Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:11])[S:9][CH:10]=1)=[O:5])[CH3:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)Cl>ClCCCl>[Br:12][CH2:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1csc(C)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1csc(CBr)n1
Temperature: 70 °C
Yield: 8 %

Procedure:
A mixture of ethyl-2-methylthiazole 4-carboxylate (500 mg, 2.9 mmol), N-bromosuccinimide (877 mg, 4.9 mmol), and benzoyl peroxide (5–10 mg) in 1,2-DCE (3 mL) was heated at 70° C. for 85 h. After cooling to room temperature, DCM (10 ml) was added and washed with water (3 times). The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by preparative chromatography to yield the above-titled compound (58 mg). 1H NMR (CDCl3): 8.23 (1H, s), 4.77 (2H, s), 4.43 (2H, q), 1.42 (3H, t).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:9]([CH3:10])=[N:8][CH:7]=[CH:6][N:5]=1.N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[NH2:3][C:4]1[C:9]([CH3:10])=[N:8][C:7]([Br:1])=[CH:6][N:5]=1
Reactant: Cc1nccnc1N
Reactant: BrBr
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1nc(Br)cnc1N
Reaction time: 1 h
Yield: 28 %

Procedure:
A solution of bromine (0.26 ml) in chloroform (40 ml) was added dropwise to a stirred solution of 2-amino-3-methylpyrazine (0.453 g) and pyridine (0.4 ml) in chloroform (100 ml) with shielding from sunlight, over a period of 1 hour. The reaction mixture was stirred for a further 30 minutes and then water (25 ml) was added. The organic layer was separated, dried (MgSO4) and evaporated to afford a brown oil. The oil was purified by chromatography on silica gel, eluting with dichloromethane, to give 2-amino-5-bromo-3-methylpyrazine as a white solid (0.312 g, 28%), m.p. 51-52°° C.; mass spectrum (+ve CI): 188 (M+H)+.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][C:23]([C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[C:24]([Br:28])[C:25]=1[O:26][CH3:27])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][C:23]([C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[C:24]([Br:28])[C:25]=1[O:26][CH3:27])=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1c(C(=O)NC(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)sc(-c2ccnn2C)c1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(=O)NC(CN)Cc2ccccc2)sc(-c2ccnn2C)c1Br
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl[2-({[4-bromo-3-(methyloxy)-5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part e) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (3% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [F:1][CH:2]([F:42])[O:3][C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([C:38]([F:41])([F:40])[F:39])[CH2:34][CH2:33]2)[CH:11]=[CH:10][C:5]=1[C:6]([NH:8][OH:9])=[NH:7].C(N(C(C)C)CC)(C)C.Cl[C:53](OC1C=CC=CC=1)=[O:54].O>O1CCCC1>[F:42][CH:2]([F:1])[O:3][C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=3)=[N:18][C:17]=2[CH2:31][N:32]2[CH2:33][CH2:34][CH:35]([C:38]([F:41])([F:40])[F:39])[CH2:36][CH2:37]2)[CH:11]=[CH:10][C:5]=1[C:6]1[NH:7][C:53](=[O:54])[O:9][N:8]=1
Reactant: N=C(NO)c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CN2CCC(C(F)(F)F)CC2)cc1OC(F)F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c(-c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3CN3CCC(C(F)(F)F)CC3)cc2OC(F)F)no1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 475 mg of 2-difluoromethoxy-N-hydroxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-benzamidine in 7.8 mL of tetrahydrofuran at 0° C. was added 1.8 mL of diisopropylethylamine followed by 0.1 mL of phenyl chloroformate. The resulting mixture was stirred for 5 minutes at 0° C. then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved 7.8 mL of tetrahydrofuran and 0.33 mL of diisopropylethylamine. The resulting solution was heated in a sealed tube to 150° C. under microwave irradiation for 15 minutes. After allowing it to cool down to room temperature, the mixture was poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (diisopropyl ether 100 followed by a gradient from dichloromethane 100 to dichloromethane 90/methanol 10) followed by another column chromatography on silica gel (gradient from dichloromethane 100 to dichloromethane 90/tetrahydrofuran 10) to give 70 mg of 3-{2-difluoromethoxy-4-[2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-ylmethoxy]-phenyl}-4H-1,2,4-oxadiazol-5-one.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[O:8])[CH3:7].[C:9](=O)([O:12]C)[O:10][CH3:11].[H-].[Na+].Cl>C(OCC)(=O)C.O.O1CCCC1>[O:8]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH2:7][C:9]([O:10][CH3:11])=[O:12]
Reactant: CC(=O)c1nccs1
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC(=O)c1nccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 50 mL of a tetrahydrofuran solution containing 5.0 g of 1-(1,3-thiazol-2-yl)ethanone, 6.3 mL of dimethyl carbonate and 3.0 g of 60% sodium hydride were added at 10° C. The temperature of the reaction mixture was increased to room temperature, and the mixture was stirred for 16 hours. Thereto was further added 0.75 g of 60% sodium hydride, and the mixture was stirred for 4 hours. Water and ethyl acetate were then added thereto, and the reaction mixture was adjusted to pH 3.0 with 6 mol/L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=5:1] to obtain 2.3 g of a yellow oily substance, methyl 3-oxo-3-(1,3-thiazol-2-yl)propionate.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=1)#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:18]([F:24])[C:17]=1[SH:25]>>[F:22][C:21]1[C:16]2[N:2]=[C:1]([CH2:3][C:4]3[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[C:8]([I:10])[CH:9]=3)[S:25][C:17]=2[C:18]([F:24])=[CH:19][C:20]=1[F:23]
Reactant: N#CCc1cc(I)cc(CC#N)c1
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cl
Product: N#CCc1cc(I)cc(Cc2nc3c(F)c(F)cc(F)c3s2)c1
Yield: 36.3 %

