Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.O>CN1C(=O)CCC1>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-fluoro-2-nitroaniline (1 g), 1-methylpiperazine (0.752 mL) and TEA (1.86 mL) in NMP (1.5 mL) was heated at 100° C. in a microwave oven for 20 h. After cooling down, H2O (50 mL) was added, the resulting suspension was stirred for 20 min and filtrated off. The yellow solid was washed with water and dried under high vacuo (1.45 g). LC-MS (B): tR=0.47 min; [M+H]+: 237.19.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=O.[H-].[Na+].CCOP(Cl)(OCC)=O.[CH2:25]([C:27]1[O:31][N:30]=[C:29]([CH2:32][N+:33]#[C-:34])[N:28]=1)[CH3:26]>CN(C=O)C>[CH2:25]([C:27]1[O:31][N:30]=[C:29]([C:32]2[N:33]=[CH:34][N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:11](=[O:12])[N:2]([CH3:1])[C:3]=23)[N:28]=1)[CH3:26]
Reactant: [C-]#[N+]Cc1noc(CC)n1
Reactant: Cn1c(=O)[nH]c2ccccc2c1=O
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(-c2ncn3c4ccccc4c(=O)n(C)c23)no1

Procedure:
3-methyl-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline (5 mmol) was dissolved in dry dimethyl formamide DMF (20 ml) and charged with sodium hydride (6 mmol). The resulting solution was cooled under N2 to -20° C., whereafter chlorodiethylphosphate (6 mmol) was added. The reaction mixture was kept under N2 with stirring and was allowed to reach room temperature and was then charged with a -30° C. cold solution of 5-ethyl-3-isocyanomethyl-1,2,4-oxadiazole(6 mmol) and K-t-butylate (6 mmol) in dry DMF (15 ml). The resulting mixture was stirred at room temperature for one hour whereafter the reaction mixture was evaporated in vacuo. The residue was partitioned between ethyl acetate and 4M sodium hydroxide. The organic phase was dried and evaporated. Yield 120 mg of title compound. M.p. 199.4°-202.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Cl)ccc1CBr
Yield: 67.4 %

Procedure:
303 g of 4-chloro-2-methoxytoluene are dissolved in 1665 ml of carbon tetrachloride and, together with 355 g of N-bromosuccinimide, heated at reflux for 2 h while 4.0 g of AIBN are added. The solid is filtered off and wasted with a small amount of carbon tetrachloride, the filtrate is concentrated, and the residue which remains is fractionated. 307 g of colorless oil are obtained (b.p. 103° C./1.5 mbar, m.p. 42-45° C.).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH:11]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:10]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:35][N:36](C)C=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:35]#[N:36])[CH:8]=3)[CH2:13][CH2:12][CH:11]2[NH:17][C:18](=[O:19])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1Cc1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(C)OC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
DPPF (8.1 mg, 0.015 mmol) and Pd2dba3 (3.35 mg, 0.00365 mmol) were suspended in dimethylformamide (0.4 mL) and after stirring at room temperature under an inert atmosphere of nitrogen for 20 min 7-[(tert-butoxycarbonyl)amino]-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (38 mg, 0.073 mmol) and zinc cyanide (12.87 mg, 0.110 mmol) were added. The reaction mixture was stirred at 90° C. for 1 h. The solvent was evaporated in vacuo. Water (10 mL) was added to the crude product and the aqueous layer was extracted with ethyl acetate (two times with 10 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane, silica gel). Yield: 16 mg (0.040 mmol, 55%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][OH:13].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: OCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCCSc1ccc(F)cc1
Temperature: 80 °C
Yield: 51.7 %

