Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH2:13]>>[CH2:11]([OH:12])[C@H:9]1[O:10][C@H:2]([O:1][C@H:7]2[C@H:5]([OH:6])[C@@H:3]([OH:4])[C@H:2]([OH:1])[O:13][C@@H:9]2[CH2:11][OH:12])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 90 °C

Procedure:
A liquefied starch solution having a DE (Dextrose Equivalent) of about 0.5 was prepared by adding to a suspension of 1 part by weight of potato starch in 10 parts by weight of water a commercial bacterial liquefying alpha-amylase (EC 3.2.1.1), heating the mixture to 90° C. to effect gelatinization, and further heating it quickly to 130° C. to suspend enzymatic reaction. To the solution was added 100 units/g starch of isoamylase (EC 3.2.1.68) prepared from a culture of Pseudomonas amyloderamosa ATCC 21262, and 50 units/g starch of "#1500", a beta-amylase (EC 3.2.1.2) derived from soybean, commercialized by Nagase & Company, Ltd., Osaka, Japan, and the resultant mixture was saccharified at pH 5.0 for 40 hours to obtain a high-purity maltose having a maltose content of 92.5% DS. The high-purity maltose was then purified by carbon decolorization and resin refining, and concentrated in vacuo to obtain a high-concentration syrup having a moisture content of 6.5 w/w %. The syrup was then placed in a kneader, and added with 1% DS crystalline alpha-maltose and 1% DS crystalline beta-maltose hydrate while keeping at 95° C. The resultant mixture was then kneaded for 3 minutes at this temperature, extruded in sheet shape, aged at 80° C. for 3 hours, further aged at 40° C. for 48 hours, and pulverized to obtain a maltose powder containing crystalline beta-maltose hydrate, moisture content of about 6.0 w/w %, in the yield of about 94% DS against the starting starch.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[C:43]([Cl:48])[CH:42]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[CH2:8][N:9]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[NH:40][C:41]2[CH:46]=[CH:45][C:44]([OH:47])=[C:43]([Cl:48])[CH:42]=2)[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN1CCC(C(=O)O)C1
Reactant: Nc1ccc(O)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(C(=O)Nc2ccc(O)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-tert-Butoxycarbonylmethyl-pyrrolidine-3-carboxylic acid, Lithium salt (0.5 g, 2.12 mmol) and HOBt (0.45 g, 3.3 mmol) in DMF (10 ml) at 0° C. was added EDCl (630 mg, 3.3 mmol). The formed reaction mixture was stirred at 0° C. for 0.5 hour and then 4-amino-2-chloro-phenol was added. After stirred at RT for overnight, the reaction mixture was added to ice-water (50 g) and the formed precipitated was collected by filtration, washed with sodium bicarbonate and HCl (0.1 N). After drying in air, the crude product (720 mg) was used directly in the next step. Mass Spec ES (355.2, M+H)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH3:5])[CH3:2].C([Li])CCC.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)C(C)C)(C)C>[Cu]I>[CH2:1]([O:3][CH:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:5])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOC(C)Oc1cccc(OC)c1
Agent: [Cu]I
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1c(OC)cccc1OC(C)OCC
Yield: 96 %

