Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C@@H:3]1[C@H:8]([C:9](O)=[O:10])[CH2:7][CH:6]=[CH:5][CH2:4]1.[NH2:34][OH:35]>>[OH:35][NH:34][C:9]([C@H:8]1[C@@H:3]([N:2]([CH3:1])[S:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH2:4][CH:5]=[CH:6][CH2:7]1)=[O:10]
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CC=CC[C@H]3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)N(C)[C@H]3CC=CC[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 94 %

Procedure:
According to the procedure of Example 10, Step 2, the reaction of 255.5 mg (0.4 mmol) of cis-6-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxylic acid with hydroxylamine provided 200.1 mg of cis-N-hydroxy-6-[methyl({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohex-3-ene-1-carboxamide in 94% yield. MS: 482.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C)C=O.S(Cl)([Cl:31])=O>>[Cl:31][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1

Procedure:
6-Methoxy-7-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one (1.22 g) was stirred in thionyl chloride (10 ml) with dimethylformamide (0.1 ml) at 85° C. for 1 hour. The reaction was evaporated to dryness, and then azeotroped with toluene. The residue was partitioned between methylene chloride and saturated sodium bicarbonate. The organic phase was separated and evaporated to dryness. The saturated sodium bicarbonate phase was basified with 2M sodium hydroxide and was extracted with methylene chloride. The two organic phases were combined and dried over sodium sulphate, filtered and the filtrate evaporated to dryness. This residue was purified by eluting through a silica column with 5% methanol in methylene chloride to yield 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline as a solid, (0.5 g, 39%); NMR: 1.95 (m, 2H), 2.4 (broad m, 6H), 3.55 (m, 4H), 3.98 (s, 3H), 4.26 (t, 2H), 7.36 (s, 1H), 7.41 (s, 1H), 8.83 (s, 1H); m/s: M+H+ 338, 340.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:6]1)(=[O:3])[CH3:2].ClS([N:32]=[C:33]=[O:34])(=O)=O.O>C(#N)C>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][CH2:26][O:27][C:33](=[O:34])[NH2:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(=O)S[C@H]1C[C@@H](COCCO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CC#N
Solvent: O
Product: CC(=O)S[C@H]1C[C@@H](COCCOC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-(2-hydroxyethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.1 g) in acetonitrile (20 ml) was added chlorosulfonyl isocyanate (0.32 ml) at 0°-5° C. and the mixture was stirred at 20°-25° C. for 1 hour. Water (3 ml) was added to the solution at the same temperature and the mixture was stirred for 20 hours. After the solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water, saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated to give (2S,4S)-4-acetylthio-2-(2-carbamoyloxyethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.19 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2ccc(-c3cccs3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(-c4cccs4)cc3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(4-thiophen-2-yl-benzyl)-piperidine-4-carboxylic acid ethyl ester (1.3 g, 2.61 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 950 mg (77%); brown solid; mp 235° C.; MS: 471.8 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.Br[C:16]1[S:17][C:18]([Br:21])=[CH:19][N:20]=1>>[CH2:4]1[O:3][C:2]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][O:12][C:16]3[S:17][C:18]([Br:21])=[CH:19][N:20]=3)=[CH:9][CH:8]=2)([CH3:1])[O:6][CH2:5]1
Reactant: CC1(c2ccc(CO)cc2)OCCO1
Reactant: Brc1cnc(Br)s1
Product: CC1(c2ccc(COc3ncc(Br)s3)cc2)OCCO1
Yield: 60 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 43 which is concerned with the preparation of starting materials, 4-(2-methyl-1,3-dioxolan-2-yl)benzyl alcohol was reacted with 2,5-dibromothiazole to give 4'-(5-bromothiazole-2-yloxymethyl)acetophenone ethylene acetal in 60% yield as an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[O:21][CH2:22][C:23](Cl)=[O:24]>C(#N)C>[CH3:17][C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[O:21][CH2:22][C:23]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:24]
Reactant: Cc1cc(C)cc(OCC(=O)Cl)c1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(C)cc(OCC(=O)N[C@@H](CCC(=O)O)C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-dimethylphenoxyacetic acid (9.0 g, 50 mmole) in benzene (100 mL) was added thionyl chloride (10.89 mL). The resulting mixture was refluxed for 2 hr, then the benzene was removed by distillation. The residual material was dried in vacuo to give 3,5-dimethylphenoxyacetyl chloride, which was dissolved in 20 ml of acetonitrile and used in situ. L-Glutamic acid (8.8 g, 60 mmole) was dissolved in a solution of sodium carbonate (12.72 g, 150 mL, 120 mmole) and the 3,5-dimethylphenoxyacetyl chloride in the acetonitrile solution was slowly added while the pH 8 was adjusted from time-to-time by adding sodium carbonate solution. The reaction mixture was stirred at room temperature for 2 hr, and acidified to pH 2 to give a solid precipitate. The solid precipitate was collected by filtration, treated with hot benzene, filtered, again and washed again with benzene to give Intermediate 31 (9.2 g).
Reaction SMILES: [OH:1][C@H:2]([C@@H:13]([OH:24])[C:14]([O:16]N1C(=O)CCC1=O)=O)[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]2[C:53]3[C:48](=[C:49]([Cl:55])[CH:50]=[C:51]([Cl:54])[CH:52]=3)[CH2:47][N:46]([CH3:56])[CH2:45]2)[CH:39]=1)(=[O:37])=[O:36]>>[Cl:54][C:51]1[CH:52]=[C:53]2[C:48](=[C:49]([Cl:55])[CH:50]=1)[CH2:47][N:46]([CH3:56])[CH2:45][CH:44]2[C:40]1[CH:39]=[C:38]([S:35]([NH:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][NH:25][C:3](=[O:5])[C@H:2]([OH:1])[C@@H:13]([OH:24])[C:14]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]3[C:53]4[C:48](=[C:49]([Cl:55])[CH:50]=[C:51]([Cl:54])[CH:52]=4)[CH2:47][N:46]([CH3:56])[CH2:45]3)[CH:39]=2)(=[O:37])=[O:36])=[O:16])(=[O:37])=[O:36])[CH:43]=[CH:42][CH:41]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCN)c2)C1
Reactant: O=C(ON1C(=O)CCC1=O)[C@H](O)[C@@H](O)C(=O)ON1C(=O)CCC1=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCNC(=O)[C@H](O)[C@@H](O)C(=O)NCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Yield: 15.3 %

