Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].O>ClCCl>[CH2:1]([N:8]([C@H:9]([CH3:12])[CH2:10][OH:11])[C:15](=[O:16])[CH2:14][Cl:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: C[C@H](CO)NCc1ccccc1
Solvent: ClCCl
Solvent: O
Product: C[C@H](CO)N(Cc1ccccc1)C(=O)CCl
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
(R)-2-(Benzylamino)propan-1-ol (16.58 g, 100 mmol) was dissolved in dichloromethane (125 mL) and TEA (18.1 mL, 130 mmol) before being cooled to −10° C. in a methanol/ice bath. Chloroacetic acid chloride (8.78 mL, 110 mmol) was added dropwise and the mixture was stirred for 1.5 h at −10° C. A small amount of water was then added to remove the amine. The reaction mixture was poured into a separatory funnel, washed 2×50 mL with dichloromethane, separated, organic layers dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1>>[CH:9]1([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1ccc(C)cc1
Reactant: C1=CCCCC1
Product: Cc1ccc(C)c(C2CCCCC2)c1
Temperature: 141 °C

Procedure:
p-Xylene (50 g, 0.47 moles), 2 g (0.024 moles) of cyclohexene and 1 g of Y-20 zeolite catalyst were placed in a 100 M1, 3-neck flask bottle with a stirrer and water condenser. The flask was purged with nitrogen and the reaction mixture heated until refluxing began at 126° C.. Cyclohexene was added in 2 g increments and the reflux temperature gradually increased to 141° C. A total of 12 g of cyclohexene was added during a total reaction time of 7 hours.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Nc1ncccc1OCc1ccc(F)cc1F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(F)c1

Procedure:
A mixture of 2-amino-3-(2,4-difluorobenzyloxy)pyridine (2.10 g, 0.009 mol), 4chlorophenyl isothiocyanate (1.81 g, 0.01 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield2.94 g (81%), m.p.154°-156 ° C.
Reaction SMILES: Cl[O-].[Na+].[CH3:4][O:5][C:6]1[C:7]([CH:20]=[N:21][OH:22])=[CH:8][C:9]2[C:10]([CH3:19])([CH3:18])[CH2:11][CH2:12][C:13]([CH3:17])([CH3:16])[C:14]=2[CH:15]=1.[C:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1)#[CH:24]>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([C:23]2[O:22][N:21]=[C:20]([C:7]3[C:6]([O:5][CH3:4])=[CH:15][C:14]4[C:13]([CH3:16])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:18])([CH3:19])[C:9]=4[CH:8]=3)[CH:24]=2)=[CH:26][CH:27]=1)#[N:30]
Reactant: C#Cc1ccc(C#N)cc1
Reactant: COc1cc2c(cc1C=NO)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [O-]Cl
Product: COc1cc2c(cc1-c1cc(-c3ccc(C#N)cc3)on1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.5 %

Procedure:
17.2 g of a 10% strength aqueous sodium hypochlorite solution were added dropwise at 10°-15° C. to a solution of 5.0 g (19 millimoles) of 5,6,7,8-tetrahydro-3-methoxy-5,5,8,8-tetramethyl-2-naphthaldoxime and 2.4 g (19 millimoles) of 4-ethynylbenzonitrile. The mixture was stirred for 1.5 hours at room temperature. Thereafter, the reaction mixture was poured onto water, the phases were separated and the aqueous phase was extracted again with methylene chloride The combined organic extracts were washed with sodium bisulfite solution, dried over sodium sulfate and evaporated down. The residue was digested in hot methanol, the mixture was allowed to cool and the crystals were filtered off under suction and dried to give 5.4 g of the title compound of melting point 202°-203° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[N:50]1(C(OC(C)(C)C)=O)[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:50]6[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCCNCC4)c3)c2C)c1
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) along with 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (48 μL, 0.00024 mol) and sodium triacetoxyborohydride (68 mg., 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The crude product was taken up in 1,2-dichloroethane (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on a Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a pale brown colored solid [40.6 mg (36%)]. LC-MS m/z 743.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11](=O)[N:10]([CH2:14][CH2:15][CH3:16])[N:9]=2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11](=[S:26])[N:10]([CH2:14][CH2:15][CH3:16])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCN1N=C(c2ccc(Cl)cc2)CC1=O
Solvent: Cc1ccccc1
Product: CCCN1N=C(c2ccc(Cl)cc2)CC1=S
Yield: 131.9 %

