)(=O)=O>C(O)(=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:12]2[N:11]3[CH2:31][CH2:32][N:33]([CH:36]([CH3:38])[CH3:37])[C:34]([OH:35])=[C:10]3[C:9]([OH:8])=[C:14]([OH:15])[N:13]=2)=[C:18]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH:19]=1
Reactant: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3ccc(F)cc3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)N1CCN2C(Cc3ccc(Cl)cc3-c3ccc(F)cc3)=NC(O)=C(O)C2=C1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80107.1 %

Procedure:
To a stirred solution of 9-benzyloxy-6-(5-chloro-4′-fluoro-biphenyl-2-ylmethyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (385) (30 mg, 0.056 mmol) in acetic acid (1 mL), concentrated H2SO4 (0.001 mL, 0.011 mmol) was added and the reaction mixture was stirred for 4 h at room temperature (monitored by LC-MS). From the reaction, volatiles was removed and the residue was quenched with ice cold water (5 mL). Aqueous saturated NaHCO3 was added to adjust the pH up to 8. The quenched mass was extracted with ethyl acetate (2×15 mL). The combined organic part was dried, concentrated and purified by preparative HPLC to get 6-(5-chloro-4′-fluoro-biphenyl-2-ylmethyl)-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-diol (386) (11.2 mg, 44.86 mmol) as an off-white solid.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:21](OC1C=CC=CC=1)=[O:22].[O:30]1[C:34]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31]1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:21]([N:37]4[CH2:38][CH2:39][C:34]5([O:30][CH2:31][CH2:32][CH2:33]5)[CH2:35][CH2:36]4)=[O:22])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: C1COC2(C1)CCNCC2
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)N3CCC4(CCCO4)CC3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine, phenyl chloroformate and 1-oxa-8-aza-spiro[4.5]decane, the title compound was prepared as light brown powder. MS: m/e=448(M+H+).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6]1[C:24]([O:25][CH3:26])=[CH:23][C:9]([C:10]([C:12]2[C:13](Cl)=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])=[O:11])=[C:8]([CH3:27])[CH:7]=1.O>C1(C)C=CC=CC=1>[CH3:4][O:5][C:6]1[C:24]([O:25][CH3:26])=[CH:23][C:9]([C:10]([C:12]2[C:13]([O:2][CH3:1])=[N:14][CH:15]=[CH:16][C:17]=2[C:18]([F:21])([F:20])[F:19])=[O:11])=[C:8]([CH3:27])[CH:7]=1
Reactant: COc1cc(C)c(C(=O)c2c(C(F)(F)F)ccnc2Cl)cc1OC
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(C(F)(F)F)ccnc2OC)cc1OC
Yield: 100.5 %

Procedure:
0.9 g (16 mmol) of sodium methoxide was added to a solution having 1.5 g (4.2 mmol) of 3-(4,5-dimethoxy-2-methylbenzoyl)-2-chloro-4-trifluoromethylpyridine synthesized in accordance with a process in Synthesis Example 1 dissolved in 20 ml of toluene, followed by stirring under reflux by heating for 4 hours. The mixture was cooled, and then 20 ml of water was added thereto to terminate the reaction, the aqueous solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and subjected to filtration by using a silica gel cake. The solvent was distilled off under reduced pressure to obtain 1.5 g (yield 99%) of 3-(4,5-dimethoxy-2-methylbenzoyl)-2-methoxy-4-trifluoromethylpyridine (compound No. 32; m.p. 125-127° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][OH:14])[CH:8]=2)=[CH:4][C:3]=1[F:17].CCN(CC)CC.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C=O)C>[Si:25]([O:14][CH2:13][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:15]=[CH:16][C:2]([NH2:1])=[C:3]([F:17])[CH:4]=2)[CH:12]=[CH:11][N:10]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: Nc1ccc(Oc2ccnc(CO)c2)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.2 %

Procedure:
A solution of (4-(4-amino-3-fluorophenoxy)pyridin-2-yl)methanol (750 mg, 3.2 mmol) and Et3N (821 mg, 8 mmol) in DMF (10 ml) at 0° C. was treated with tert-butyldimethylsilyl chloride (624 mg, 4.16 mmol). The resulting solution was stirred at RT for 4 hours. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to provide 4-(2-((tert-butyldimethylsilyloxy)methyl)pyridin-4-yloxy)-2-fluorobenzenamine (370 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J=5.6 Hz, 1H), 7.02 (s, 1H), 6.67-6.82 (m, 4H), 4.76 (s, 2H), 3.71 (s, 2H), 0.89 (s, 9H), 0.07 (s, 6H); MS (ESI) m/z: 349.2 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.[H-].[Na+]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:15]2[CH2:16][O:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCCCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 5 g of 5-phenyl-1-pentanol, 4.99 ml of epibromohydrin, 1.31 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 80 ml of anhydrous dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography, using a 1:6 by volume mixture of ethyl acetate and hexane as the eluent, to give 4.2 g of the title compound as a colorless oil having an Rf value of 0.49 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([CH2:19][O:20]S(C)(=O)=O)[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:18]=[C:17]([CH2:19][O:20][C:32]3[CH:33]=[CH:34][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:30][CH:31]=3)[O:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc(COS(C)(=O)=O)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2noc(COc3ccc(S(C)(=O)=O)cc3)n2)CC1
Temperature: 50 °C

Procedure:
A mixture of 4-(5-methanesulfonyloxymethyl-[1,2,4]oxadiazol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.33 mmol), 4-methanesulfonyl-phenol (86 mg, 0.5 mmol) and Cs2CO3 (0.33 g, 1 mmol) in acetonitrile (5 mL) was heated at 50° C. for 2 hours. After cooling, the solid was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was purified on silica gel (EtOAc-hexanes, 1:1) to afford the desired product. 1H NMR (CDCl3): δ 7.9 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=8.8 Hz), 5.34 (2H, s), 4.2˜4.05 (2H, m), 3.03 (3H, s), 3.04˜2.85 (3H, m), 2.05˜1.96 (2H, m), 1.8˜1.7 (2H, m), 1.45 (9H, s).
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:22][C:23]([O:25][CH3:26])=[O:24])=[CH:8][C:9]([N+:19]([O-])=O)=[C:10]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd]>[NH2:19][C:9]1[CH:8]=[C:7]([O:22][C:23]([O:25][CH3:26])=[O:24])[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][C:10]=1[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CCc1cc(C2CCCC2)c(OC(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CCOC(=O)CCc1cc(C2CCCC2)c(OC(=O)OC)cc1N
Reaction time: 6 h
Yield: 73.5 %

Procedure:
A flask containing ethyl 3-(5-cyclopentyl-4-methoxycarbonyloxy-2-nitro-phenyl)propanoate (258 mg, 0.71 mmol) and 10% Pd/C (26 mg) was evacuated and flushed with N2. Ethanol (3 mL) was added and the reaction stirred for 6 h under H2 atmosphere. The reaction was filtered and the solvent was removed under reduced pressure to provide ethyl 3-(2-amino-5-cyclopentyl-4-(methoxycarbonyloxy)phenyl)propanoate (175 mg, 74% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 6.83 (s, 1H), 6.33 (s, 1H), 4.94 (s, 2H), 4.06-4.01 (m, 2H), 3.79 (s, 3H), 2.88-2.79 (m, 1H), 2.68 (t, J=7.4 Hz, 2H), 2.55-2.50 (m, obscured by DMSO peak, 2H), 1.84-1.77 (m, 2H), 1.72-1.66 (m, 2H), 1.62-1.55 (m, 2H), 1.45-1.36 (m, 2H), 1.17 (td, J=7.1, 3.4 Hz, 3H).
Reaction SMILES: C([O+](CC)CC)C.[C:8]1([C:14]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]3[C@H:18]([CH2:19][N:20]([C:23](=O)[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])[CH2:21]3)[C:17](=[O:34])[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH3:41].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[NH:41]=[C:23]([N:20]1[CH2:19][C@H:18]2[C@H:22]([C:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:15][CH2:16][C:17]2=[O:34])[CH2:21]1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]
Reactant: N
Reactant: COc1ccccc1CC(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Agent: CC[O+](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccccc1CC(=N)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Temperature: -15 °C
Reaction time: 20 h