Procedure:
Compound 218 was prepared following the procedure outlined in Example 168 using (2R,3R)-bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxysuccinate (10.2 mg, 0.0298 mmol) and N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 168.2, 30 mg, 0.0597 mmol). Purification by preparative HPLC gave the title compound (5.1 mg) as the TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.92 (d, J=7.8 Hz, 2H), 7.82 (m, 2H), 7.67 (t, J=7.8 Hz, 2H), 7.57 (m, 2H), 7.55 (d, J=6.9 Hz, 2H0, 6.86 (m, 2H), 4.84 (s, 2H), 4.79 (s, 2H), 4.54 (d, 2H), 4.48 (s, 2H), 3.92 (m, 2H), 3.53 (m, 22H), 3.18 (s, 6H), 3.07 (t, J=5.4 Hz, 4H). MS (m/z): 1119.04 [M+H]+.
Reaction SMILES: P([O-])([O-])([O-])=O.[CH3:6][CH2:7][C@H:8]1[O:23][C:21](=[O:22])[C@H:20]([CH3:24])[C@@H:19]([O:25][C@@H:26]2[O:31][C@@H:30]([CH3:32])[C@H:29]([OH:33])[C@@:28]([O:35][CH3:36])([CH3:34])[CH2:27]2)[C@H:18]([CH3:37])[C@@H:17]([O:38][C@@H:39]2[O:44][C@H:43]([CH3:45])[CH2:42][C@H:41]([N:46]([CH3:48])[CH3:47])[C@H:40]2[OH:49])[C@@:16]([OH:51])([CH3:50])[CH2:15][C@@H:14]([CH3:52])[C:12](=[O:13])[C@H:11]([CH3:53])[C@@H:10]([OH:54])[C@@:9]1([OH:56])[CH3:55].[CH3:57]O>>[CH3:6][CH2:7][C@H:8]1[O:23][C:21](=[O:22])[C@H:20]([CH3:24])[C@@H:19]([O:25][C@@H:26]2[O:31][C@@H:30]([CH3:32])[C@H:29]([OH:33])[C@@:28]([O:35][CH3:36])([CH3:34])[CH2:27]2)[C@H:18]([CH3:37])[C@@H:17]([O:38][C@@H:39]2[O:44][C@H:43]([CH3:45])[CH2:42][C@H:41]([N:46]([CH3:47])[CH3:48])[C@H:40]2[OH:49])[C@@:16]([O:51][CH3:57])([CH3:50])[CH2:15][C@@H:14]([CH3:52])[C:12](=[O:13])[C@H:11]([CH3:53])[C@@H:10]([OH:54])[C@@:9]1([OH:56])[CH3:55]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: CO
Agent: O=P([O-])([O-])[O-]
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(OC)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O

Procedure:
Each fraction was analyzed by thin layer chromatography (E. Merck Darmstadt. thin layer chromatography plate silica gel 60 silanized precoated, thickness 0.25 mm), developing in a mixture of methanol and a 0.1 M phosphate buffer solution (pH 7.0) (3:2). The fractions having Rf value 0.42 (c.f., erythromycin A, Rf value 0.46) were combined and most of the methanol was evaporated in vacuo. The residue was made alkaline with sodium carbonate and extracted with chloroform. The chloroform layer was washed with water, dried and concentrated in vacuo. The crystals obtained were recrystallized from a mixture of chloroform and diisopropyl ether (1:2), giving 700 mg of pure 6-O-methylerythromycin A (formula(I), R1 is hydrogen) in the form of colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH2:5][C:6](=O)[NH:7]2.[N+:20]([CH2:22][C:23]1[N:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[O:25][N:24]=1)#[C-:21]>>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]([C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH2:5][C:6]1[N:7]2[CH:21]=[N:20][C:22]=1[C:23]1[N:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[O:25][N:24]=1
Reactant: O=C1CN(C(=O)N2CCCC2)c2c(F)cccc2N1
Reactant: [C-]#[N+]Cc1noc(C(C)C)n1
Product: CC(C)c1nc(-c2ncn3c2CN(C(=O)N2CCCC2)c2c(F)cccc2-3)no1

Procedure:
Following the general procedure of EXAMPLE 30 and making non-critical variations but using 5-fluoro-1,2,3,4-tetrahydro-4-[(pyrrolidino)carbonyl]quinoxalin-2-one (XXXII, EXAMPLE 29, 0.978 g) and 3-isocyanomethyl-5-isopropyl-l,2,4-oxadiazole (0.673 g) are converted to the title compound, mp 169°-170°; MS (m/z) at 396; IR (mineral oil) 1657, 1495, 1216, 1614 and 785 cm-1 ; NMR (CDCl3) 1.47, 1.86, 3.30, 3.34, 5.13, 7.08, 7.22, 7.38 and 8.12 δ.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[C:8]([O:17][CH:18]([CH3:20])[CH3:19])(=[O:16])[CH2:9][C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11].Br[CH2:22][C:23]([O:28][CH3:29])([O:26][CH3:27])[CH2:24]Br>O>[CH:18]([O:17][C:8]([C:9]1([C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])[CH2:24][C:23]([O:28][CH3:29])([O:26][CH3:27])[CH2:22]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Reactant: COC(CBr)(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Temperature: 145 °C