Procedure:
4-Fluorobenzenethiol (788 mg, 6.15 mmol) and 3-bromopropanol (0.535 ml, 6.16 mmol) was dissolved in tetrahydrofuran (20 ml). The solution was added with 1N aqueous solution of sodium hydroxide (6.2 ml, 6.2 mmol) and heated at 80° C. for 3 hours with stirring. The reaction mixture was diluted with a mixed solvent of ethyl acetate-hexane and washed with diluted aqueous solution of sodium hydroxide, water, and then with saturated brine, and dried over magnesium sulfate. Insoluble solids were moved by filtration and the filtrate was concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound as colorless oil (592 mg, yield: 52%).
Reaction SMILES: CS(O[CH:6]([CH:18]1[CH2:20][CH2:19]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=O)=O.C([O-])(C)(C)C.[K+]>CS(C)=O>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]1[CH2:7][CH:6]1[CH:18]1[CH2:20][CH2:19]1)([O-:17])=[O:16]
Reactant: CS(=O)(=O)OC(CCc1ccccc1[N+](=O)[O-])C1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1C1CC1C1CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
The 1-cyclopropyl-3-(2-nitrophenyl)-propyl methanesulfonate is dissolved in 15 ml of dimethyl sulfoxide and 0.28 g of potassium tert-butanolate (2.48 mmol) is added, and stirring is carried out for 3 hours at ambient temperature. The reaction mixture is added to ice-water. Extraction is carried out with ethyl acetate, and the organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel is carried out in order to remove by-products (eluant: ethyl acetate/hexane 1:15). After removal of the eluant, 0.3 g of 2-(2-nitrophenyl)-bicyclopropane (65% of theory) is obtained in the form of a brownish liquid (trans:cis ratio: 4.7:1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]#[C:8][CH2:9][N:10]1[CH2:33][CH2:32][CH2:31][C@:12]2([O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3[O:27][CH:28]([CH3:30])[CH3:29])[CH2:13]2)[C@@H:11]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CS(C)=O.O>[N:1]([CH2:6][C:7]#[C:8][CH2:9][N:10]1[CH2:33][CH2:32][CH2:31][C@:12]2([O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][C:18]=3[O:27][CH:28]([CH3:30])[CH3:29])[CH2:13]2)[C@@H:11]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)Oc1ccc(C(F)(F)F)cc1[C@H]1CO[C@]2(CCCN(CC#CCCl)[C@H]2c2ccccc2)C1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1ccc(C(F)(F)F)cc1[C@H]1CO[C@]2(CCCN(CC#CCN=[N+]=[N-])[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Sodium azide (15 mg) was added to a solution of (3S,5R,6S)-7-(4-chlorobut-2-yn-1-yl)-3-[2-isopropoxy-5-(trifluoromethyl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4,5]decane (Description 75, 100 mg) in dimethylsulfoxide (1 ml). The mixture was stirred at room temperature overnight, diluted with water (20 ml) and extracted with ether (3×5 ml). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under pressure to give the title compound as a colorless oil (98 mg). m/z (ES+) m/z 513 (M+1).
Reaction SMILES: C([N:3](CC)CC)C.C(O[CH:11]=[C:12]([C:24](=[O:26])[CH3:25])[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])=[O:14])C.Cl.NO>C(#N)C>[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]([C:12]1[CH:11]=[N:3][O:26][C:24]=1[CH3:25])=[O:14])([O-:23])=[O:22]
Reactant: CCOC=C(C(C)=O)C(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CC#N
Product: Cc1oncc1C(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Triethylamine (1.9 g) was added to a mixture of 2-ethoxymethylene-1-(2-nitrophenyl)-butan-1,3-dione (4.9 g) and hydroxylamine hydrochloride (1.3 g) in acetonitrile (100 ml) with stirring. The mixture was stirred for 2 hours and left to stand overnight. The mixture was evaporated almost to dryness and water (100 ml) was added. The mixture was extracted with ethyl acetate (2×75 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 4-(2-nitrobenzoyl)-5-methylisoxazole (compound 2, 2.4 g) as a brown solid, mp 104.5°-105.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:33])([O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[CH:30][NH:29][C:28]2=[O:32])=[CH:23][CH:22]=1)[CH:17]([F:19])[F:18]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:29]1[CH:30]=[CH:31][N:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:16]([F:33])([F:15])[CH:17]([F:19])[F:18])=[CH:26][CH:25]=2)[C:28]1=[O:32])[CH3:13]
Reactant: O=c1[nH]ccn1-c1ccc(OC(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ccn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 18.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.01 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2oxiranyl]ethanol and 1.15 g of 1-[4-(1,1,2,2tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone, 0.36 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-2(1H,3H)-imidazolone was obtained as colorless needles.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[N:14]=2)=[CH:6][CH:5]=1>C(O)(=O)C>[Br:1][C:12]1[S:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)=[N:14][C:13]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)Cc1csc(-c2ccc(Cl)cc2)n1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)Cc1nc(-c2ccc(Cl)cc2)sc1Br
Temperature: 0 °C
Yield: 75.2 %

