Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[C:23]2[OH:31].[H-].[Na+]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[C:23]2[O:31][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc2nc(C)cc(O)c2c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2nc(C)cc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 100-mL, round bottomed flask containing 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.26 g, 1.0 mmol) and 6-methoxy-2-methyl-quinolin-4-ol (0.19 g, 1.0 mmol, Ubichem) in DMF (5 mL), was added NaH (48 mg, 1.2 mmol, 60% in mineral oil, Aldrich) at room temperature The solution was then stirred at room temperature for 24 h. After the solvent was removed in vacuum, EtOAc (30 mL) was added to the residue, and the mixture was washed with brine (2×15 mL), dried over Na2SO4, filtered, and concentrated in vacuum. After the product was purified by silica gel chromatography (5:1 hexanes/EtOAc), the resulting solid was dissolved in acetone (10 mL) and MeOH (8 mL). Water (15 mL) was then added dropwise to afford a white precipitate, which was collected by filtration, washed with water (2 mL), and dried under vacuum at 50° C. for 48 h to furnish the title compound. Mp: 165–166° C. MS (ESI, pos. ion) m/z: 412; Anal. Calcd for C22H16F3N3O2: C, 64.23; H, 3.92; N, 10.21. Found: C, 64.20; H, 3.85; N, 10.14.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:17])[CH:14]=[N+]=[N-])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([OH:21])(=[O:20])[CH3:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:17])[CH2:14][O:21][C:18](=[O:20])[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C=[N+]=[N-]
Product: CC(=O)OCC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
A solution of 1.00 g of the diazoketone product of Example 1 in acetic acid (15 ml) was refluxed for 10 minutes. The mixture was cooled, filtered and the acetic acid removed under reduced pressure to give (S)-1-t-butoxycarbonyl-2-(2-acetoxy-1-oxoethyl)-pyrrolidine, which was purified by chromatography on silica gel eluting with 3:1-hexane; ethyl acetate (Rf =0.3).
Reaction SMILES: [CH:1]1([C:6]2([CH2:11][C:12]#[N:13])[O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:15][OH:16].N>>[CH:1]1([C:6]2([CH2:11][C:12](=[N:15][OH:16])[NH2:13])[O:10][CH2:9][CH2:8][O:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#CCC1(C2CCCC2)OCCO1
Reactant: NO
Agent: Cl
Agent: N
Product: NC(CC1(C2CCCC2)OCCO1)=NO

Procedure:
According to the procedure described in Example 133A Step 3, 2-(2-cyclopentyl-1,3-dioxolan-2-yl)acetonitrile (1.5 g, 8.3 mmol) was reacted with hydroxylamine hydrochloride (3.17 g, 45.5 mmol) and liquid ammonia (7.8 mL, 7N in methanol), to afford 2-(2-cyclopentyl-1,3-dioxolan-2-yl)-N′-hydroxyacetimidamide, which was used directly in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.11 (bs, 2H), 4.20-3.95 (m, 4H), 2.38 (s, 2H), 2.33-2.22 (m, 1H), 1.73-1.41 (m, 8H); LC-MS (ESI) m/z 215 (M+H)+
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Br[CH2:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=1>CCOC(C)=O.CCCCCC>[C:18]1([C:15]2[CH:14]=[C:13]([CH2:12][N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[O:17][N:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrCc1cc(-c2ccccc2)no1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1ccc(-c2cc(CN3CCc4ccccc4C3)on2)cc1
Yield: 81 %