Procedure:
A mixture of 1.0 g (3.8 mmol) of 3-(4-chlorophenyl)-1-propyl-4, 5-dihydropyrazol-5-one, 1.2 g (3.0 mmol) of Lawesson's reagent, and 10 ml of toluene was heated under reflux for 2 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1 (v/v)) to give 1.0 g of the object compound as a yellow oil (yield 94%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].I[CH2:9][CH2:10][CH3:11]>>[CH2:9]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])[CH2:10][CH3:11]
Reactant: CCCI
Reactant: COC(=O)[C@@H](C)O
Product: CCCOC(C)C(=O)OC
Reaction time: 1 h
Yield: 71.7 %

Procedure:
160 g of methyl D-lactate and 524 g of 1-iodopropane were mixed in a four-necked flask, and 471 g of freshly prepared Ag2O was gradually added. Then, the mixture was stirred at 60°-65° C. for 1 hour and subjected to filtration. The filtrated product was washed with ether and the ether was distilled off from the filtrate, which was then distilled in vacuo to obtain 161 g of methyl 2-propoxypropionate.
Reaction SMILES: [F:1][C:2]1([Cl:9])[CH2:4][C:3]1([CH3:8])[C:5](O)=[O:6].S(Cl)([Cl:12])=O>>[F:1][C:2]1([Cl:9])[CH2:4][C:3]1([CH3:8])[C:5]([Cl:12])=[O:6]
Reactant: CC1(C(=O)O)CC1(F)Cl
Reactant: O=S(Cl)Cl
Product: CC1(C(=O)Cl)CC1(F)Cl
Yield: 95.7 %

Procedure:
In a distillation equipment, a mixture of 51 g (0.33 mol) of 2-fluoro-2-chloro-1-methylcyclopropanecarboxylic acid and 60 g (0.5 mol) of thionyl chloride is heated slowly with stirring, during which process excess thionyl chloride distils over first and the desired product later. In this manner, 54 g (97% of theory) of 2-fluoro-2-chloro-1-methylcyclopropanecarbonyl chloride are obtained in the form of a liquid of boiling point 82°-85° C./100 mbar.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([N:11]1[CH2:12][C@H:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])(=[O:17])=[O:16])[CH2:14][C@H:10]1[C:8](=[O:9])[NH:7][C:4]1([C:2]#[N:3])[CH2:6][CH2:5]1)=[O:27])[CH3:30]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
L44. (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was acylated with ethyl chloroformate in analogy to experiment L21 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-2-(1-cyano-cyclopropylcarbamoyl)-pyrrolidine-1-carboxylic acid ethyl ester as a colorless oil. MS: 426.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18]C)[CH:15]=[C:14]2[C:9]=1[CH2:10][CH:11]([CH3:28])[CH2:12][N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C([OH:47])C=2)CCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH:11]([CH3:28])[C:12](=[O:47])[N:13]2[C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Reactant: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)CC(C)C2
Product: CC1Cc2c(-c3ccccc3Cl)cc(O)cc2N(c2c(Cl)cccc2Cl)C1=O