Procedure:
Following the procedure of Pigou and Scheisser (J. Org. Chem. 1988, 53, 3841), a 500 mL, 3-neck flask, fitted with a reflux condenser and thermocouple, was charged with NaH (60% in mineral oil, 4 g, 0.210 mol). DMF (100 mL) was added via syringe and the slurry was stirred under N2. Diisopropyl malonate was added at a rate so that the internal temperature did not rise above 70° C. After the H2 evolution had ceased, the flask was briefly opened and 1,3-dibromo-2,2-dimethoxypropane was added. The bath temperature was raised to 145° C. The reaction mixture was maintained at this temperature for 48 h. After this time the dark brown mixture was allowed to cool to rt. Water (50 mL) was added and the solvents were removed in vacuo. The residue was partitioned between ether (200 mL) and sat'd aq NH4Cl (200 mL) and the mixture filtered through a pad of Celite to remove solid impurities. The aqueous layer was extracted with ether (2×100 mL). The combined ether extracts were washed with brine, dried over Na2SO4, filtered and evaporated. Flash chromatography (SiO2, O-25% EtOAc in hexanes) gave semi-pure diisopropyl-3,3-dimethoxycyclobutane-1,1-dicarboxylate (28.5 g), which was used in the next step.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:46]/[O:47][C:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([CH3:50])[CH3:49])/[C:27]([NH:29][CH:30]2[C:44](=[O:45])[N:32]3[C:33]([C:41]([O-:43])=[O:42])=[C:34](/[CH:37]=[CH:38]\[CH2:39]Cl)[CH2:35][S:36][C@H:31]23)=[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.[I-:58].[Na+]>CC(C)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:46]/[O:47][C:48]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])([CH3:50])[CH3:49])/[C:27]([NH:29][CH:30]2[C:44](=[O:45])[N:32]3[C:33]([C:41]([O:43][CH:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[O:42])=[C:34](/[CH:37]=[CH:38]/[CH2:39][I:58])[CH2:35][S:36][C@H:31]23)=[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
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(/C=C\CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 204.9 %

Procedure:
To a solution of 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-[(Z)-3-chloro-1-propen-1-yl]-3-cephem-4-carboxylate (IXa) (1.23 g, 1.24 mmole) in acetone (5 ml) was added a solution of sodium iodide (560 mg, 3.72 mmol) in acetone (7 ml). The mixture was stirred at room temperature for 1.5 hour, and diluted with ethyl acetate (150 ml) and aqueous sodium thiosulfate solution. The organic layer was separated, dried over magnesium sulfate, and concentrated to give 1.38 g of diphenylmethyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-[(E)-3-iodo-1-propen-1-yl]-3-cephem-4-carboxylate (Xa) (see also Example 23 below) as an amorphous powder. Compound Xa was dissolved in ether (50 ml). The insoluble was filtered off and the filtrate was chilled in an ice-water bath, and was treated with a solution of 5,6-diacetoxy-2-methyl-2-isoindoline (600 mg, 2.4 mmol) in ether (50 ml). The mixture was stirred over 30 min, and the precipitate was collected by filtration to obtain 446 mg (27% yield) of the title iodide as a tan powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)(=O)=O.[Li+].[Cl-].[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:21]([C:7]1[C:8]([C:13]([O:15][CH3:16])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1)=[CH2:22]
Reactant: COC(=O)c1ncccc1OS(=O)(=O)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1cccnc1C(=O)OC
Temperature: 100 °C