Procedure:
Prepared from 1,2,3,4-tetrahydroisoquinoline and 5-(bromomethyl)-3-phenylisoxazole under typical conditions. Purification by flash chromatography on silica gel 60, eluting with 25% EtOAc in hexane produced adduct 21A (81% yield). 1H NMR(300 MHz, CDCl3, δ): 7.83-7.80 (m, 2H), 7.48-7.40 (m, 3H), 7.16-7.11 (m, 3H), 7.08-6.99 (m, 1H), 6.57 (s, 1H), 3.91 (s, 2H), 3.76 (s, 2H), 3.00-2.80 (m, 4H). 13C NMR(300 MHz, CDCl3, δ): 170.25, 162.45, 134.04, 133.75, 129.97, 129.12, 128.92, 128.72, 126.81, 126.56, 126.36, 125.78, 101.26, 85.61, 53.20, 50.75, 29.03. MS(CI, NH3) m/e 291 (base, M+H+). HRMS(CI, NH3) m/e Calc'd for (M+H+): 291.1497. Found: 291.1512.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C:16]([O:47][CH3:48])([NH:17][C:18](=[O:46])[C:19](=[N:25][O:26]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:49])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1>C(=O)(O)[O-].[Na+]>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@:16]([NH:17][C:18](=[O:46])[C:19](=[N:25][OH:26])[C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)([O:47][CH3:48])[C:15](=[O:49])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: COC1(NC(=O)C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)c2cccs2)C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Product: CO[C@@]1(NC(=O)C(=NO)c2cccs2)C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@@H]21
Reaction time: 0.17 h

Procedure:
t-Butyl (6R,7R and S [ca 1:8])-3-acetoxymethyl-7-methoxy-7[2-triphenylmethoxyimino-2-(thien-2-yl)-acetamido]-ceph-3-em-4-carboxylate (1.172 g, 1.56 mmole) was stirred with anisole (1.5 ml) and trifluoroaracetic acid (5 ml) for 1 hour at +20°. The solution was added dropwise to vigorously stirred saturated aqueous sodium bicarbonate solution (400 ml); the mixture was stirred for 10 minutes and then washed with ethyl acetate (3×80 ml). The aqueous layer was covered with ethyl acetate (80 ml) and adjusted to pH 3 with orthophosphoric acid. The aqueous layer was extracted with ethyl acetate (3×80 ml) and the combined ethyl acetate layers were washed with brine, then passed through Whatman l PS phase-separating paper and evaporated. The residual foam was chromatographed on kieselgel G (60 g) in 4:1:5 butan-l-ol:ethanol:water. The appropriate fractions were combined and evaporated and the residue was dissolved in acetone, filtered through Celite, and evaporated to provide the title compound as a pale-brown amorphous solid containing 0.8 mole butan-l-ol, and 0.07 mole acetone (nmr) and 5 mole water (416 mg, 0.66 mole, 42.5%), paper chromatography Rf/Rf cephaloram 0.84,[α]D +40° (Me2SO), λmax (pH 6-buffer) 264.5 nm, inflexion at 290 nm (ε15,200 and 10,700 respectively).
Reaction SMILES: [C:1]12(O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(=O)(=O)(O)O.C(OC(=O)C)(=O)C.[F:24][C:25]1[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:26]=1[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28]>ClCCl.CCCCCCC>[C:1]12([C:36]3[C:25]([F:24])=[C:26]([CH:33]=[CH:34][C:35]=3[OH:37])[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: C=CCOC(=O)c1ccc(O)cc1F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CC(=O)OC(C)=O
Product: C=CCOC(=O)c1ccc(O)c(C23CC4CC(CC(C4)C2)C3)c1F
Reaction time: 3 h
Yield: 58.5 %

Procedure:
In a 250 ml three-necked flask, under nitrogen, one introduces 3.04 g 1-adamantanol, 10 ml of n-heptane and 63 μl concentrated sulfuric acid. Dropwise, 2.16 ml of acetic anhydride are added and stirring is conducted for 3 hours at room temperature. Dropwise, 540 μl concentrated sulfuric acid are added and one adds portionwise 3.92 g of allyl 2-fluoro-4-hydroxybenzoate. After this addition, one adds 25 ml of dichloromethane and agitates at room temperature for 24 hours. After vacuum drying, the solid is taken up in water, neutralized to pH 7 with sodium bicarbonate and extracted with ethyl ether. The organic layer is washed with water and then with a concentrated aqueous sodium chloride solution. After drying over magnesium sulfate, one filters and evaporates the filtrate to obtain 7 g of crude product which is chromatographed on a silica column and eluted with dichloromethane. After trituration with hexane, filtration and drying in an oven at 50° C. there were obtained 3.86 g of the desired product, melting at 219°-222° C.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:32][CH2:33][CH2:34][CH3:35])=O)C1C=CC=CC=1>[Pd].CO>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OCCC)C2)oc1CC
Agent: [Pd]
Solvent: CO
Product: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCCC)C2)oc1CC
Yield: 94.3 %

