Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][N:17]([CH3:19])[CH3:18])=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:20])C.[OH-].[Li+].OS([O-])(=O)=O.[Na+]>O1CCOCC1.O>[Cl:20][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[C:12]([CH2:16][N:17]([CH3:18])[CH3:19])[CH:11]=2)[C:6]=1[CH2:5][C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)Cc1c(Cl)ccc2cc(CN(C)C)ccc12
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)Cc1ccc2c(CC(=O)O)c(Cl)ccc2c1
Temperature: 60 °C

Procedure:
(2-Chloro-6-dimethylaminomethyl-naphthalen-1-yl)-acetic acid ethyl ester (223 mg, 0.73 mmol) is dissolved in dioxane (2.6 ml). Water (0.96 ml) and lithium hydroxide (21 mg, 0.88 mmol) are then added, and the reaction mixture is warmed to 60° C. for 4 h. HPLC analysis indicates complete conversion of starting material. The reaction is diluted with water, adjusted to pH 6-7 by addition of 1 M aqueous NaHSO4, and extracted with EtOAc. The water layer is then concentrated, and the solid residue is repeatedly extracted with MeOH to yield pure title compound. ES+-MS: 278.3, 280.1 [M+H]+.
Reaction SMILES: O.CS[C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>>[CH2:16]([NH:19][C:4]1[NH:9][C:8]2[CH:10]=[CH:11][N:12]=[CH:13][C:7]=2[S:6](=[O:15])(=[O:14])[N:5]=1)[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: CSC1=NS(=O)(=O)c2cnccc2N1
Solvent: O
Product: C=CCNC1=NS(=O)(=O)c2cnccc2N1
Temperature: 120 °C

Procedure:
A mixture of 3-methylsulfanyl-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide monohydrate (0.5 g) and allylamine (4 mL) was heated in a sealed bumb for 4-5 h at 120° C. After cooling, the amine was removed by distillation under reduced pressure. The residue was dissolved in 0.5N NaOH, treated with charcoal, filtered, and the filtrate was adjusted to pH 6 with 1N HCl. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound as a dihydrate (yield: 0.44 g); m.p. 206°-208° C. (Compound 15).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](Cl)=[O:10])[CH2:5][CH2:4]1)#[N:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[N:28]=2)[CH:25]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:15][C:16]2[CH:37]=[CH:36][CH:35]=[C:18]([O:19][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]5[CH2:33][CH2:34]5)=[O:31])[N:28]=4)[CH:25]=3)[CH:17]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)nn5c4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (5.0 mL) was added N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.485 mmol), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100), and the obtained oil was triturated with ethyl acetate, toluene and diisopropyl ether to give the title compound (175 mg, 63%) as a colorless powder.
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([CH3:9])[C:5](OC)=[O:6].[C:10]([O:13][CH3:14])(=[O:12])[CH3:11].Cl>>[F:3][CH:4]([CH3:9])[C:5](=[O:6])[CH2:11][C:10]([O:13][CH3:14])=[O:12]
Reactant: COC(C)=O
Reactant: COC(=O)C(C)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CC(=O)C(C)F
Temperature: 32.5 °C
Yield: 92 %

Procedure:
To a liquid in which 1.31 g of a 62.8% sodium hydride had been suspended in 10 ml of tetrahydrofaran was added dropwise a mixed solution of 2.00 g of methyl 2-fluoropropionate and 2.10 g of methyl acetate over 10 minutes, and the mixture was then heated at 30 to 35° C. for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, neutralized with 1N-hydrochloric acid, and subjected to liquid separation. When the organic layer was quantitated by the gas chromatography internal standard method. As a result, it was found that 2.57 g of methyl 4-fluoro-3-oxopentanoate was formed (yield: 92%). When this organic layer was concentrated under reduced pressure and then distilled under reduced pressure, 2.03 g of methyl 4-fluoro-3-oxopentanoate could be obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:36])([F:35])[O:24][C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.CC(O)=O.CC(O)=O.[Pd]>[F:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:11]1[N:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]([F:22])([F:35])[F:36])=[CH:30][CH:29]=3)=[CH:3][CH:4]=2)=[CH:13][N:12]=1
Reactant: OB(O)Oc1ccc(OC(F)(F)F)cc1
Reactant: Fc1cccc(F)c1-c1ncc(-c2ccc(Br)cc2)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: O
Product: Fc1cccc(F)c1-c1ncc(-c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cn1