Procedure:
854.0 g of 1-(1-ethoxyethoxy)-3-methoxybenzene (content: 717.4 g (3.66 mol)) was put into a 20 L reactor under a nitrogen atmosphere and rinsed in with 7174 mL of tetrahydrofuran and the mixture was stirred. A coolant which was set to 4° C. was circulated through the jacket of the reactor and 1156 g (4.41 mol) of n-butyllithium [2.71 M, n-hexane solution] was added dropwise for 41 minutes, and the reaction mixture was stirred at the same temperature for about 1.5 hours. The coolant temperature was set to −20° C., and after it was confirmed that the mixture's temperature lowered below −10° C., 417.8 g (2.19 mol) of copper (I) iodide was added portionwise divided into three to the reaction mixture and the reaction mixture was stirred at the same temperature for about 14 hours. The coolant temperature was changed to −90° C. and 702.1 g (4.20 mol) of ethyl bromoacetate was added dropwise to the reaction mixture over 26 minutes and rinsed in with 10 mL of tetrahydrofuran. After the dropwise addition was completed, the reaction mixture was stirred for 44 minutes, and the liquid cooling temperature was changed to −35° C. and the reaction mixture was further stirred for about 1.8 hours. The coolant temperature was changed to −20° C., and the reaction mixture was stirred for one hour after the time point when temperature of the mixture exceeded −20° C. and progress of the reaction was confirmed by HPLC. 1435 mL of 28% ammonium hydroxide solution was added to the reaction mixture at the same temperature for about 30 minutes and the coolant temperature was changed to 25° C. The reaction mixture was added and extracted with 7174 mL of toluene and the organic layer was washed with 1440 mL of 28% ammonium hydroxide solution and 1435 mL×3 water sequentially. The obtained organic layer was added with 127 mL (0.73 mol) of N,N-diisopropylethylamine and concentrated in vacuo to afford a pale orange oil containing the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]3[S:18][CH:19]=[C:20]([CH2:22][C:23]([O:25]C)=[O:24])[N:21]=3)=[CH:15][N:16]=2)[CH2:8][CH2:7]1.[OH-].[Na+]>C1COCC1.CO>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]3[S:18][CH:19]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[N:21]=3)=[CH:15][N:16]=2)[CH2:8][CH2:7]1
Reactant: COC(=O)Cc1csc(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)s2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1csc(-c2cnc(N3CCC(Oc4ccccc4C(F)(F)F)CC3)s2)n1

Procedure:
A mixture of methyl (2′-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-2,5′-bi-1,3-thiazol-4-yl)acetate (220 mg, 0.44 mmol) in THF/MeOH (4:1) (v/v) (5 mL) was treated with 1 N NaOH (1 mL, 1 mmol) and heated at reflux temperature for 2 h. Volatile materials were removed in vacuo. The residue was diluted with water, acidified with 1 N HCl and extracted with EtOAc. The EtOAc extract was washed twice with water, dried (Na2SO4) and concentrated to give the title compound as a yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[NH3:19].C1OCCOC1>C(Cl)Cl.C1(C)C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([NH2:19])=[O:12]
Reactant: O=C(O)CCc1ccccc1Br
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)CCc1ccccc1Br
Reaction time: 2 h

Procedure:
To a solution of commercially available 3-(2-bromophenyl)propanoic acid (1 eq.) in CH2Cl2 (0.22M) at room temperature was added oxalyl chloride (16 eq) and a catalytic amount of DMF. The mixture was stiffed for 2 h, diluted with toluene (0.022M) and concentrated. To the residue diluted in CH2Cl2 (0.1M) at 0° C. was added ammonia (0.5M in dioxanne (3 eq.). The mixture was stiffed 2 h at room temperature, concentrated, quenched with aqueous NaOH 1N and then extracted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4 filtered and concentrated. Recrystallization in Et2O/hexane (1:1) afforded the desired compound as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[N:10].[CH2:12]([O:14]CC)C>CO>[NH:10]=[C:9]([O:14][CH3:12])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:11]
Reactant: CCOCC
Reactant: COC(=O)CCCCC#N
Agent: Cl
Solvent: CO
Product: COC(=N)CCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
Bubble hydrogen chloride (g) through a 0° C. solution of 5-cyano-pentanoic acid methyl ester (3.0 mL; 1.00 equiv; 22.02 mmoles) in methanol (5 mL), and ethyl ether (10 mL) for 1 hour. Allow the solution to warm to room temperature then add 50 mL ethyl ether, stir vigorously for 15 minutes, then filter and collect the resulting precipitate. Wash the solid with ethyl ether to afford methyl 6-imino-6-methoxy-hexanoate (3.82 g; 83%): 1H NMR (DMSO) δ 1.47-1.62 (m, 4H), 2.31 (t, 2H), 2.59 (t, 2H), 3.56 (s, 3H), 4.03 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:18]#[C:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[C:9]([OH:17])=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:19]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:18]2
Reactant: COc1ccc(C(=O)Cc2ccccc2)c(C#CCC(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(O)c(-c3ccccc3)c(CC(C)C)cc2c1
Yield: 90.1 %