Procedure:
The same operation as in Example (95b) was performed using butyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-propoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (113g) (1.01 g, 2.1 mmol), 10% Pd/C (0.25 g) and methanol (15 mL), to obtain 0.70 g of the title compound as a light yellow oily substance (95%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]#[C:15][Si](C)(C)C)[CH:13]=1)[O:10][CH:9]([C:20]([F:23])([F:22])[F:21])[C:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7]2.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C(Cl)Cl>[C:14]([C:12]1[CH:13]=[C:4]([O:3][C:2]([F:30])([F:1])[F:29])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:20]([F:23])([F:22])[F:21])[C:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7]2)#[CH:15]
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(C#C[Si](C)(C)C)c2OC1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 6-(trifluoromethoxy)-2-(trifluoromethyl)-8-[(trimethylsilyl)ethynyl]-2H-chromene-3-carboxylate prepared as in Step 1 (22.8 g, 50.3 mmole) in anhydrous CH2Cl2 (200 mL) was added a solution of TBAF (62.9 mL-1.0 M in THF), 62.9 mmole) under a dry N2 atmosphere. The mixture was stirred for 10 minutes and then poured into sat. NH4Cl (200 mL) and extracted with EtOAc (500 mL). The EtOAc extract was washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give 40 g of a dark brown oil. The crude product was purified by silica chromatography (98:2 hexanes:CH2Cl2) to give 13.9 g (73% yield) of the product as a yellow crystalline solid: EIHRMS m/z 380.0505 (M+, C16H10F6O4, Calc'd 380.0483).
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[OH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:26][CH2:25][C:20]3([O:24][CH2:23][CH2:22][O:21]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.C1COCC1.O1CCOCC1>O>[O:21]1[C:20]2([CH2:19][CH2:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][N:9]([OH:8])[C:6]([NH2:5])=[O:7])=[CH:12][CH:13]=3)[CH2:26][CH2:25]2)[O:24][CH2:23][CH2:22]1
Reactant: ONCc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N(O)Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
Trimethylsilyl isocyanate (2.1 mL, 14.85 mmol) was added dropwise into a mixture of 8-{4-[(hydroxyamino)methyl]phenyl}-1,4-dioxa-8-azaspiro[4.5]decane (2.61 g, 9.9 mmol) (which was obtained in Example 52), THF(20 mL) and dioxane (20 mL). The mixture was stirred at room temperature for 24 hours, poured into water and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate/methyl alcohol 10/5/1) gave a white solid (2.2 g, 73% yield); mp 153–154° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.70 (m, 4H), 3.21 (m, 4H), 3.89 (s, 4H), 4.37 (s, 2H), 6.23 (brs, 2H), 6.86 (m, 2H), 7.10 (m, 2H), 9.19 (s, 1H); MS (ES) m/z: 308 (MH+); Anal. Calcd. for C15H21N3O4: C, 58.62; H, 6.89; N, 13.67. Found: C, 58.37; H, 6.78; N, 13.47
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12].Cl.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:19]1[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=1)=[O:12]
Reactant: Fc1ccccc1
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Aluminum chloride (1.3 g) was added to a solution of 6-bromohexanoyl chloride (2 g) in fluorobenzene (20 ml) under ice-cooling and the mixture was stirred at room temperature for 2 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure to give 2.47 g of 6-bromo-1-(4-fluorophenyl)-1-hexanone.
Reaction SMILES: [C:1]([C:3]1([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[CH2:5][CH2:4]1)#[N:2]>[Ni]>[NH2:2][CH2:1][C:3]1([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1(C#N)CCS(=O)(=O)CC1
Agent: [Ni]
Product: CC(C)(C)OC(=O)NC1(CN)CCS(=O)(=O)CC1
Reaction time: 1 h

