Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:5].Br[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[S:31][C:32]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=3[N:34]=2)=[C:25]([F:40])[CH:24]=1.[F:41][C:42]1[CH:43]=[C:44]([C:63]2[CH:68]=[CH:67][C:66]([C:69]([C@@H:71]3[CH2:75][CH2:74][CH2:73][C@H:72]3[C:76]([O:78]C)=[O:77])=[O:70])=[CH:65][CH:64]=2)[CH:45]=[CH:46][C:47]=1[NH:48][C:49]1[S:50][C:51]2[CH:57]=[C:56](OC(F)(F)F)[CH:55]=[CH:54][C:52]=2[N:53]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:40][C:25]1[CH:24]=[C:23]([C:20]2[CH:19]=[CH:18][C:3]([C:4]([C@@H:6]3[CH2:10][CH2:9][CH2:8][C@H:7]3[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:5])=[CH:2][CH:21]=2)[CH:28]=[CH:27][C:26]=1[NH:29][C:30]1[S:31][C:32]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=2[N:34]=1.[F:41][C:42]1[CH:43]=[C:44]([C:63]2[CH:64]=[CH:65][C:66]([C:69]([C@@H:71]3[CH2:75][CH2:74][CH2:73][C@H:72]3[C:76]([OH:78])=[O:77])=[O:70])=[CH:67][CH:68]=2)[CH:45]=[CH:46][C:47]=1[NH:48][C:49]1[S:50][C:51]2[CH:57]=[C:56]([F:39])[CH:55]=[CH:54][C:52]=2[N:53]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccccc1Br
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC(F)(F)F)cc4s3)c(F)c2)cc1
Reactant: Fc1ccc2nc(Nc3ccc(Br)cc3F)sc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1
Yield: 77 %