Procedure:
Bromine (15.9 g, 5.15 ml, 0.1 mol) was added dropwise to 2-(4-chlorophenyl) thiazol-4-yl acetic acid (24 g, 0.096 mol) suspended in glacial acetic acid (200 ml) and the resulting mixture was heated at 60°-70° C. for 5 hours. The reaction mixture was cooled to 0° C. (ice bath) and the solid which separated was filtered and washed with CHCl3. The residue was then washed with cold ethanol to afford the desired product (24 g, 75%)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:16][C:11]=2[N:10]([CH3:23])[C:9]1=[O:24].CN(C)C=O.[Cl-].[Al+3].[Cl-].[Cl-]>O1CCCC1>[CH3:23][N:10]1[C:11]2[CH:16]=[C:15]3[C:14](=[CH:13][C:12]=2[N:8]([CH3:7])[C:9]1=[O:24])[C:20](=[O:22])[CH2:19][CH2:18][CH2:17]3
Reactant: Cn1c(=O)n(C)c2cc(CCCC(=O)O)ccc21
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1c(=O)n(C)c2cc3c(cc21)CCCC3=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
Oxalyl chloride (7.0 ml, 81 mmol) was added by portions to a solution of 4-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)butanoic acid (20 g, 81 mmol) obtained in Reference Example 136 and dimethylformamide (1 ml) in tetrahydrofuran under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated, the reaction residue was dissolved in nitroethane, and aluminum chloride (21.6 g, 162 mmol) was added by portions under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture was poured into ice (500 g), extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was crystallized from ethanol-diethyl ether to give the title compound as colorless crystals (18.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH2:10]([O:12]CC)[CH3:11]>>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([CH2:11][CH2:10][OH:12])=[CH:7][N:6]=1
Reactant: CCOCC
Reactant: COc1ccc(Br)cn1
Product: COc1ccc(CCO)cn1
Yield: 62.7 %

Procedure:
5-Bromo-2-methoxypyridine (2.628 g) synthesized as reported in Tetrahedron, 1373 (1985). was dissolved in diethyl ether (40 ml) and then treated as in the above Production Example 16-1 to give the title compound (1.342 g) as a pale yellow oil (yield: 62.7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:20])[C:5]2=O.Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:6](=[O:20])/[C:5]/2=[N:23]/[NH:24][C:25]([NH2:27])=[O:26]
Reactant: NNC(N)=O
Reactant: CC(C)N(CCN1C(=O)C(=O)c2cc(Br)ccc21)C(C)C
Agent: Cl
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2cc(Br)ccc21)C(C)C
Yield: 72.6 %