Procedure:
Methanol (800 mL) was bubbled with ammonia gas. After 1 hour, Raney Nickel (50 g) and tert-butyl (4-cyano-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)carbamate (70 g, 255 mmol) were added. The reaction mixture was stirred under a hydrogen atmosphere. After 16 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl [4-(aminomethyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]carbamate. MS ESI calc'd. for C11H23N2O4S [M+H]+ 279. found 279. 1H NMR (400 MHz, CDCl3) δ 4.54 (s, 1H), 3.25-3.15 (m, 2H), 3.00-2.90 (m, 4H), 2.64-2.60 (m, 2H), 2.13-2.06 (m, 2H), 1.78 (bs, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH3:14])[CH:2]1[O:4][CH2:3]1.[NH:15]1[CH:20]=[CH:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1>>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([C:18]2[CH2:19][CH2:20][N:15]([CH2:3][CH:2]([OH:4])[CH2:1][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[N:7]=[C:6]3[CH3:14])[CH2:16][CH:17]=2)=[CH:22]1
Reactant: Cc1nc2ccccc2n1CC1CO1
Reactant: C1=CC(c2c[nH]c3ccccc23)CCN1
Product: Cc1nc2ccccc2n1CC(O)CN1CC=C(c2c[nH]c3ccccc23)CC1
Yield: 8.4 %

Procedure:
A methanolic solution of 1-N-glycidyl-2-methylbenzimidazole (0.64 g, 3.4 mmole) from example 7 and 3-(4-tetrahydropyridinyl)indole (0.67 g, 3.4 mmole) was refluxed under nitrogen for 24 hours. The reaction mixture was concentrated in vacuo and the product purified by flash silica gel chromatography (10% methanol in ethyl acetate) to afford the titled compound as a pale yellow colored solid (0.11 g, 9% yield). Treatment with a 0.25M ethanolic solution of fumaric acid (0.5 equivalents) gave the required product as a yellow colored solid. The product was recrystallized from ethanol.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=2)[CH2:4]1.C(N(C(C)C)CC)(C)C.[C:32]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[Na].C(=O)(O)[O-].[Na+]>ClCCCl>[CH:32]1([N:3]2[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]3[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=3)[CH2:4]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCNC2)cn1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(C3CCCCC3)C2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
To a solution of ethyl (2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl}acrylate dihydrochloride (300 mg) in 1,2-dichloroethane (5 mL) were added diisopropylethylamine (222 mg) and cyclohexanone (93 mg), and the mixture was stirred at ambient temperature for 5 min. To the mixture was added sodium triacetoxybrohydryde (364 mg) and stirred for 4 hrs, and resulting mixture was poured into saturated sodium bicarbonate solution, and extracted with chloroform. The organic layer was washed with water, and brine, and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography (chloroform-MeOH-10-1) to give ethyl (2E)-3-(5-{[(3R)-1-cyclohexyl-3-piperidinyl]amino}-2-pyrazinyl)acrylate (235 mg) as an amorphous powder.
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][N:10]=[C:11]([C:34]1[N:39]=[C:38]([NH2:40])[CH:37]=[CH:36][N:35]=1)[C:12]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([O-:31])=[O:30])=[C:19]([CH2:22][N+:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][S:21][C@H:16]12)=[O:13])=[O:7])(C)(C)C.C1(OC)C=CC=CC=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[C:6]([CH2:8][O:9][N:10]=[C:11]([C:34]1[N:39]=[C:38]([NH2:40])[CH:37]=[CH:36][N:35]=1)[C:12]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([O-:31])=[O:30])=[C:19]([CH2:22][N+:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:20][S:21][C@H:16]12)=[O:13])([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nccc(N)n1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: Nc1ccnc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)[O-])=C(C[n+]4ccccc4)CS[C@H]23)n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 44 %

Procedure:
A mixture of 7-[2-t-butoxycarbonylmethoxyimino-2-(4-aminopyrimidin-2-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (1.31 g) and anisole (2.5 ml) in trifluoroacetic acid (7.5 ml) was stirred for 50 minutes under cooling in an ice-bath and for 70 minutes at room temperature. The mixture was poured into cold diisopropyl ether (60 ml) and the resulting precipitates were collected by filtration. The powder was dissolved in water (30 ml) and the mixture was adjusted to pH 4 to 5 with aqueous sodium bicarbonate and subjected to column chromatography on a non ionic adsorption resin "Diaion HP 20" (60 ml). After the column was washed with water, the elution was carried out with 30% aqueous methanol. The eluate was evaporated to remove methanol under reduced pressure and lyophilized to give 7-[2-carboxymethoxyimino-2-[4-aminopyrimidin-2-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (0.52 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28]Cl>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:26][O:27][CH3:28])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCCl
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCSc1nc(N)c2nc(O)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (134 mg, 0.49 mmol) was suspended in dimethylformamide (65 ml). To the suspension were added potassium carbonate (100 mg, 0.72 mmol) and chloromethyl methyl ether (0.056 ml, 0.73 mmol) in order. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (2% methanol/chloroform) to give the subject compound (107 mg, yield 69%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[N+:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: c1ccccc1
Product: O=[N+]([O-])c1ccccc1

Procedure:
The benzene excess based on nitric acid of 2.0% to 20%, preferably of 5.0% to 10% of the theoretical value, relates to the molar ratio of benzene and nitric acid. Theoretically, one mole of nitric acid reacts with one mole of benzene to form one mole of nitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH-].[Na+].[N+:16]([CH3:19])([O-:18])=[O:17]>>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[CH2:19][N+:16]([O-:18])=[O:17])=[CH:6][CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(C(F)(F)F)nc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])CC(O)c1ccc(C(F)(F)F)nc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a stirred solution of 2-chloro-6-(trifluoromethyl)nicotinaldehyde (Int-17) (70 g, 1.0 eq.) in nitro methane (700 mL) was added sodium hydroxide (6.7 g, 0.5 eq.) at room temperature. The resulting reaction mixture was heated to 100° C. and stirred for 2 h. The progress of the reaction was monitored by TLC. After completion of reaction, the reaction mixture was concentrated under reduced pressure to remove nitro methane quenched with ice water (500 mL) and extracted with ethyl acetate (2×1.0 L). The combined organic layer was washed with water (500 mL), brine (500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get pure 1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-2-nitroethanol (Int-18) (65.0 g, 72.0%).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([CH2:13]I)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1>>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](CI)C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1cc(I)ccn1
Product: COC(=O)[C@H](Cc1ccnc(C(F)(F)F)c1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to previously reported procedure (see pending U.S. patent application Ser. No. 11/575,187) from (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 4-iodo-2-(trifluoromethyl)pyridine (this starting material was prepared according to a procedure described in Eur. J. Org. Chem. 2003, 1559-1568).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3].[CH2:9](O)[CH2:10]/[CH:11]=[CH:12]\[CH2:13]C.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCCCCCC)CCCCCCC.C([O-])(=O)CCCCCCCCCCC>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH3:13])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3]
Reactant: C/C=C(/C)C(=O)OC
Reactant: CC/C=C\CCO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCCCCCC[Sn+2]CCCCCCCC
Solvent: Cc1ccccc1
Product: C/C=C(/C)C(=O)OCC/C=C\CC

Procedure:
A mixture of 20.0 g. of methyl angelate, 26.34 g. of (Z)-3-hexenyl alcohol, 100 ml. of toluene and 1.2 g. of dioctyltin laurate was placed in a 300 ml. glass flask, which was equipped with a Soxhlet extractor filled on the top with molecular sieve 4A and a reflux cooler.