Procedure:
The title compound was prepared from 43 mg of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-methoxy-3-methyl-3,4-dihydroquinolin-2(1H-one by a procedure analogous to that described in INTERMEDIATE 3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([OH:13])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([OH:13])[C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:6][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@H](O)[C@@H](N)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (2R,3S)-β-phenyl isoserine methyl ester (2) (Preparation 1, 2 mM) in pyridine containing a small amount of DMAP is cooled in an ice bath and treated with benzyl chloroformate (0.8 ml). After stirring at room temperature overnight, the reaction is diluted with ethyl acetate, washed with 5% aqueous sodium bisulfate, dried and evaporated. The product is obtained pure by silica gel chromatography in ethyl acetate-hexane mixtures. Mp 120-121° C. NMR(CDCl3, TMS): δ3.26 (m, 1H); 3.79 (s, 3H); 4.47 (m, 1H); 5.06 (m, 2H); 5.27 (d, 1H); 5.75 (m, 1H); 7.20-7.50 (m, 10 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:2].[CH2:23](Br)[CH:24]=[CH2:25]>>[CH2:1]([N:3]([CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:4][CH2:5][N:6]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:25][CH:24]=[CH2:23])[CH3:2]
Reactant: CCN(CCCCC(C)C)CCNc1ccc([N+](=O)[O-])cc1
Reactant: C=CCBr
Product: C=CCN(CCN(CC)CCCCC(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to Preparation 12 react N-Ethyl-N-(5-methylhexyl)-N'-(4-nitrophenyl)-1,2-ethanediamine with allyl bromide to provide the title compound.
Reaction SMILES: [CH2:1]([O:11][C:12]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH3:31]>>[CH2:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[CH2:24][NH:23][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[C:12]=1[O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH3:31]
Reactant: COc1cccc(C(=O)O)c1OC/C=C(\C)CCC=C(C)C
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1cccc(OC)c1OC/C=C(\C)CCC=C(C)C
Yield: 89 %

Procedure:
In a manner identical to Example 15, 2-geranyloxy-3-methoxybenzoic acid(1.52 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.84 g(89%) of the aimed compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH3:16][Mg]Br.[NH4+].[Cl-]>C1COCC1>[OH:1][C:2]1([CH3:16])[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:3]1
Reactant: O=C1CC(C(=O)OCc2ccccc2)C1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CC(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
A −78° C. solution of benzyl 3-oxocyclobutanecarboxylate (11.05 g, 54.1 mmol) in THF (155 mL) was treated drop-wise with methyl magnesium bromide (3M in Et2O, 27.1 mL, 81 mmol) and the mixture stirred at −78° C. for 30 min. Saturated NH4Cl was added, the mixture extracted with EtOAc (2×) and the combined organic extracts were dried, evaporated and purified via silica gel chromatography (acetone/Hex) to afford benzyl 3-hydroxy-3-methylcyclobutanecarboxylate (5.589 g, 47%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.36-7.29 (m, 5H); 5.08 (m, 3H); 2.75-2.66 (m, 1H); 2.13-2.12 (m, 4H); 1.21 (s, 3H); MS (ESI) m/z: 243.1 (M+Na+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=3[O:13][N:12]=2)[CH2:7][CH2:6]1.[C@@H:21]12[C:30](=O)[O:29][C:27](=[O:28])[C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26]2.[ClH:32]>N1C=CC=CC=1.C(O)C>[ClH:32].[F:20][C:18]1[CH:17]=[CH:16][C:15]2[C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][N:1]4[C:27](=[O:28])[C@H:22]5[C@H:21]([CH2:26][CH2:25][CH2:24][CH2:23]5)[C:30]4=[O:29])[CH2:6][CH2:7]3)=[N:12][O:13][C:14]=2[CH:19]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: NCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1[C@H]2CCCC[C@H]2C(=O)N1CCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-(3-aminopropyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.01 g, 10.8 mmol) and cis-1,2-cyclohexane-dicarboxylic anhydride (1.9 g, 12.3 mmol) in dry pyridine (30 ml) was heated at reflux for 16 hours. The dark brown solution was concentrated to dryness on a rotary evaporator. The crude residue was purified twice by flash chromatography over a silica gel column. The pure product thus obtained weighed 2.5 g (67%). This was converted to the hydrochloride salt by treatment with HCl in ethanol (50 ml). The cis-2-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-hexahydro-1H-isoindole-1,3-dione hydrochloride crystals so obtained weighed 3.0 g, m.p.=242°-245° C.
Reaction SMILES: Cl.[CH:2]1([O:7][C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3]1.[N:17]([O-])=O.[Na+].[F:21][B-:22]([F:25])([F:24])[F:23].[Na+]>O>[F:21][B-:22]([F:25])([F:24])[F:23].[CH:2]1([O:7][C:8]2[CH:9]=[C:10]([N+:11]#[N:17])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=N[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: COc1ccc([N+]#N)cc1OC1CCCC1
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
A stirred solution of concentrated hydrochloric acid (1.7 mL) in water (5 mL) from 0° C. and 5° C. is treated with 3-cyclopentyloxy-4-methoxyaniline (0.83 g), followed by a solution of sodium nitrite (0.29 g) in water (0.6 mL), at such a rate that the temperature remains from 0° C. and 5° C. The resulting solution is stirred for a further 10 minutes, while keeping the temperature below 5° C. The stirred solution, while still maintained at below 5° C., is then treated dropwise with a solution of sodium tetrafluoroborate (0.88 g) in water (1.8 mL). The resulting precipitate is filtered off, washed with cold water (3 mL) and dried in vacuo, to give 3-cyclopentyloxy-4-methoxyphenyldiazonium tetrafluoroborate (1.24 g) in the form of a gray solid, m.p. 120° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C@@H:12]2[CH2:16][O:15]C(C)(C)[O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(O)C.Cl>O1CCCC1>[Cl:1][C:2]1[N:3]([CH2:10][CH2:11][C@@H:12]([OH:13])[CH2:16][OH:15])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC1(C)OC[C@@H](CCn2cc([N+](=O)[O-])nc2Cl)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: O=[N+]([O-])c1cn(CC[C@@H](O)CO)c(Cl)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.3 %