Procedure:
A solution of 1-[4-(methyloxy)-2-(4-methyl-1-pentyn-1-yl)phenyl]-2-phenylethanone (104) (0.73 g, 2.39 mmol) in toluene was treated with a KHMDS solution in toluene to give 0.66 g (91%) of the title compound (105) as a light yellow viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.73 (d, J=6.8 Hz, 6H), 1.55-1.70 (m, 1H), 2.38 (d, J=7.1 Hz, 2H), 3.93 (s, 3H), 5.15 (s, 1H), 7.05-7.10 (m, 2H), 7.18 (s, 1H), 7.30-7.36 (m, 2H), 7.42-7.48 (m, 1H), 7.49-7.55 (m, 2H), 8.08 (d, J=8.8 Hz, 1H). LCMS (APCI): m/z 307 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:10]2[C:15]([C:16]=1[N:17]=[C:18]=[O:19])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]([C:38]1[C:42]([NH2:43])=[CH:41][S:40][CH:39]=1)=[O:37].C(OCC)(=O)C>FC(C1C=CC=CC=1)(F)F>[C:1]([O:5][C:6]([C:8]1[N:9]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[C:10]2[C:15]([C:16]=1[NH:17][C:18]([NH:43][C:42]1[C:38]([C:36]([O:35][CH3:34])=[O:37])=[CH:39][S:40][CH:41]=1)=[O:19])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cscc1N
Reactant: CC(C)(C)OC(=O)c1c(N=C=O)c2cc(C(F)(F)F)ccc2n1C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: FC(F)(F)c1ccccc1
Product: COC(=O)c1cscc1NC(=O)Nc1c(C(=O)OC(C)(C)C)n(C(=O)OCc2ccccc2)c2ccc(C(F)(F)F)cc12
Temperature: 150 °C
Yield: 74.6 %

Procedure:
To a solution of 1-benzyloxycarbonyl-3-isocyanato-5-trifluoromethylindole-2-carboxylic acid tert-butyl ester 5E (˜4.10 mmol) in trifluoromethylbenzene (10 mL) was added 4-aminothiophene-3-carboxylic acid methyl ester 5F (1.30 g, 8.28 mmol). The reaction mixture was heated in a microwave reactor at 150° C. for 30 minutes. Ethyl acetate (100 mL) was added and the organic layer was washed with 1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide 1-benzyloxycarbonyl-3-[3-(4-methoxycarbonylthiophen-3-yl)-ureido]-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 5G (1.89 g, 3.06 mmol).
Reaction SMILES: [CH3:1][C:2](=[CH2:12])[CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[BH4-].[Na+].[CH3:15][OH:16]>[OH-].[Na+].[Hg]>[CH3:15][O:16][C:2]([CH3:1])([CH3:12])[CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1
Reactant: CO
Reactant: C=C(C)CCOC1CCCCO1
Agent: [BH4-]
Agent: [Hg]
Agent: [Na+]
Product: COC(C)(C)CCOC1CCCCO1
Yield: 93 %

Procedure:
To 2-(3-methyl-3-butenyloxy)tetrahydropyran (150.0 g, 881.0 mmol) in methanol (600 ml) was added mercuric acetate (309 g, 969 mmol) and the mixture was stirred until it became homogeneous. To this solution was added 0.5N NaOH (500 ml) in one portion followed by dropwise addition of 0.5N NaBH4 in 0.5N NaOH (500 ml). The mixture is stirred until mercury metal congeals at the bottom of the flask. The solution is decanted into a separatory funnel and extracted with ether (3×300 ml). The combined ethereal extracts are dried (MgSO4) and concentrated to afford 166 g (93%) of 2-(3-methoxy-3-methylbutyloxy)tetrahydropyran as a colorless liquid.
Reaction SMILES: Br[C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:6]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1>>[CH:25]1([C:2]2[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[N:6]=2)[CH2:27][CH2:26]1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)OCc2ccccc2)nc1Br
Reactant: OB(O)C1CC1
Product: C[Si](C)(C)CCOCn1cc(C(=O)OCc2ccccc2)nc1C1CC1

Procedure:
The title compound was prepared using the procedure described in Example 59(a) starting from benzyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (7.31 mmol, 3 g) and cyclopropylboronic acid (14.63 mmol, 1.25 g). Yield 1.02 g. 1H-NMR (400 MHz; CDCl3): δ −0.02 (s, 9H), 0.91 (t, 2H), 0.99 (bs, 2H), 1.15 (bs, 2H), 1.87-1.94 (m, 1H), 3.52 (t, 2H), 5.32 (s, 2H), 5.34 (s, 2H), 7.29-7.43 (m, 5H), 7.59 (s, 1H). LC-MS: [M+1]=373.31.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:20].ClC(OCC)=O.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][C:8]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:10])=[CH:17][C:18]=1[Cl:19]
Reactant: C1COCCN1
Reactant: Nc1c(Cl)cc(C(=CC(=O)O)c2ccccc2)cc1Cl
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccccc2)cc1Cl