Procedure:
Triethyloxonium tetrafluoborate (4 g) is added to a solution of (3aR,7aR)-7,7-diphenyl-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolone (7.7 g) in anhydrous dichloromethane (13 cc). Stirring of the reaction mixture is continued for 20 hours at ambient temperature; the mixture is then cooled to -15° C. and a 5.4N ethanolic ammonia solution (2.6 cc) is then added. The temperature of the reaction mixture is allowed to rise to ambient temperature and stirring is continued for 5 hours and a half. The reaction mixture is treated with a 10% aqueous solution (20 cc) of potassium carbonate; the precipitate formed is drained and washed with dichloromethane (10 cc). The organic phases are combined, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (10 cc); the crystals obtained are drained, washed with acetonitrile (5 cc) and with isopropyl ether (10 cc) and dried. They are then chromatographed on a Pechiney CBT1 neutral alumina gel column (diameter 4.5 cm, height 28 cm), eluting with a mixture (200 cc) of 1,2-dichloroethane and methanol (98/2 by volume) and then with a mixture of 1,2-dichloroethane and methanol (90/10 by volume), collecting 25 cc fractions. Fractions 8 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from acetonitrile (10 cc); the crystals obtained are drained and dried. (3aR,7aR)-2-[1-imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenyl-4-perhydroisoindolone (1.6 g) melting at 190° C. is obtained; [α]20D =-254° (c=1, methanol).
Reaction SMILES: C(#N)C.[I-:4].[Na+].Br[CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[O:8]1.CC(OCC1CS[C@@H]2[C@H](NC(CC3SC=CC=3)=O)C(=O)N2C=1C(O)=O)=O>CS(C)=O>[I:4][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[O:8]1
Reactant: [I-]
Reactant: O=C1OC(Br)c2ccccc21
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: [Na+]
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C1OC(I)c2ccccc21
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
Iodophthalide was prepared immediately prior to use by mixing acetonitrile solutions of sodium iodide (1.5mmole) and bromophthalide (1.5mmole) and stirring for 3 minutes. This solution was filtered (to remove precipitated sodium bromide) into an ice cooled DMSO solution of cephalothin (1mmole), stirred 10 minutes and poured into ice water to precipitate the required ester. Yield of crude, neutral product after work up -- 90%. TLC and NMR indicate >90% ceph-3-em ester. δ (CDCl3 /trace DMSO) = 2.08 (d, 3H, --OCOCH3), 3.61 (broad s, 2H, C2--H), 3.88 (s, 2H, α-CH2), 4.6 - 5.4 (ABq + d, 3H, --CH2O-- + C6), 5.6 - 6.0 (m, 1H, C7) 6.9 - 7.4 (d, + t, 3H, thienyl aromatics), 7.5 - 8.2 (m, ca. 5H, phthalidyl aromatics and --OCHO--), 8.2 - 8.6 (2d, 1H, amide N-H). νmax (CHCl3) 3370, 2960, 1793, 1743, 1682, 1505, 1230, 982cm-1 ; λmax (EtOH) 275nm (ε, 7000)
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH3:19])=[CH:10][C:9]=1[CH2:20][OH:21].[Br:22]C(F)(F)C(F)(F)Br.O>C1COCC1>[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH3:19])=[C:10]([Br:22])[C:9]=1[CH2:20][OH:21]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: COc1cc(CO)c(OC)c2ccccc12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(Br)c(CO)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
n-Butyllithium (2.9 mL, 7.33 mmol, 2.5 M in hexanes) was added dropwise to a solution of 23a (400 mg, 1.83 mmol) in THF (25 mL) at −78° C. under argon. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. 1,2-dibromotetrafluoroethane (0.26 mL, 2.20 mmol) was added dropwise and the solution was stirred for 1 h. Water (10 mL) was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered and evaporated. Column chromatography of the crude product (35:65 EtOAc:hexanes) afforded 23d (273 mg, 50%, 63% based on recovered 23a, 84 mg) as a yellow solid; Rf=0.62 (35:65 EtOAc:hexanes); mp=115-117° C.; 1H NMR (CDCl3): δ 8.11 (m, 2H), 7.57 (m, 2H), 5.03 (s, 2H), 4.02 (s, 3H), 3.99 (s, 3H), 2.36 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14](O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.S(Cl)([Cl:23])=O>>[Cl:23][CH:14]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:2]([Cl:1])[CH:3]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(O)c1ccc(C2CCCCC2)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C(Cl)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 221.75 g. (0.747 mole) of ethyl 3-chloro-4-cyclohexylphenylglycolate prepared as described in U.S. Pat. No. 3,852,323 is stirred with 106.67 g. (0.895 mole) of thionyl chloride at room temperature for 24 hours and then heated to reflux for 6 hours. The cold reaction mixture is poured into 1125 ml. of ice-cold water with stirring. The mixture is extracted with 800 ml. of ether. The ethereal solution is washed with 450 ml. of cold saturated sodium hydrocarbonate solution followed by washing twice, each time with 250 ml. of cold water. The ethereal solution is dried over anhydrous sodium sulfate and filtered. The solvent is removed in vacuo to obtain ethyl α,3-dichloro-4-cyclohexylphenylacetate.