Procedure:
While stirring a tetrahydrofuran solution (700 ml) of 2-chloro-1-[2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)ethyl]-4-nitro-1H-imidazole (196.2 g) at room temperature, 1.0 M hydrochloric acid ethanol solution (1,100 ml) was added thereto and stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, hexane was added to the residue obtained and concentrated under reduced pressure. Thereafter, ethyl acetate was added thereto and concentrated under reduced pressure. Isopropyl ether was added to the resulting solid and stirred for a while. The precipitated crystal was collected by filtration to afford the title compound as a colorless solid (166.5 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1([CH3:15])[O:14]CCO1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23]3=[C:24]([CH2:26][O:27][CH2:28][CH2:29][N:22]3[C@H:21]3[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH2:33][C@@H:20]23)[CH:25]=1>>[CH2:29]1[N:22]2[C:23]3[C:19]([C@@H:20]4[CH2:33][NH:32][CH2:31][CH2:30][C@@H:21]42)=[CH:18][C:17]([NH:16][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[C:10](=[O:14])[CH3:15])=[CH:25][C:24]=3[CH2:26][O:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Reactant: COc1ccc(Br)c(C2(C)OCCO2)c1
Product: COc1ccc(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c(C(C)=O)c1

Procedure:
Using 2-(2-bromo-5-methoxyphenyl)-2-methyl-1,3-dioxolane and following the procedures described in EXAMPLE 116, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 118. 1H NMR(CDCl3) δ: 9.95 (s, 1H), 7.22 (d, 1H, J=2.5 Hz), 6.99-6.92 (m, 2H), 6.86 (d, 1H, J=1.8 Hz), 6.75 (d, 1H, J=1.9 Hz), 4.58 (ABq, 2H, JAB=14.2 Hz), 4.20 (app d, 1H), 3.77 (s, 3H), 3.72 (app t, 1H), 3.42-3.37 (m, 1H), 3.35-3.20 (m, 2H), 3.10 (dd, 1H), 3.01-2.90 (m, 2H), 2.71 (app t, 1H), 2.59 (s, 3H), 2.50 (app t, 1H), 2.02-1.90 (m, 2H). LRMS (ES)+: 394.4 (M+H)+.
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:11]=[CH:12][C:13]([NH:15][NH2:16])=[O:14])([CH3:7])[CH3:6].C(=O)(O)[O-].[Na+].O>O1CCOCC1>[NH2:1][C:2]1[O:14][C:13](/[CH:12]=[CH:11]/[C:10]2[CH:9]=[C:8]([C:5]([CH3:4])([CH3:6])[CH3:7])[C:19]([OH:20])=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=2)=[N:15][N:16]=1
Reactant: CC(C)(C)c1cc(C=CC(=O)NN)cc(C(C)(C)C)c1O
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(/C=C/c2nnc(N)o2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
Cyanogen bromide (0.7 g, 0.0067 mole) is added to a solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamic acid, hydrazide (1.9 g, 0.0067 mole) and sodium bicarbonate (0.56 g, 0.0067 mole) in dioxane (10 ml)/water (10 ml). The resulting mixture is stirred two hours at room temperature. The solution is concentrated to half volume in vacuo and the residue diluted with water. The resulting solid is filtered and recrystallized from ethyl acetate/hexane to provide 1.1 g (2.1 g theor., 52%) of (E)-4-[2-(5-amino-1,3,4-oxadiazole-2-yl)ethenyl]-2,6-bis(1,1-dimethylethyl)phenol