Procedure:
tert-Butyl (1R,2R)-2-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylate was prepared from tert-butyl (1R,2R)-2-(bromobenzoyl)-cyclopentanecarboxylate and N-(4-bromo-2-fluorophenyl)-N-(6-fluoro-1,3-benzothiazol-2-yl)amine in a similar manner to that described above for methyl (1R,2R)-2-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate. A solution of the tert-butyl ester (1.5 g, 2.81 mmol) in 2.0 mL TFA and 10 mL CH2Cl2 was stirred at rt overnight. After the solvent was removed by rotary evaporation, 50 mL EtOAc and 50 mL water were added. The organic layer was separated, washed with 50 mL water, and then dried over Na2SO4. After the solvent was removed by rotary evaporation, 5 mL EtOAc was added to the residue, followed by 5 mL hexanes. The precipitate that formed was collected by filtration to afford the desired product as a light yellow solid (1.0 g, 77%, 95.2% ee). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (br s, 1 H), 10.50 (bs, 1 H), 8.70 (t, 1 H), 7.60–8.10 (m, 8 H), 7.20 (t, 1 H), 4.10 (m, 1 H), 3.20 (m, 1 H), 2.20 (m, 1 H), 2.00 (m, 1 H), 1.50–1.90 (m, 4 H); LC-MS m/z 479.3 (MH+), ret. time 3.64 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)[CH2:4][CH3:5].[C:17]([N:36]1[C:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]2[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=2)=[N:39][N:38]=[N:37]1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:3]([C:6]1[N:15]([CH2:51][C:50]2[CH:49]=[CH:48][C:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[C:40]3[N:36]([C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:37]=[N:38][N:39]=3)=[CH:54][CH:53]=2)[C:14](=[O:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)[CH2:4][CH3:5]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc2ccccc2c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2ccccc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of sodium hydride (60% dispersion in mineral oil, 0.3 g) in DMF (50 ml) was added 2-propyl-4(3H)-quinazolinone (1.0 g) and the mixture was stirred at room temperature for 15 minutes. After addition of 4-[2'-(N-trityltetrazol-5-yl)phenyl]benzyl bromide (5.0 g), the reaction mixture was stirred at room temperature for 19 hours and concentrated to dryness. The residue was extracted with ethyl acetate-water and the organic layer was washed with water, dried and concentrated to dryness. The resulting syrup was purified by column chromatography on silica gel to give a colorless amorphous (2.34 g, 66%).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.[OH-].[Na+]>ClCCl>[CH2:30]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:22]=[CH:23][C:18]([N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:8][CH2:9][CH2:10]3)=[N:19][CH:20]=2)[CH2:25][CH2:26]1)[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)CN1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)c4ccccc43)nc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)CN1CCN(c2ccc(N3CCNc4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
4-[5-(4-Isobutylpiperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester (0.39 g, 0.86 mmol) is placed in 1.7 ml of dichloromethane and then 4N HCl in dioxane (3.24 ml, 12.95 mmol) is added. The reaction medium is stirred at ambient temperature for 18 h. After hydrolysis with a 1N aqueous sodium hydroxide solution up to a pH of 10, extraction is carried out with dichloromethane. The organic phase is washed with a saturated aqueous sodium chloride solution and then dried over MgSO4 and concentrated to dryness. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of methanol in dichloromethane varying from 0% to 10%. 0.27 g of 1-[5-(4-isobutylpiperazin-1-yl)pyridin-2-yl]-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:10][C:11]1[N:16]=[C:15]([SH:17])[N:14]=[C:13]([OH:18])[CH:12]=1.C(N(CC)CC)C>C(O)C>[F:9][C:4]1[C:3]([CH2:2][S:17][C:15]2[N:14]=[C:13]([OH:18])[CH:12]=[C:11]([CH3:10])[N:16]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Fc1ncccc1CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2cccnc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
3-(bromomethyl)-2-fluoropyridine, 6-methyl-2-sulfanylpyrimidin-4-ol (1.42 g, 10 mmol) and triethylamine (1.54 mL, 11 mmol) were mixed in ethanol (50 mL). The mixture was stirred at room temperature for 2 hours. After evaporation, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide pure titled product (1.8 g, 72% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.17 (s, 3H), 4.35 (s, 2H), 6.00 (br, 1H), 7.28 (m, 1H), 8.05 (m, 1H), 8.11 (m, 1H); M+ 252.
Reaction SMILES: [CH:1]1(C2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]O.[CH:15]1(C2C=CC=CC=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.S(=O)(=O)(O)[OH:28].C(=O)([O-])[O-:33].[Na+].[Na+]>>[C:1]1([OH:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1(=[O:33])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(O)O
Reactant: c1ccc(C2CCCCC2)cc1
Agent: [Na+]
Agent: [O-]O
Product: O=C1CCCCC1
Product: Oc1ccccc1
Reaction time: 0.17 h

Procedure:
Cyclohexylbenzene oxidation products (including cyclohexylbenzene hydroperoxide, CHBHP) using NHPI as the first catalyst with varying CHBHP concentrations are used (without first concentrating the hydroperoxide) in this example. An amount of 5.0 milliliters of such feed was charged into a glass flask held at 58° C. Toward this feed was added 5000 ppm of sulfuric acid diluted in acetone in a semi-batch mode. Cleavage reaction occurred instantaneously as indicated by the reaction exotherm. An aliquot was taken after 10 min and sulfuric acid was neutralized using 10 wt % sodium carbonate solution. The sample was analyzed by GC and the results are listed in Table 4. High conversion of CHBHP and high yield to phenol and cyclohexanone were observed in all cases.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:26][C:27](N)=[O:28])=[O:25].O>N1C=CC=CC=1>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:27]([NH:26][C:24]([C:20]2[O:19][CH:23]=[CH:22][CH:21]=2)=[O:25])=[O:28])[CH2:7][CH2:6]1
Reactant: NC(=O)NC(=O)c1ccco1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC(=O)c1ccco1)NC1CCN(Cc2ccc3ccccc3c2)CC1
Yield: 17.5 %