Procedure:
0.70 g of 5-(4-bromophenyl)-2-(2,6-difluorophenyl)-pyrimidine, 0.53 g of 4-trifluoromethoxyphenyl-boric acid and 0.07 g of palladium-II-acetate are heated under reflux for 1½ hours, under nitrogen, in a mixture of 20 ml of dimethoxyethane and 20 ml of saturated, aqueous potassium carbonate solution. The reaction mixture is then cooled, diluted with water and the crystalline precipitate filtered. After dissolving the precipitate in ethyl acetate, drying with magnesium sulfate, filtering and concentrating, the title compound is obtained in the form of light yellow crystals with a melting point of 215-216° C.
Reaction SMILES: C(N(CC)CC)C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:9].[CH2:22]([N:29]1[C@H:33]2[CH2:34][O:35][C:36](=O)[C@H:32]2[N:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:30]1=[O:45])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CN=C1>N1C=CC=CC=1C.O.C(OCC)(=O)C>[CH2:22]([N:29]1[C@H:33]2[CH2:34][S:9][C:36](=[O:35])[C@H:32]2[N:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:30]1=[O:45])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1OC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Triethylamine (300 ml) and phosphorus pentasulfide (41 g) are added to a solution of 10.0 g of cis-1,3-dibenzyl-hexahydrofuro[3,4-d]imidazole-2,4-dione ([α]D20 + 62° (C = 2 in CHCl3)) and imidazole (21 g) in 150 ml of α-picoline. The mixture is stirred at room temperature for 1 hour and refluxed at about 100° C for 48 hours. Ethyl acetate (300 ml) and Celite-535 (5 g) are added to the reaction mixture cooled in an ice water bath, followed by addition of water (150 ml) and a saturated solution of sodium chloride (100 ml) and filtration of the resulting mixture. The organic layer is washed with water and concentrated in vacuo. The resulting residue is dissolved in 200 ml of toluene, followed by the addition of 7 % hydrochloric acid (100 ml) and zinc powder (10 g). The mixture is stirred and warmed at 60° to 65° C for 2 hours. The reaction mixture is cooled to room temperature and filtered off. The toluene layer is washed with water and concentrated in vacuo. The residue is triturated with ether, and the precipitate is filtered to give cis-1,3-dibenzyl-hexahydrothieno[-3,4-d]imidazole-2,4-dione (8.9 g, 85 %). M.P. 124° to 126° C. [α]D20 + 86° (C = 2 in CHCl3).
Reaction SMILES: [NH2:1][NH2:2].[N+:3]([C:6]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[CH2:7][CH2:8][C:9](Cl)=[O:10])([O-:5])=[O:4]>CO>[N+:3]([C:6]([N+:15]([O-:17])=[O:16])([N+:12]([O-:14])=[O:13])[CH2:7][CH2:8][C:9]([NH:1][NH:2][C:9](=[O:10])[CH2:8][CH2:7][C:6]([N+:3]([O-:5])=[O:4])([N+:15]([O-:17])=[O:16])[N+:12]([O-:14])=[O:13])=[O:10])([O-:5])=[O:4]
Reactant: O=C(Cl)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Reactant: NN
Solvent: CO
Product: O=C(CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])NNC(=O)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]

Procedure:
Low temperatures also reduce side reactions with hydrazine as well as the reaction of the acid chloride with methanol Therefore the hydrazine solution and the 4,4,4-trinitrobutyryl chloride solution are mixed together at a temperature in the range of preferably about -40° C. to -100° C., more preferably from -60° C. to -90° C., and still more preferably from -70° C. to -85° C., with about -78° C. being most preferred. The resulting reaction solution is then put in ambient (room) temperature environment and allowed to warm up to a temperature in the range of from about -5° C. to about 25° C. The product N,N'-bis(4,4,4-trinitrobutyryl)hydrazine is then isolated using conventional techniques as illustrated in the example.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:23]([O-])=O)[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O.[H][H]>C(O)(=O)C.[Pd]>[NH2:23][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([NH2:1])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(OC)cc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)c(Oc2ccc(OC)cc2)c(N)c1
Yield: 31.8 %