Procedure:
This compound was prepared from 4-amino-3,5-dichloro-β-phenyl-cinnamic acid (isomer ratio A:B=1.5:1), ethyl chloroformate, triethylamine and morpholine analogous to Example 1(c).
Reaction SMILES: [CH3:1][O:2][C@:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][C@@H:4]1[CH3:8].Cl.[NH2:25][OH:26]>>[CH3:1][O:2][C@:3]1([C:9]2[CH:10]=[C:11]([S:14][C:15]3[CH:20]=[CH:19][C:18](/[C:21](=[N:25]/[OH:26])/[CH3:22])=[CH:17][CH:16]=3)[S:12][CH:13]=2)[CH2:7][CH2:6][O:5][C@@H:4]1[CH3:8]
Reactant: NO
Reactant: CO[C@]1(c2csc(Sc3ccc(C(C)=O)cc3)c2)CCO[C@@H]1C
Agent: Cl
Product: CO[C@]1(c2csc(Sc3ccc(/C(C)=N/O)cc3)c2)CCO[C@@H]1C
Yield: 87 %

Procedure:
Using an analogous procedure to that described in Example 66, 4'-{4-[(2R,3S)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{4-[(2R,3S)-3-methoxy-2-methyltetrahydrofuran-3-yl]thien-2-ylthio}acetophenone oxime in 87% yield, m.p. 89°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:9]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:9]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 6.0 g. of p-[2,2-bis(p-chlorophenyl)acetamido]benzoic acid, ethyl ester, 920 mg. of potassium hydroxide, and 50 ml. of 95% ethanol is stirred at 75° C. for 9 hours, cooled, diluted with 100 ml. of water, and the pH is adjusted to 2.0 with 37% hydrochloric acid. The precipitate is collected, washed with water, dried and recrystallized from 100 ml. of ethanol, giving 2.78 g. of the desired product as colorless crystals, m.p. 272°-274° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])[CH3:3].[Cl:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:14][C:15]1[N:16]=[C:17]([NH:1][CH:2]([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH3:3])[CH:18]=[N:19][CH:20]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COC(=O)c1cccc(C(C)N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(C(C)Nc2cncc(Cl)n2)c1
Temperature: 150 °C
Yield: 15.3 %

Procedure:
A mixture of methyl 3-(1-aminoethyl)benzoate (120 mg, 0.67 mmol), 2,6-dichloropyrazine (150 mg, 1 mmol) and potassium carbonate (280 mg, 2 mmol) in dioxane (5 mL) was heated in a microwave reactor at 150° C. for 6 hours. After this time the mixture was cooled to room temperature, filtered and concentrated under reduced pressure to give a yellow oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give methyl 3-{1-[(6-chloropyrazin-2-yl)amino]ethyl}benzoate (30 mg, 15%) as a pale yellow oil.
Reaction SMILES: [Cl-].[Li+].BrCCBr.Br[CH2:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1.[Cl:20][C:21]1[CH:22]=[C:23](I)[CH:24]=[CH:25][C:26]=1[Cl:27].[Cl-].[NH4+]>C1COCC1.[Zn].CC(C1C=CC=C(C(C)C)C=1N1[CH-]N(C2C(C(C)C)=CC=CC=2C(C)C)CC1)C.C1C=NC=C(Cl)C=1.Cl[Pd]Cl.C[Si](Cl)(C)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=1
Reactant: Clc1ccc(I)cc1Cl
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cccc(C(C)C)c1N1[CH-]N(c2c(C(C)C)cccc2C(C)C)CC1
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCOC(=O)c1ccc(Cc2ccc(Cl)c(Cl)c2)cc1
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
A mixture of zinc (404 mg, 6.17 mmol) and lithium chloride (261 mg, 6.17 mmol) under argon was warmed for 15 minutes using a hot air gun, allowed to cool and then anhydrous THF (20 mL) added. The zinc was activated by treatment with 1,2-dibromoethane (19 mg, 0.10 mmol) and TMSCl (2.2 mg, 0.02 mmol). To the resulting mixture at 25° C. was added ethyl 4-(bromomethyl)benzoate (500 mg, 2.06 mmol) and the mixture stirred for 15 minutes. A solution of 3,4-dichloro-iodobenzene (392 mg, 1.44 mmol) in anhydrous THF (5 mL) was added, followed by (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride [PEPPSI™-SlP] (14 mg, 0.02 mmol) and the mixture stirred at 25° C. for 1 hour. Saturated ammonium chloride solution was added and the crude product extracted with ether. The ether extract was washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was purified by silica gel column chromatography eluting with 7:3 hexane:ethyl acetate to afford the title compound (240 mg, 38%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]([CH:17]=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].[CH3:37][Mg]I.[Cl-].[NH4+]>O1CCCC1.C1(C)C=CC=CC=1.CCOCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C:14]([CH:17]([OH:18])[CH3:37])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 36.3 %