Procedure:
4-Amino-1-(naphth-2-ylmethyl)piperidine (1.2 g, 0.005 m) and 2-furoylurea (0.7 g) in pyridine (5 ml) was refluxed for 6 hours, then cooled. Water was added and the precipitate collected by filtration. The solid was dissolved in chloroform with a little methanol and filtered. The solvent was removed under reduced pressure and the residue was purified by medium pressure liquid chromatography on silica using CHCl3 : MeOH (9:1 v/v) as eluent. The isolated product (1st component eluted) was dissolved in ethyl acetate and acidified with ethanolic HCl to give a precipitate. This was filtered and dried to give 0.3 g of the title compound as the HCl, 3/4 H2O salt, mp. 157°-159° C.
Reaction SMILES: [NH2:1][C:2](=[S:16])[CH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[F:15].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=O>C(O)C>[F:15][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:4]=1[CH2:3][C:2]1[S:16][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=2)[N:1]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1ccc(CC(N)=S)c(F)c1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Solvent: CCO
Product: CCOC(=O)c1ccc(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c(F)c1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
To a solution (4 mL) of the compound (400 mg, 1.7 mmol) obtained in Example 189c in ethanol was added 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (530 mg, 2.0 mmol), and the mixture was heated under reflux overnight. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The obtained crude product was purified by recrystallization (ethyl acetate-hexane) to give the title compound (540 mg, 80%) as colorless crystals.
Reaction SMILES: [ClH:1].C(O[C:7]([N:9](C)[C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C:18](=[O:20])[CH3:19])=[C:12]([CH3:21])[C:11]=1[CH3:22])=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:7][NH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C:18](=[O:20])[CH3:19])=[C:12]([CH3:21])[C:11]=1[CH3:22]
Reactant: CC(=O)Oc1c(C)cc(N(C)C(=O)OC(C)(C)C)c(C)c1C
Agent: Cl
Solvent: C1COCCO1
Product: CNc1cc(C)c(OC(C)=O)c(C)c1C
Reaction time: 3 h

Procedure:
A mixture prepared by adding 100 ml of a 4 N solution of hydrogen chloride in 1,4-dioxane to 5.45 g of N-t-butoxycarbonyl-N-methyl-4-acetoxy-2,3,5-trimethylaniline [prepared as described in step (g) above] at room temperature was stirred for 3 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the resulting residue was triturated with diisopropyl ether. The crystals thus obtained were collected by filtration, after which they were washed with diisopropyl ether to give 4.36 g of the title compound, melting at 172-176° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([CH:13]=[O:14])[S:11][CH:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:15]Br>C(O)(=O)C.CN(C)C=O>[Br:15][C:12]1[S:11][C:10]([CH:13]=[O:14])=[CH:9][C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc(-c2cccnc2F)cs1
Reactant: BrBr
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=Cc1cc(-c2cccnc2F)c(Br)s1
Reaction time: 8 h
Yield: 38.7 %

Procedure:
4-(2-Fluoropyridin-3-yl)thiophene-2-carbaldehyde (3.35 g) was dissolved in acetic acid (20 mL) and N,N-dimethylformamide (20 mL), and bromine (7.77 g) was added at room temperature. The reaction mixture was stirred overnight and concentrated under reduced pressure. The residue was weakly basified with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=6:1→3:1), and the obtained solid was washed with diisopropyl ether to give the title compound as a pale-yellow powder (yield 1.79 g, 39%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][N:9]=1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.O>CN(C=O)C>[CH3:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH2:20][CH2:21][O:22][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)[N:9]=1
Reactant: O=Cc1ccc(OCCBr)cc1
Reactant: Cc1n[nH]c(=O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(CCOc2ccc(C=O)cc2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
##STR30## To a stirred suspension of K2CO3 (11.3 g, 82.5 mmol) in dry DMF (50 mL) at 25-30° C. was added a solution of 4-methyl-1(2H)-phthalazinone (6.6 g, 41.25 mmol) (Ref: Chemistry of Heterocyclic Compounds; Condensed Pyridazines including Cinnolines and Phthalazines, edited by R. N. Castle; John Wiley and Sons, 27, (1973) 375-441) in dry DMF (100 mL). The reaction mixture was stirred for 30 min at 25° C. and 4-(2-bromoethoxy)benzaldehyde (9.4 g, 41.25 mmol) was added. The reaction mixture was immersed in a pre-heated oil bath at 70° C. and stirred at 65-70° C. for 24 h. The reaction mixture was cooled to room temperature and water (50 mL) was added. The reaction mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude compound was recrystallised from methanol to obtain the title compound (9.7 g, 77%). mp: 90° C.
Reaction SMILES: FC(F)(F)S([Cl:6])(=O)=O.[C:9]1([C:15](=[O:27])[CH2:16][C:17](=[O:26])[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl.Cl>[Cl:6][C:18]1[C:17](=[O:26])[CH:16]=[C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:27][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccccc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1oc(-c2ccccc2)cc(=O)c1Cl
Reaction time: 2 h