after drying in vacuo at room temperature, mp 221° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:7][C:6]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:5]=2[C:4](=O)[CH2:3]1.Cl>[Zn].C(O)(=O)C>[CH3:1][C:2]1([CH3:14])[O:7][C:6]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:5]=2[CH2:4][CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(O)cc2O1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CC1(C)CCc2ccc(O)cc2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.6 %

Procedure:
2,3-Dihydro-2,2-dimethyl-7-hydroxy-4H-benzo[b]pyran-4-one (9.98 g), amalgamated zinc dust (50.0 g), 5 N hydrochloric acid (400 ml) and glacial acetic acid (100 ml) were stirred and refluxed for 4 hours then stirred at room temperature for 18 hours. The reaction mixture was extracted with diethyl ether, washed with water, dried and evaporated in vacuo to afford a dark red oil which was distilled to give 2,3-dihydro-2,2-dimethyl-7-hydroxy-4H-benzo[b]pyran (4.22 g) as an orange oil, bp 138°-146° C. (0.02 mm).
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH2:9]1[CH2:14][CH2:13][CH:12]([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:11][CH2:10]1>C(#N)C>[C:16]([NH:15][CH:12]1[CH2:11][CH2:10][CH2:9][CH2:14][CH2:13]1)([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:1]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C1CCC(=O)N1O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
Ligand A (150 mg; 0.4 mmol), N-hydroxysuccinimide (60 mg; 0.522 mmol) and DCC (101 mg; 0.49 mmol) were stirred in 4 ml of acetonitrile at room temperature for 2 hours. Dicyclohexylurea formed was removed by filtration and rinsed with about I ml of acetonitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[CH2:10][S:11][C@@H:12]2[C@H:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C:31](=[O:42])[N:13]2[C:14]=1[C:15]([O:17]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:16].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[CH2:10][S:11][C@@H:12]2[CH:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C:31](=[O:42])[N:13]2[C:14]=1[C:15]([OH:17])=[O:16]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3cnccn3)CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(C=Cc3cnccn3)CS[C@H]12
Reaction time: 0.17 h
Yield: 87 %

Procedure:
To a solution of 147 mg of benzhydryl 3-(2-pyrazinylvinyl)-7β-(2-thienylacetamido)-3-cephem-4-carboxylate in 1.5 ml anisole at 0° was added 3 ml of cold trifluoroacetic acid. The solution was kept 10 minutes at 0° and then placed directly on a vacuum pump and evaporated. The residue was flushed with 1 ml anisole and reevaporated. The residue was triturated with 4 ml boiling ether and the ether was cooled and siphoned off. This procedure was repeated twice more. The remaining insoluble material weighed 116 mg yield 87% (calculated as mono--CF3COOH salt) and was characterized by n.m.r. and electrophoresis.