Procedure:
To a stirred solution of diphenylmethyl 7-(2-thienylacetamido)-3-formyl-2-cephem-4-carboxylate (1.556 g) in a mixture of tetrahydrofuran (30 ml) and toluene (30 ml) is added a solution of methylmagnesium iodide (1.853 mM/ml) in ether (13 ml) during 4 minutes at -40° C. After 15 minutes, the reaction mixture containig diphenylmethyl 7-(2-thienylacetamido)-3-(1-iodomagnesium oxyethyl)-2-cephem-4-carboxylate is poured into an aqueous saturated solution of ammonium chloride (30 ml), and is extracted with acetate. The extract solution is washed with saturated saline, dried over sodium sulfate, and evaporated under reduced pressure to give diphenylmethyl 7-(2-thienylacetamido)-3-(1-hydroxyethyl)-2-cephem-4-carboxylate, IR: νmaxCHCl 3 3400, 3350, 1780, 1750, 1685, 1505 cm-1. The product is dissolved in pyridine (16 ml), and is mixed with acetyl chloride (0.47 ml) under ice cooling. After 35 minutes, the reaction mixture is decomposed with a small amount of ice, poured into water after 10 minutes, and is stirred with ethyl acetate under ice cooling. The solution is neutralized with 4N-hydrochloric acid to pH 2.5, and is extracted with ethyl acetate. The extract solution is washed with saturated saline, dried over sodium sulfate, and evaporated under reduced pressure. Purification of the residue (1.66 g) by chromatography over silica gel (68 g) gives from fractions eluted with a mixture of benzene and ethyl acetate (6:1) diphenylmethyl 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-2-cephem-4-carboxylate (625 mg: a mixture of stereoisomers). Colorless amorphous powder. Yield: 36.3%. NMR: δCDCl 3 1.21d(7.3Hz)3H, 1.73s+1.83s3H, 3.80s2H, 5.0-5.6m4H, 6.38br-slH, 6.9-7.4ml4H. IR: νmaxCHCl 3 3400, 1782, 1746, 1690, 1502 cm-1.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:36])=[C:5]([C:32]([O:34][CH3:35])=[O:33])[CH:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:7]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][N:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:15])[N:9]=1.[H-].[Na+].[CH3:39]I>CN(C=O)C>[CH2:16]([N:14]([CH2:13][C:10]1[N:9]=[C:8]([C:7]2[CH:6]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:5]([C:32]([O:34][CH3:35])=[O:33])=[C:4]([CH3:36])[N:3]([CH3:39])[C:2]=2[CH3:1])[O:12][N:11]=1)[CH3:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CI
Reactant: COC(=O)C1=C(C)NC(C)=C(c2nc(CN(C)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(C)C(C)=C(c2nc(CN(C)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
To a stirred solution of 250 mg of methyl 1,4-dihydro-2,6-dimetyl-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-4-(3-nitrophenyl)pyridine-5-carboxylate in 5 ml of dry DMF was added 24 mg of 60% sodium hydride with ice-cooling. After the mixture was stirred for 10 minutes, there was added 76 mg of methyl iodide. The reaction mixture was allowed to stand at room temperature for 6 hours, diluted by addition of ice-water and then extracted with ethyl acetate. The extracts were washed with water, dried and evaporated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol (30:1) as eluent to give 190 mg of methyl 1,4-dihydro-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-1,2,6-trimethyl-4-(3-nitrophenyl)pyridine-5-carboxylate, IR νmaxneat cm-1 : 1690, 1635, 1580, 1520, 1340, 900.