Procedure:
Trifluoromethane sulphonyl chloride (3.95 ml) was added over 10 minutes to a stirred solution of ethyl 6-phenyl-2,4,6-trioxohexanoate (8.1 g) and triethylamine (6.5 ml) in dichloromethane (100 ml) at 0° to 5° C. The solution was stirred for 2 hours at 0° to 5° C., then made acidic by passing in hydrogen chloride gas. The mixture was stirred for 3 hours at room temperature, washed with water and evaporated to a brown oil which crystallised from ethanol-water. The product was recrystallised from ethanol-water and from ethyl acetate-petroleum ether 60°-80° C. to give ethyl 3-chloro-4-oxo-6-phenyl-4H-pyran-2-carboxylate (mp 121° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=1.[CH2:13](N(CC)CC)C.CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[CH:6]=1
Reactant: CCN(CC)CC
Reactant: Brc1cnn(C2CCNCC2)c1
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCC(n2cc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 4-(4-bromopyrazol-1-yl)piperidine (480 mg, 2.09 mmol) and triethylamine (0.295 ml, 2.1 mmol) in DMF (4 ml) was added methyl iodide (2.1 ml of a 1.0M solution in DMF, 2.1 mmol) under an inert atmosphere. The reaction was stirred at room temperature overnight, then partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the product (260 mg), which was used without further purification. 1H NMR (400 MHz, CDCl3): 7.47 (1H, s), 7.45 (1H, s), 4.16-4.04 (1H, m), 3.09-2.92 (2H, m), 2.34 (3H, s), 2.30-2.10 (4H, m), 2.10-1.96 (2H, m).
Reaction SMILES: BrC1C=CC(OC2C=CC(C#N)=C(Cl)[N:8]=2)=CC=1C1OCCO1.[Br:23][C:24]1[CH:39]=[CH:38][C:27]([O:28][C:29]2[N:36]=[C:35](Cl)[CH:34]=[CH:33][C:30]=2[C:31]#[N:32])=[CH:26][C:25]=1[CH:40]1[O:44][CH2:43][CH2:42][O:41]1.BrC1C=C[C:49]([OH:52])=[CH:48]C=1C1OCCO1>C(#N)C>[Br:23][C:24]1[CH:39]=[CH:38][C:27]([O:28][C:29]2[N:36]=[C:35]([NH:8][CH2:48][CH2:49][OH:52])[CH:34]=[CH:33][C:30]=2[C:31]#[N:32])=[CH:26][C:25]=1[CH:40]1[O:44][CH2:43][CH2:42][O:41]1
Reactant: Oc1ccc(Br)c(C2OCCO2)c1
Reactant: N#Cc1ccc(Oc2ccc(Br)c(C3OCCO3)c2)nc1Cl
Reactant: N#Cc1ccc(Cl)nc1Oc1ccc(Br)c(C2OCCO2)c1
Solvent: CC#N
Product: N#Cc1ccc(NCCO)nc1Oc1ccc(Br)c(C2OCCO2)c1
Temperature: 80 °C
Yield: 41 %