Procedure:
To a Parr shaker bottle containing a suspension of methyl 3,5-dinitro-4-(4-methoxyphenoxy)-benzoate (20.2 g; 77.5 mmol) in glacial acetic acid (80 ml) was added 10% palladium on charcoal (0.7 g). The bottle was shaken under an atmosphere of hydrogen (3 atm) until no more hydrogen was consumed. The catalyst was filtered off and the resulting solution concentrated to approximately 10 ml. The residue was dissolved in acetone (50 ml) and heated on a steam bath while water (100 ml) was added in portions. Upon cooling, medium brown needles formed which were collected by suction filtration and dried to give 7.1 g (86%) of methyl 3,5-diamino-4-(4-methoxyphenoxy)benzoate. 300 MHz 1H NMR (CDCl3) d 3.73 (s, 3H, OCH3), 3.80 (bs, 4H, ArNH2) 3.86 (s, 3H, OCH3), 6.84 (m, 4H, ArH), 6.91 (s, 2H, ArH).
Reaction SMILES: Cl.N[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2.[N-]=[N+]=[N-].[Na+].C([O-])(=O)C.[Na+].[OH-].[Na+].[CH:24]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([SH:34])[C:28]=2[CH:27]=[CH:26][N:25]=1>C(OCC)(=O)C.O>[CH:8]1[C:9]2[C:4](=[C:3]([S:34][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:28]=3[CH:27]=[CH:26][N:25]=[CH:24]4)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1cccc2cnccc12
Reactant: Sc1cccc2cnccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: O
Product: c1cc(Sc2cccc3cnccc23)c2ccncc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.6 %

Procedure:
To an aqueous 4N hydrochloric acid solution 24 ml of 5-aminoisoquinoline 1.00 g (6.9 mmol), a water solution 2 ml of sodium azide 480 mg (6.9 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 30 minutes and neutralized with sodium acetate, and insoluble materials were filtered. The filtrate was added to a sodium hydroxide solution (300 mg/3 ml) of 5-isoquinolinethiol 1.23 g (7.6 mmol), and the mixture was stirred for 1.5 hours at 80° C. After adding ethyl acetate, the reaction solution was washed with 1N sodium hydroxide and saturated sodium chloride, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (ethyl acetate), and 5-(5-isoquinolylsulfanyl)isoquinoline 230 mg (11.5%) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:42][CH2:43][CH3:44])=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:43]([O:42][C:34]1[CH:33]=[CH:32][C:31]([NH:30][C:2]2[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])=[CH:15][C:14]=3[O:28][CH3:29])[N:3]=2)=[C:39]2[C:35]=1[CH2:36][N:37]([CH3:41])[C:38]2=[O:40])[CH3:44]
Reactant: CCOc1ccc(N)c2c1CN(C)C2=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOc1ccc(Nc2nc(Nc3ccc(CP(=O)(OCC)OCC)cc3OC)ncc2C(F)(F)F)c2c1CN(C)C2=O

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-4-ethoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 206A). MS (ES+): m/z 624.28 (100) [MH+]; HPLC: tR=1.16 min (UPLC, purity).
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:6][C:5](=[O:7])[CH2:4]1)#[N:2].[BH4-].[Li+].[Cl-].[NH4+].Cl>O1CCCC1.O>[C:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:9]=2)[CH2:6][CH:5]([OH:7])[CH2:4]1)#[N:2]
Reactant: COc1ccc(C2(C#N)CC(=O)C2)cc1OC1CCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2(C#N)CC(O)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.9 %

Procedure:
To a solution of 3-cyano-3-(3-cyclopentyloxy-4-methoxyphenyl)cyclobutan-1-one (8.63 g, 30.3 mmol) in tetrahydrofuran (200 mL) at -78° C. under an argon atmosphere was added over 75 min a slurry of lithium borohydride (1.98 g, 90.8 mmol) in tetrahydrofuran (200 mL). The reaction was stirred for 0.5 h, and was carefully poured into a 0° C. saturated solution of ammonium chloride. 10% Hydrochloric acid was used to adjust to pH 3-4, the mixture was warmed to room temperature, was diluted with water and was extracted with three portions of tert butyl methyl ether. The organic extract was dried (magnesium sulfate) and evaporated to provide crude product (8.96 g, 100%) as a pale green oil. 1H-NMR shows an isomer ratio of ~3:1 cis: trans.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[N:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>[Ni].C(O)(=O)C>[CH2:1]([C:5]1[O:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[N:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: [Ni]
Solvent: CC(=O)O
Product: CCCCc1nnc(-c2ccc(N)cc2)o1
Yield: 74 %

Procedure:
A mixture of 24.7 parts of 2-butyl-5-(p-nitrophenyl)-1,3,4-oxadiazole, 2.5 parts of an aqueous Raney nickel suspension and 250 parts of glacial acetic acid is hydrogenated at room temperature, while shaking. When the absorption of hydrogen is complete, 2.5 parts of active carbon are added, the mixture is filtered, the filtrate is poured into saturated aqueous sodium chloride solution, and the resulting precipitate is filtered off under suction, washed with water and dried. 16 parts (74% of theory) of 2-butyl-5-(p-aminophenyl)-1,3,4-oxadiazole of melting point 125° C. (toluene) are obtained.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]=[C:4]1[CH:18]1[CH2:23][CH2:22][N:21](C(OCCCC)=O)[CH2:20][CH2:19]1>C(Cl)Cl>[ClH:1].[ClH:1].[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[N:5]=[C:4]1[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: CCCCOC(=O)N1CCC(c2nc(-c3cccc(C(F)(F)F)c3)cn2C)CC1
Agent: Cl
Solvent: ClCCl
Product: Cn1cc(-c2cccc(C(F)(F)F)c2)nc1C1CCNCC1
Reaction time: 2 h
Yield: 103.5 %

Procedure:
Add hydrogen chloride (4 M in 1,4-dioxane, 5 mL, 20 mmol) to a solution of tert-5 butyl 4-(1-methyl-4-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (400 mg, 1.10 mmol) in CH2Cl2 (10 mL) at 0° C. under nitrogen and stir for 2 h. Concentrate the mixture in vacuo to provide 4-(1-methyl-4-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidine dihydrochloride (435 mg, >99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]([NH:18][CH:19]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH:36]([CH3:38])[CH3:37])[C:20]1=[O:39])=[O:17])[CH3:15]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]([NH:18][CH:19]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH:36]([CH3:38])[CH3:37])[C:20]2=[O:39])=[O:17])[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(C)N1C(=O)C(NC(=O)[C@H](C)N)N=C(c2ccccc2)c2ccccc21
Product: CC(C)N1C(=O)C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)N=C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure D above using 3,5-difluorophenylacetic acid (Oakwood Products, Inc.) and 3-(L-alaninyl)amino-2,3-dihydro-1-isopropyl-5-phenyl-1H-1,4-benzodiazepin-2-one (Example 8-L), the title compound was prepared as a solid (mp.=208-209° C.). The product was purified by slurrying in ether/hexanes (1:1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]([CH3:32])[CH3:31]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:29][CH:30]([CH3:32])[CH3:31])[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CC(C)CBr
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(OCC(C)C)c1OC
Temperature: 80 °C
Yield: 21.1 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.266 mmol) in acetonitrile was added potassium carbonate (110 mg, 0.798 mmol) and isobutyl bromide (146 mg, 1.064 mmol) and the resultant reaction mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (20 mg, 21%).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].C[Si]([N-][Si](C)(C)C)(C)C.[CH:20]([C@@H:23]1[CH2:24][CH2:25][C:26](=[O:34])[CH2:27][CH2:28][CH2:29][C:30](=[CH2:33])[CH:31]=[CH:32]1)([CH3:22])[CH3:21].C1(O[S:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)(=S)=O)C=CC=CC=1.[Cl-].[Na+]>O1CCCC1.C([Li])CCC.CCCCCC>[CH:20]([C@@H:23]1[CH2:24][CH2:25][C:26](=[O:34])[CH:27]([S:42][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:28][CH2:29][C:30](=[CH2:33])[CH:31]=[CH:32]1)([CH3:22])[CH3:21]
Reactant: O=S(=S)(Oc1ccccc1)c1ccccc1
Reactant: C=C1C=C[C@H](C(C)C)CCC(=O)CCC1
Agent: C=C1/C=C/[C@H](C(C)C)CCC(=O)C(Sc2ccccc2)CC1
Agent: C=C1/C=C/[C@H](C(C)C)CCC(=O)CCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1C=C[C@H](C(C)C)CCC(=O)C(Sc2ccccc2)CC1
Temperature: -70 °C