Procedure:
By using 5-bromo-1-(2-diisopropylaminoethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-5-bromo-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 149°-153° C. (yield: 72.6%, recrystallizing solvent: chloroform-hexane).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C@@H:13]([CH3:16])[CH2:14][OH:15]>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:15][CH2:14][C@@H:13]([NH:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH3:16])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](N)CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)COS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
p-Toluenesulfonyl chloride (25.38 g, 133.1 mmol) was dissolved in 70 mL dry pyridine and cooled to 0° C. (S)-2-Aminopropan-1-ol (43, 5.0 g, 66 mmol) in 20 mL dry pyridine was added dropwise via an addition funnel and the resulting mixture was stirred for 20 h at RT. The reaction mixture was concentrated and the residue was partitioned between EtOAc and H2O. The organic layer was washed with 1N HCl (4×50 mL), H2O, 5% NaHCO3, brine, dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (80% Hex:20% Acetone) to afford the title compound. MS (m/z): 384.2 (M+H) (Calc'd for C17H21NO5S2: 383.48).
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26](=[O:35])[CH2:27][C:28]([C:30]1[NH:31][CH:32]=[CH:33][N:34]=1)=[O:29])=[O:23])[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[CH:16]1([CH2:15][CH2:14][CH2:13][C@@H:12]([C@@H:21]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:22]([NH:24][N:25]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:26](=[O:35])[CH2:27][C:28]([C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[O:29])=[O:23])[C:10](=[O:11])[NH:9][OH:8])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC(=O)c1ncc[nH]1)[C@H](CCCC1CCCC1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC(=O)c1ncc[nH]1)[C@H](CCCC1CCCC1)C(=O)NO
Yield: 75.2 %

Procedure:
A solution of 0.130 g of 2(R)-[1(S)-(N-benzyloxycarbamoyl)-4-cyclopentylbutyl]-2′-isobutyl-2′-[2-(imidazoyl)acetyl]-4-methylvalerohydrazide in 3 ml of methanol was hydrogenated in the presence of 0.040 g of 5% palladium-on-carbon for 4 hours. Filtration and evaporation gave a residue which was triturated with diethyl ether. Filtration gave 0.083 g of 2(R)-[4-cyclopentyl-1(S)-(hydroxycarbamoyl)butyl]-2′-isobutyl-2′-[2-(imidazoyl)acetyl]-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: C(OC(=O)C)(=O)C.O[C:9]1[C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:24]([OH:26])=[O:25]>>[CH2:27]([CH:23]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:9]=2[O:25][C:24]1=[O:26])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCC(C(=O)O)c1cccc(Oc2ccccc2C)c1O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCC1C(=O)Oc2c(Oc3ccccc3C)cccc21
Yield: 73.5 %

Procedure:
Acetic anhydride (5 ml) was added to 2-[2-hydroxy-3-(o-tolyloxy)phenyl]-n-nonanoic acid (4.3 g), and the mixture was refluxed under heating for 10 minutes and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 60 g, benzene) to give 3-(n-heptyl)-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one (3.0 g).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]([NH:14][OH:15])=[NH:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[C:16]1([C:22]2[CH:30]=[CH:29][C:25]([C:26](Cl)=O)=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:22]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:23]=[CH:24][C:25]([C:26]2[O:15][N:14]=[C:12]([CH:9]3[CH2:10][CH2:11][N:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH2:7][CH2:8]3)[N:13]=2)=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCC(CC)N1CCC(C(=N)NO)CC1
Product: CCC(CC)N1CCC(c2noc(-c3ccc(-c4ccccc4)cc3)n2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 35a, starting from 1-(1-ethylpropyl)-N-hydroxypiperidine-4-carboxamidine and 4-phenylbenzoyl chloride.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([CH3:10])[O:7][C:6](=[O:11])[CH:5]=1.CN(C=O)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(P(N(C)C)(N(C)C)=O)C>[CH2:17]([O:3][C:4]1[CH:9]=[C:8]([CH3:10])[O:7][C:6](=[O:11])[CH:5]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)cc(=O)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2)cc(=O)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
Sodium hydride (2.2 gm, 50% oil, 0.0458 mol) was added portionwise to a solution of 4-hydroxy-6-methyl-2-pyrone (5 gm, 0.0396 mol) in anhydrous tetrahydrofuran. When the gas evolution ceased, anhydrous DMF (80 ml) was added, along with tetra-n-butylammonium iodide (1 gm). The solution was stirred at room temperature for 30 minutes. A solution of benzyl bromide (5.2 ml, 0.0425 mol) in HMPA (5 ml) was added. After 16 hours at room temperature, the volatile component was removed by evaporation. DMF was removed under high vacuum (1 mm Hg). The residual oil was partitioned between 10% HCl and ethyl acetate. The ethyl acetate layer was dried over magnesium sulphate and evaporated to an oil. This material was purified by flash column chromatography (Whatman LPS-II silica gel, elution gradient: 10-50% ethyl acetate:pet. ether 30-60; product Rf =0.4 at 30% ethyl acetate:pet. ether 30-60). The material was recrystallized from ether to give 4-benzyloxy- 6-methyl-2-pyrone (3.42 gm, 40% yield), m.p. 90°-91° C.; IR (KBr): 1740, 1575, 1650 cm-1, Anal. calcd. for C13H12O3 : C, 72.21, H, 5.59. Found: C, 72.31, H, 5.64.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.[C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])[CH:33]=[CH2:34].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[C:37]([O:36][C:32](=[O:35])[CH:33]=[CH:34][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
Reactant: C=CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C=Cc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Temperature: 135 °C
Yield: 34.2 %