Procedure:
To a solution of 6-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile and 2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile, (4+5, 2.5 g, 6.6 mmol) in acetonitrile (anhydrous, 50 mL) was added 2-amino-ethanol (2) (3.96 g, 66 mmol). The reaction was heated at 80° C. for 2 hours. After the reaction cooled to room temperature, all volatile components were removed in vacuo. Purification was accomplished by silica gel chromatography, eluting with 25%-100% EtOAc/Hexane gradient, to give 1.1 g of title compound in 41% yield.
Reaction SMILES: [NH:1]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:2]([C:6]([N:8]1[CH2:37][CH2:36][CH2:35][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])[CH2:18][CH:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20](=[O:22])[OH:21])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].FC(F)(F)C(O[C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=O>N1C=CC=CC=1>[NH:1]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[C@H:2]([C:6]([N:8]1[CH2:37][CH2:36][CH2:35][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:28]([NH:30][CH2:31][C:32]([O:34][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][CH:51]=1)=[O:33])=[O:29])[CH2:18][CH:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20](=[O:21])[OH:22])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(OC(C)(C)C)C(=O)O)C(=O)NCC(=O)O
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(OC(C)(C)C)C(=O)O)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
XIX (1.32 g, 2.15 mmol) and p-nitrophenyl trifluoroacetate (0.607 g, 2.58 mmol) were reacted in pyridine (10 ml) in the same manner as described for the preparation of X in part (b). The resulting oil was triturated with ether and petroleum ether. The solid obtained was composed of one major component (Rf1 0.44) and one minor component (Rf1 0.33). Repeated recrystallization from chloroform-petroleum ether and further purifications using several organic solvents were attempted, but these attempts were only of limited effect in fractionating the major component as pure XX. The component (1.13 g, Rf1 0.44) containing only traces of the component (Rf1 0.33) was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3OC=C[O:19]3)=[CH:14][CH:13]=2)[NH:7][C:6]1=[O:23])[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([N:5]1[C:9](=[O:10])[CH:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[CH:16][CH:17]=2)[NH:7][C:6]1=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)NC(Cc2ccc(C3OC=CO3)cc2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CCCCN1C(=O)NC(Cc2ccc(C=O)cc2)C1=O

Procedure:
3-n-Butyl-5-[4-(1,3-dioxol-2-yl)benzyl] hydantoin (5.5 g., 0.017 mole) was dissolved in acetone (150 ml.) and stirred overnight at room temperature with p-toluene sulphonic acid (0.5 g). The acetone was evaporated off in vacuo and the residual oily solid partitioned between water and chloroform. The chloroform phase was washed with sodium carbonate solution (2% W/V), then evaporated in vacuo to give a yellow oil which slowly crystallised and was recrystallised from petroleum ether 60/80° C./ethyl acetate (3/1 V/V) to give 3-n-butyl-5-(4-formylbenzyl) hydantoin, 4.5 g (95%), m.p. 160° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[Br-:1].[CH2:2]([P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 100 °C

Procedure:
A magnetically stirred suspension of 1-bromononane (Aldrich, 40 g, 0.1931M) and triphenylphosphine (101.3 g, 0.3862 mole) was heated at 100° C. (oil bath) for 2 hours. The resulting homogeneous solution was then cooled and triturated with ether (8X) to remove most of the unreacted triphenylphosphine. A viscous gum was obtained which was dissolved in CH2Cl2 and concentrated in vacuo to give the title phosphonium salt as a light yellow, extremely hygroscopic foam weighing 85 g (80.1%). TLC, neat CH2Cl2, Rf =0.78, PMA.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:48][O:49][CH3:50])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([CH:46]=O)=[C:35]3[C:39]([O:41][C:42](C)(C)[CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:52][OH:53]>N1C=CC=CC=1.CCOCC.C(OCC)(=O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:48][O:49][CH3:50])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([CH:46]=[N:52][OH:53])=[C:35]3[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NO
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(C=O)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C=NO)SCC2C(NC(=O)C(=NOC)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reaction time: 0.83 h

Procedure:
Under an inert atmosphere, 142 mg of (1,1-dimethyl)ethyl 7-[2-(2-tritylamino-thiazol-4-yl)-2-methoxyimino-acetamido]-3-formyl-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate, (prepared in Step A of Example 52) and 42 mg of hydroxylamine hydrochloride were dissolved in 0.4 ml of pyridine and the solution was stirred for 50 minutes and diluted with ether and with ethyl acetate. The mixture was washed with 6 ml of N hydrochloric acid and after extracting the aqueous phase with ethyl acetate, the organic phases were dried and concentrated to dryness. The residue was chromatographed under pressure on silica and eluted with a mixture of ethyl acetate and methylene chloride (25-75) to obtain 91 mg of 1,1-dimethy]-ethyl 7-[2-(2-tritylamino-thiazol-4-yl)-2-methoxyimino-acetamido]-3-hydroxyiminomethyl-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate.