Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH2:15]>COC(C)(C)C.C(O)(C)C>[CH3:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH:15][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9]
Reactant: CN(C)CCCN
Reactant: S=C=Nc1ccccc1
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: CN(C)CCCNC(=S)Nc1ccccc1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
Phenyl isothiocyanate (5.283 g, 39.1 mmole) in 30 mL t-butyl methyl ether was added to a solution of 3-(dimethylamino)propylamine (3.993 g, 39.1 mmole) in 10 mL isopropanol. After stirring 2 hr at room temp., the solid which separated was filtered out and washed with t-butyl methyl ether to afford 6.51 g of 1-[3-(dimethylamino)propyl]-3-phenylthiourea (mp 112–114° C.), part of which (2.374 g, 10 mmole) was dissolved in ethanol (20 mL) containing conc. HCl (1.67 mL, 20 mmole) and added to 2-methylnaphthoquinone dissolved in warm ethanol (35 mL). After 4 days in a stoppered flask at room temp., the mixture was concentrated, and dissolved in ethyl acetate. The solid which separated after 16 hr was filtered out, but became sticky on the filter and was discarded. The filtrate was stored another 12 days at room temp. The powder which separated was filtered out to give 600 mg of pinkish-buff powder. Of this, 325 mg was recrystallized from 10 mL methanol+60 mL ethyl acetate containing a few drops of water to give 260 mg of the title compound, mp 238–240° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:3]1.Cl[C:12]1[N:17]=[CH:16][C:15](/[C:18](/[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[C:19](\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[CH2:20][CH3:21])=[CH:14][CH:13]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:12]2[N:17]=[CH:16][C:15](/[C:18](/[C:28]3[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=3)=[C:19](\[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)/[CH2:20][CH3:21])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(CCO)CC1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCN2CCN(C)CC2)nc1)c1ccccc1
Yield: 121.1 %

Procedure:
Following the same procedure as described in example 3, 2-(4-methylpiperazin-1-yl)ethanol (430 mg, 10 eq) was reacted with (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)phenol (100 mg, 1 eq, prepared from example 1) to give the desired product (160 mg, 95% yield). 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.17-7.22 (m, 2H), 7.00-7.15 (m, 5H), 6.97 (d, J=8.0 Hz, 1H), 6.76 (d, J=8.8 Hz, 2H), 6.03 (d, J=8.8 Hz, 1H), 4.27 (t, J=5.6 Hz, 2H), 2.75 (t, J=5.6 Hz, 2H), 2.48-2.57 (m, 12H), 2.32 (s, 3H), 0.92 (t, J=7.6 Hz, 3H); m/z=444 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[NH:12]C(=O)[O:10][C:8](=O)[C:7]2=[CH:14][CH:15]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>CN(C)C=O>[NH2:12][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]=1[C:8]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:10]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Reactant: COc1ccc(N)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2N)cc1
Temperature: 80 °C
Yield: 95 %

Procedure:
A mixture of 4-nitroisatoic anhydride (2.08 g, 10.0 mmol) and p-anisidine (1.35 g, 11.0 mmol) in N,N-dimethylformamide (10 mL) was heated at 80° C. for 2.5 h. After cooling, the reaction was poured into ice cold 3 N hydrochloric acid (60 mL). The resulting solid was filtered and washed with 1 N hydrochloric acid and water. Drying in vacuo gave 2.73 g (95%) of the title compound as a greenish yellow solid; mp 193-7° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:12][C:13]([CH3:15])=[CH2:14])[C:10]=1[OH:11])[CH:7]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:6][CH2:5]2.C(N(CC)CC)C.S([O-])([O-])(=[O:32])=S.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[C:10]2[O:11][C:13]([CH2:15][OH:32])([CH3:14])[CH2:12][C:9]=2[C:8]2[CH:7]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: C=C(C)Cc1c(O)c(Br)cc2c1C(CCNC(=O)CC)CC2
Reactant: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCCC1CCc2cc(Br)c3c(c21)CC(C)(CO)O3
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A solution of N-(2-(5-bromo-6-hydroxy-7-(2-methyl-2-propenyl)indan-1-yl)ethyl]propionamide (550 mg, 1.5 mmol.) in dichloromethane (5 mL) was cooled with ice. To the solution were added triethylamine (0.2 mL, 1.5 mmol.) and methachloroperbenzoic acid (1.0 g, 4.1 mmol.). The mixture was stirred for two hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium thiosulfate. The organic matter was extracted with ethyl acetate. The extract solution was washed with 1N HCl and a saturated aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was dissolved in dichloromethane, to which was added triethylamine (1 mL). The mixture was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by means of silica gel column chromatography (chloroform:methanol=10:1) to afford the title compound (yield 420 mg, 73%) as an oily product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1.[CH:23]([C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][C:35]=1[OH:36])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:23]([C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][C:35]=1[O:36][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24]
Reactant: BrCCCc1ccc(OCCCCOc2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C=O)c1
Temperature: 40 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
1.37 g (3.76 mmol) of 1-(3-bromopropyl)-4-(4-phenoxybutoxy)benzene, 0.79 g (3.76 mmol) of ethyl 3-formyl-4-hydroxybenzoate [CAS No. 82304-99-2] and 0.78 g (5.64 mmol) of potassium carbonate are dissolved in 20 ml of DMF, and the mixture is stirred at 40° C. for 16 hours. It is then concentrated, and the residue is taken up in 200 ml of water and extracted with dichloromethane (three times 100 ml). The combined organic phases are dried (sodium sulphate) and concentrated, and the crude product is purified by chromatography on silica gel (mobile phase gradient cyclohexane-->cyclohexane/ethyl acetate 5:1). 1.45 g of product are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][CH:22]3[C:25]([F:28])([F:27])[F:26])=[CH:18][C:17]=2[O:29][CH3:30])[C@@H:9]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C.FC(C1C=CC(OC(F)(F)F)=C(C=1)CN[C@H]1CCCN[C@H]1C1C=CC=CC=1)(F)C>>[CH3:30][O:29][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][C:16]=1[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH:22]([C:25]([F:28])([F:26])[F:27])[CH2:21][CH2:20]2
Reactant: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)C(C(F)(F)F)CC2
Agent: CC(F)(F)c1ccc(OC(F)(F)F)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1
Product: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)C(C(F)(F)F)CC2

Procedure:
This Compound was prepared from Compound 66 in the same manner of Compound 27.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23](N(OC)C)=[O:24])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:29]([Li])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].Cl.CCO>C1COCC1>[CH2:1]([N:4]([CH2:8][C:9]1[S:13][C:12]([S:14]([N:17]2[CH2:18][CH2:19][CH:20]([C:23](=[O:24])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22]2)(=[O:16])=[O:15])=[CH:11][CH:10]=1)[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: [Li]CCCCCC
Reactant: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(C(=O)N(C)OC)CC2)s1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(C(=O)CCCCCC)CC2)s1
Temperature: -20 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
327b (376 mg, 0.88 mmol) was dissolved in anhydrous THF and cooled to −20° C. To this solution was added dropwise at −20° C. hexyllithium (2M in hexane) (2.46 mL, 6.2 mmol). The reaction was allowed to warm to rt. during 3 h and poured on 100 mL HCl/EtOH (5%). The aqueous phase was extracted with CH2Cl2 and the combined organic layers are washed with NaOH (2N) and brine, dried over MgSO4 and evaporated to dryness. The crude material was purified by flash chromatography on silica gel using cyclohexane/EtOAc 4:1 as eluent to obtain 186 mg (47%) of (327c) as a brownish oil: H1 NMR (CDCl3) δ 7.40 (d, J=3.6 Hz, 1H), 725 (d, J=3.6 1H), 5.95 (m, 2H), 5.50 (m, 4H), 4.32 (s, 2H), 3.70-3.50 (m, 6H), 2.50 (m, 2H), 2.32 (m, 3H), 1.85 (m, 2H), 1.68 (m, 2H), 1.46 (m, 2H), 0.130-1.12 (m, 6H), 0.80 (t, J=6.6 Hz, 3H), M/Z APCI: 453.2 (M+1)
Reaction SMILES: F[C:2]1[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:3]=1[CH:4]=[C:5]1[S:9]C(=S)N[C:6]1=[O:11].[OH-:20].[Na+].Cl>O>[F:19][C:12]1[C:3]2[CH:4]=[C:5]([C:6]([OH:20])=[O:11])[S:9][C:2]=2[C:15]([F:16])=[C:14]([F:17])[C:13]=1[F:18]
Reactant: O=C1NC(=S)SC1=Cc1c(F)c(F)c(F)c(F)c1F
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2c(F)c(F)c(F)c(F)c2s1
Temperature: 90 °C

Procedure:
78 g of 2,3,4,5,6-pentafluorobenzylidene rhodanine were added in small portions to a stirred solution of 68 g of NaOH in 300 ml of water. The resultant clear red solution was heated to 90° C. for one hour, cooled in ice, acidified with concentrated HCl, and the cream coloured solid which was produced was filtered and washed. The crude product (59 g) was purified by sublimation to give 4,5,6,7-tetrafluorobenzothiophen-2-carboxylic acid having a melting point of 200° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[NH:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:29]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38](=[O:40])[CH3:39].O>CN(C=O)C>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH2:37][C:38](=[O:40])[CH3:39])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:29]=1
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3n[nH]c(=O)o3)c1)C2=O
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(CC(C)=O)c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
(S)-5-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3,4-oxadiazol-2(3H)-one (140 mg, 0.34 mmol) obtained in Step 1 of Example 89 was dissolved in DMF (3.0 mL), and the mixture was stirred at room temperature for 1 hour after adding potassium carbonate (94 mg, 0.68 mmol) and chloroacetone (0.030 mL, 0.38 mmol). Thereafter, water was added to the mixture, and the precipitated pale yellow solid was filtered off to obtain (S)-5-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-(2-oxopropyl)-1,3,4-oxadiazol-2(3H)-one (144 mg, 91%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[CH:6][NH:7][C:8]=1I)([CH3:3])[CH3:2].[CH3:10][C:11]1[CH:12]=[C:13]([SH:18])[CH:14]=[C:15]([CH3:17])[CH:16]=1.[H-].[Na+]>CN(C)C=O>[CH3:10][C:11]1[CH:12]=[C:13]([S:18][C:8]2[NH:7][CH:6]=[N:5][C:4]=2[CH:1]([CH3:3])[CH3:2])[CH:14]=[C:15]([CH3:17])[CH:16]=1
Reactant: CC(C)c1nc[nH]c1I
Reactant: Cc1cc(C)cc(S)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2[nH]cnc2C(C)C)c1
Temperature: 140 °C
Yield: 52.8 %

Procedure:
In 30 ml of dry N,N-dimethylformamide was dissolved 4.0 g (16.9 mmol) of 4-isopropyl-5-iodo-1H-imidazole (4b), followed by addition of 4.68 g (33.9 mmol) of 3,5-dimethylthiophenol and 2.1 g (52.5 mmol) of 60% sodium hydride. The mixture was heated at 140° C. for 7 hours. The N,N-dimethylformamide was there distilled off under reduced pressure and, after addition of dry ice, the residue was extracted with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was fractionated by silica gel chromatography (3% methanol-methylene chloride). The eluted crude compound was recrystallized from ethyl acetate-diisopropyl ether to provide 2.2 g (yield 53%) of 5-(3,5-dimethylphenylthio)-4-isopropyl-1H-imidazole (X=Y=Me) (9).
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([O:30][CH2:31][CH3:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[C:26]([F:29])([F:28])[F:27].[Li+].[OH-]>>[CH2:31]([O:30][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[C:26]([F:27])([F:28])[F:29])[C:3]([OH:33])=[O:2])[CH3:32]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1C(F)(F)F)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1C(F)(F)F)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2-trifluoromethyl-phenyl]-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2-trifluoromethyl-phenyl]-propionic acid as colorless solid.
Reaction SMILES: [C:1]([C:3]([C:27]1[CH:31]=[C:30](Br)[S:29][C:28]=1[Br:33])([CH:24]([CH3:26])[CH3:25])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH2:9][CH2:8]1)#[N:2].[CH3:34][N:35](C)C=O.O.N>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)C>[C:1]([C:3]([C:27]1[CH:31]=[C:30]([C:34]#[N:35])[S:29][C:28]=1[Br:33])([CH:24]([CH3:26])[CH3:25])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH2:11][CH2:12]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(C#N)c2)CC1)c1cc(Br)sc1Br
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: N
Agent: [C-]#N
Solvent: O
Solvent: CCOCC
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(C#N)c2)CC1)c1cc(C#N)sc1Br
Temperature: 120 °C
Reaction time: 4 h
Yield: 6.7 %

Procedure:
In a nitrogen atmosphere, 1-(4-cyano-5-methyl-4-[(2,5-dibromo)-3-thienyl]hexyl)-4-[2-(3-cyanophenoxy) ethyl] piperazine (145 mg) was dissolved in a mixed solvent of dimethylformamide (10 mL)/water (0.1 mL) of zinc cyanide (57.3 mg) and 1,1′-bis(diphenylphosphino)ferrocene (13.5 mg). Palladium-dibenzylidene acetone complex (8.9 mg) was added thereto, the atmosphere of the mixture was replaced 3 times with nitrogen, and then the solution was stirred at 120° C. for 4 hours. Water, diethyl ether and an aqueous ammonia were added thereto, to separate the organic layer. The resulting organic layer was washed with water and brine, dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was evaporated, and the residue was purified by LC-MS (ODS column; acetonitrile/water system), to give the title compound as a yellow oil (8 mg, 6.7%).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:14])[CH:7]([CH3:13])[C:8]([O:10]CC)=[O:9])C>CO>[CH3:3][O:5][C:6](=[O:14])[CH:7]([CH3:13])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
KOH (386 mg, 6.88 mmol) was added to a solution 2-methyl-malonic acid diethyl ester (1 g, 5.74 mmol) in methanol (7 mL). The resulting mixture was stirred overnight at ambient temperature then concentrated. The resulting residue was diluted with water, acidified with conc. HCl and the product was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 360 mg (47%) of 2-methyl-malonic acid monomethyl ester
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: [I-]
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
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(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: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8]>O>[CH2:5]([CH2:4][CH:3]([NH2:2])[C:9]([OH:11])=[O:10])[CH2:6][CH2:7][NH2:8]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Solvent: O
Product: NCCCCC(N)C(=O)O
Yield: 70 %

Procedure:
In 10 ml of water is suspended 1.00 g. of CET. In the meantime, l-lysine hydrochloride is dissolved in water and the solution is passed over a basic ion exchange resin (Amberlite IRA-411 of Rohm and Haas Co., U.S.A.). The aqueous solution of free l-lysine base thus obtained (containing 0.37 g. of l-lysine) is added to the above suspension. The resultant pale-yellowish solution is lyophilized, whereupon a porous solid product is obtained. This product is recrystallized from a solvent mixture of water and ethanol to harvest crystalline CET-l-lysine salt. Yield: 70%.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[O:17])[CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH:6]=1)(=O)C.Cl>C1COCC1.[OH-].[Na+]>[O:4]=[C:5]1[C:14]2[C:9](=[C:10]([NH:15][C:16]([C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[O:17])[CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:6]1
Reactant: CC(=O)Oc1cc(-c2cccc(C(F)(F)F)c2)nc2c(NC(=O)c3cnccn3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)[nH]c12)c1cnccn1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
A solution of 8-(pyrazine-2-carboxamido)-2-(3-(trifluoromethyl)phenyl)quinolin-4-yl acetate 41 (33 mg, 0.073 mmol) in THF (2 mL) and 1N NaOH (0.5 mL) was heated at 60° C. for 48 h. The reaction mixture was cooled to room temperature and 1N HCl (5 mL) was added. The resulting precipitate was collected by filtration, rinsed with 3 mL H2O, and dried under vacuum to give Compound 409 (21 mg, 70% yield). MS (ESI) calc. for C21H13F3N4O2: 410.10. found: 411 [M+H].
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[CH:15]=1.[CH:17](OCC)=[O:18].C([O-])(O)=O.[Na+]>C1COCC1>[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([Cl:16])[C:15]=1[CH:17]=[O:18]
Reactant: Clc1cncc(Br)c1
Reactant: CCOC=O
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1c(Cl)cncc1Br
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of LDA (7.94 mL, 1.8 M in THF/heptane/ethylbenzene, 14.3 mmol) in anhydrous THF (30 mL) at −78° C. under Ar was treated dropwise with a solution of 3-bromo-5-chloro-pyridine (2.5 g, 13.0 mmol) in anhydrous THF (30 mL) The solution was stirred at −78° C. for 30 min, then a solution of ethyl formate (10.46 mL, 130 mmol) in anhydrous THF (30 mL) was added dropwise. The resulting solution was stirred at −78° C. for 1.5 h and then treated with saturated NaHCO3 with vigorous stirring. The quenched mixture was extracted with EA (2×25 mL) and the combined organic extracts were washed with saturated NaHCO3 (15 mL) and dried over Na2SO4. The residue was purified by flash chromatography on silica gel with EA/hexane to provide 3-bromo-5-chloro-pyridine-4-carbaldehyde as a yellow solid. Reduction of the aldehyde according to the synthesis of (3,5-dichloro-pyridin-4-yl)-methanol yielded the title compound. MS (m/z): 224.0 [M+H+].