Procedure:
After dissolving 2.7 ml of hexamethyldisilazane (HMD) in 50 ml of dry tetrahydrofuran under argon gas stream, 7.3 ml of a 1.72N n-butyl lithium solution in n-hexane were added dropwise to prepare a lithium-bistrimethylsilylamide solution. After cooling the solution to -70° C., a solution of 2.0 g of the product of step 1, in 5 ml of dry tetrahydrofuran, was added dropwise under stirring and the resultant solution was agitated for 1 hour. The reaction mixture was added at once under agitation to a precooled (with ice) solution of 3.16 g of phenylthiobenzenesulfonate in 40 ml of dry tetrahydrofuran. After stirring the mixture for 10 minutes, 5 ml of a saturated sodium chloride aqueous solution were added to the reaction mixture, and this mixture was concentrated under reduced pressure. After adding 50 ml of water to the residue, the solution was extracted three times, each time with 50 ml of diethyl ether. The ether phases were combined, sequentially washed with water, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated to dryness to provide (4S,5E)-4-isopropyl-7-methylene-10-phenylthio-5-cyclodecen-1-one.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]([NH:8][C@@H:9]1[C:14](=[O:15])[CH2:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C@H:10]1[O:20][CH:21]([CH3:23])[CH3:22])(=[O:7])[CH3:6]>C1COCC1>[C:5]([NH:8][C@@H:9]1[C@@:14]([OH:15])([CH:1]=[CH2:2])[CH2:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C@H:10]1[O:20][CH:21]([CH3:23])[CH3:22])(=[O:7])[CH3:6]
Reactant: C=C[Mg]Br
Reactant: COC(=O)C1=C[C@@H](OC(C)C)[C@H](NC(C)=O)C(=O)C1
Solvent: C1CCOC1
Product: C=C[C@@]1(O)CC(C(=O)OC)=C[C@@H](OC(C)C)[C@@H]1NC(C)=O
Reaction time: 2 h

Procedure:
Vinylmagnesium bromide can be added to a −78° C. solution of Example 16A in THF. The reaction mixture can be stirred for 2 hours and quenched with saturated aqueous NH4Cl. The quenched reaction mixture can be extracted several times with dichloromethane. The combined dichloromethane layers can be dried (MgSO4), filtered and concentrated. The concentrate can be purified by column chromatography to afford the desired product.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]#[CH:17])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[NH2:43][CH:44]1[C:65](=[O:66])[N:46]2[C:47]([C:52]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=3)=[O:53])=[C:48]([OH:51])[CH2:49][S:50][C@H:45]12>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][C:16]#[CH:17])[C:10]([NH:43][CH:44]2[C:65](=[O:66])[N:46]3[C:47]([C:52]([O:54][CH2:55][C:56]4[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=4)=[O:53])=[C:48]([OH:51])[CH2:49][S:50][C@H:45]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Reactant: C#CCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12)c1csc(NC=O)n1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetic acid (syn isomer, 0.506 g.), N,N-dimethylformamide (0.161 g.), phosphoryl chloride (0.337 g.) and ethyl acetate (7.9 ml.) were treated in a similar manner to that of Example 15-(1) to give the activated acid solution. On the other hand, trimethylsilylacetamide (1.85 g.) and bis(trimethylsilyl)acetamide (1.60 g.) were added to a suspension of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (0.703 g.) in ethyl acetate (10 ml.) and stirred at room temperature for an hour. To the solution was added the activated acid solution obtained above at -10° C. all at once, and stirred at the same temperature for an hour. Water (20 ml.) and ethyl acetate (20 ml.) were added to the solution. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate (8 ml.) and an aqueous solution of sodium chloride (15 ml.), and dried over magnesium sulfate. After the solution was concentrated in vacuo, the residue was pulverized with diethyl ether and the precipitates were collected by filtration to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-propargyloxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 0.71 g.).