Procedure:
A flask was charged with 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (79 mg, 0.16 mmol)(as prepared in Example 1, step (f)), t-butyl acrylate (41 mg, 0.32 mmol), cesium carbonate (57 mg, 0.18 mmol), (t-Bu3P)2Pd(0) (8.2 mg, 0.016 mmol), and 1 mL of dioxane and heated in a microwave reactor for 30 min at 135° C. The crude reaction mixture was loaded on a 10-g SPE column and the title compound was eluted with 10% EtOAc/hexanes to give 30 mg (34%) of a white solid. Mass spectrum (ESI, m/z): Calcd. for C30H40N4O4Si, 549.2 (M+H). found 548.9.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:15]([CH3:18])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClN1[C:42](=[O:43])CCC1=O>CO.C(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[C:35](=[O:36])[N:13]3[C:14]([C:19]([O:21][CH:22]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:20])=[C:15]([CH3:18])[C@@H:16]([O:43][CH3:42])[S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Solvent: CO
Solvent: ClCCl
Product: CO[C@H]1S[C@@H]2[C@@H](NC(=O)Cc3ccccc3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
To a solution of diphenylmethyl 7α-phenyl-acetamido-3-methyl-3-cephem-4-carboxylate (2.88 g, 5.8 mmole) in 40 ml of methanol and 60 ml of methylene chloride, was added N-chlorosuccinimide (882 mg, 6.6 mmol) and the mixture was stirred for 90 minutes at room temperature. The reaction solution was then washed with brine (2X) and dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The resultant yellow foam (2.84 g) was chromatographed over 100 grams of silica gel employing 10-15% of ethyl acetate in toluene as the eluting solvent. The first fraction to elute from the column was the desired 2α-methoxy cephem compound which was subsequently recrystallized from a mixture of ethyl acetate and cyclohexane to give pure diphenylmethyl 7α-phenylacetamido-2α-methoxy-3-methyl-3-cephem-4-carboxylate. (638 mg, 21% yield) (m.p. 144°-145° C.) i.r. (CHCl3) 1780, 1725 and 1680 cm-1 ; n.m.r. (CDCl 3) δ1.95 (s, 3, CH3) 3.35 (s, 3, OCH3), 3.45 (s, 2, CH2Ph), 4.60 (s, 1, C2 --H), 4.70 (d, J=2 and 8 Hz, 1, C7 --H), 4.85 (d, J=2 Hz, 1, C6 --H), 6.95 (s, 1, CH2Ph), 7.3 (m, 16, aromatic H and N-H); u.v. (CHCl3) λmax 264 nm (ε=9726).