Procedure:
To a solution of methyl 3-(trifluoromethylsulfonyloxy)picolinate (i.e. Cap 173, step a) (570 mg, 2.0 mmol), an intermediate in the preparation of Cap-174, in DMF (20 mL) was added LiCl (254 mg, 6.0 mmol), tributyl(vinyl)stannane (761 mg, 2.4 mmol) and bis(triphenylphosphine)palladium dichloride (42 mg, 0.06 mmol). The mixture was heated at 100° C. for 4 h before the solvent was removed in vacuo. The residue was taken up in acetonitrile (50 mL) and hexanes (50 mL) and the resulting mixture was washed twice with hexanes. The acetonitrile layer was then separated, filtered through Celite, and evaporated. Purification of the residue by flash chromatography on a Horizon instrument (gradient elution with 25% ethyl acetate in hexanes to 65% ethyl acetate in hexanes) afforded methyl 3-vinylpicolinate (i.e. Cap-175, step a) (130 mg, 40%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm 8.60 (1H, dd, J=4.6, 1.7 Hz), 7.94 (1H, d, J=7.7 Hz), 7.33-7.51 (2H, in), 5.72 (1H, d, J=17.2 Hz), 5.47 (1H, d, J=11.0 Hz), 3.99 (3H, s). Rt=1.29 min (Cond.-MD1); LC/MS: Anal. Calcd. for [M+H]+ C9H10NO2: 164.07; found: 164.06.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:31]C(=O)C)=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]#[N:29])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:36])[C:5]([CH3:35])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:31])=[C:17]([CH:30]=2)[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]#[N:29])=[CH:25][CH:26]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(CC#N)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(CC#N)cc3)c2)=C(C)C1=O
Yield: 72.9 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-cyanomethylaniline (0.060 g, 0.123 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.040 g, 0.0897 mmol, 73%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][C:5]=1[O:14][CH3:15].[C:18]1([O:24][C:25](=O)[O:26]C2C=CC=CC=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:17][O:16][CH:3]([O:2][CH3:1])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:25]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:26])=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: COc1cc2c(nc1C(OC)OC)NCCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(nc1C(OC)OC)N(C(=O)Oc1ccccc1)CCC2
Reaction time: 0.42 h

Procedure:
A solution of 7-(dimethoxymethyl)-6-methoxy-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 309, 76 mg, 0.319 mmol) and diphenylcarbonate (137 mg, 0.638 mmol) in THF (2 ml) at −15° C. was treated drop wise with LHMDS (1 M in THF, 0.35 ml, 0.35 mmol) and stirred for 25 min. The reaction mixture was then quenched with sat. aq. NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a yellow oil. (UPLC-MS 1) tR 0.93 min; ESI-MS 360.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:11][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: c1c[nH]cn1
Reactant: C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Cl)cc1Cl)C(Cn1ccnc1)c1ccccc1

Procedure:
A solution of 1-(2,4-dichlorophenyl)-2-phenylpropen-1-one (4g), imidazol (1.36 g) and tetramethylquanidine (0.5 ml) in tetrahydrofuran (100 ml) was heated at reflux for 12 hours. The reaction mixture was cooled and concentrated under reduced pressure to yield a gum. The gum was dissolved in ethyl acetate, washed with distilled water, and acidified with 4N hydrochloric acid. The aqueous phase was basified with sodium carbonate and extracted with ethyl acetate. The organic phase was separated, washed with distilled water, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield an oil which was chromatographed on silica gel using a mixture of methanol/dichloromethane (1:9) as an eluent to yield 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-phenylpropan-1-one (600 mg), which was treated with ethereal hydrogen chloride to yield the hydrochloride salt of 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-phenylpropan-1-one, m.p. 110° C., (Found: C, 55.38; H, 4.37; N, 7.40%; C18H15Cl3N2O.1/2H2O requires C, 55.34; H, 4.13; N, 7.17%) having the formula: ##STR28##
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:9](Cl)=[O:10].[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:14]1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:13]([NH:12][C:9]([C@H:2]3[CH2:3][CH:4]4[CH2:7][CH2:8][CH:1]3[CH2:6][CH2:5]4)=[O:10])[CH2:14]2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)C1CC2CCC1CC2
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(NC1CCN(CCc2ccc(F)cc2)C1)[C@H]1CC2CCC1CC2

Procedure:
2-Bicyclo[2.2.2]octanecarbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-2-bicyclo[2.2.2]octanecarboxamide.