Procedure:
The procedure of Example 22-i) was repeated using 1,3-biscyanomethyl-5-iodobenzene (420 mg, 1.49 mmol) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (321 mg, 1.49 mmol) and the resultant product was crystallized from ethyl acetate-hexane to give 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]-5-iodophenylacetonitrile (240 mg, 36%) as a colorless powder.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10][C@@H:11]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:12])(=O)=O.[H-].[Na+].O>CS(C)=O>[CH3:12][C@H:11]1[CH2:10][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8][CH2:7][CH2:6][N:13]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: C[C@@H](CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a solution of (S)-6-Benzyloxycarbonylamino-4-(tert-butoxycarbonyl)-4-azaheptyl methanesulfonate (425 g, 0.956 mol) in dimethyl sulfoxide (1.6 L) was added 60% sodium hydride (76.5 g, 1.91 mol) at an internal temperature of 25° C. or below, followed by stirring at room temperature for 2 hours. After confirming the disappearance of the starting materials by TLC, the reaction mixture was poured into water, followed by extracting with ethyl acetate. The resulting organic layer was washed with saturated brine, 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine in this order, and then dried over anhydrous sodium sulfate. The resulting solution was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (14% ethyl acetate-petroleum ether) to give the target product as a pale yellow oil (199 g, containing about 30 g of mineral oil, yield 50.4%).
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19]C(=O)COC4C=CC=CC=4)[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH:35]C(=O)C)[CH3:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH2:19])[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH2:35])[CH3:31])=[O:11])=[CH:40][CH:41]=1)([O-:3])=[O:2]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: C[C@@]1(COC(N)=O)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylic acid p-nitrobenzyl ester (1.17 g, 2.0 mmol) in methylene chloride (10 ml) at -40° was charged with dimethylaniline (1.03 ml, 8.0 mmol) and phosphorous pentachloride (0.92 g, 4.4 mmol). The solution was stirred at -35° to -40° for 30 minutes and cold (~-35°) methanol (4.1 ml, 100 mmol) was added dropwise. The pale green solution was stirred at -35° to -40° for 2 hours and then quenched into ice-water (10 ml). The pH was adjusted to 1.7 with conc. ammonia and the layers were separated. The aqueous was washed with CH2Cl2 (5 ml), combined with a water back-extract (5 ml), and stirred with CH2Cl2 (10 ml) during pH adjustment to 6.5 with ammonia. The organic phase was withdrawn, washed (5 ml, H2O), combined with a back-extract (CH2Cl2, 10 ml), dried (4A sieves), filtered, concentrated to 4 ml and diluted with heptane (10 ml). The suspension was concentrated to 8 ml and the liquids were decanted. The solids were treated with CH2Cl2 (4 ml) and heptane (10 ml) in the same fashion, and the product was washed with heptane and dried to an off-white solid (0.28 g) 34% nmr 100 MHz CDCl3 -D2O δ8.24 (2, d, J=8.5 Hz, 1/2 pNB AB), 7.56 (2, d, J=8.5, pNB AB), 5.68 (1, brd J=4, C5 -H), 5.32 (2, s, benzyl CH2), 4.76 (1, s, C3 -H) 4.55 (HOD overlapping C6 -H d), 4.16 and 3.97 (2, ABq J=11.5 C2 -CH2 -O), 1.43 (3, s, C3 -CH3), with 2.36 (3/4, s, ##STR78## of impurity N-acetyl analog; ~25 mol %).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]#N)[N:4]=1.[OH2:21].CC1C=CC([CH2:29][O:30]C(NNC(C2C=NC=CN=2)=O)=O)=CC=1>CO.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]([O:30][CH3:29])=[O:21])[N:4]=1
Reactant: O
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#N)n1
Reactant: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1nc(C)cc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 80 °C
Yield: 94 %

Procedure:
Concentrated aq. hydrochloric acid (42 mL, 491.4 mmol) was added to a stirred suspension of 4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine-2-carbonitrile [CAS: 951232-17-0] (8.3 g, 31.53 mmol) in methanol (248 mL). The stirred mixture was heated at block temperature of 80° C. for 20 h. The reaction mixture was cooled to ambient temperature, diluted with DCM (500 ml) and Na2CO3 solid was added with stirring. Water (500 ml) was added and the mixture transferred to a separating funnel and shaken (aqueous phase had pH10). The aq. phase was re-extracted with DCM (200 ml) and the combined organic layers were dried (Na2SO4) and evaporated to an oil which solidified, to give 7.6 g after drying. This was dissolved in DCM (30 ml) and the solution was applied to a 340 g silica cartridge which was then eluted on a Biotage SP4 system with a gradient of EtOAc/iso-hexane from 0-75% to give methyl 4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine-2-carboxylate (D29) (6.1 g, approximately 94% pure, contaminated with decarboxylated material);
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:17](=[O:19])[NH:16][C:15]=2[CH:20]=1.[H-].[Na+].[C:23]([O:26][CH2:27][CH2:28]Br)(=[O:25])[CH3:24].Cl>CN(C)C=O.O>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[S:18][C:17](=[O:19])[N:16]([CH2:28][CH2:27][O:26][C:23](=[O:25])[CH3:24])[C:15]=2[CH:20]=1
Reactant: CC(=O)OCCBr
Reactant: Cc1c(-c2ccc3sc(=O)[nH]c3c2)nc2ccccn12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCn1c(=O)sc2ccc(-c3nc4ccccn4c3C)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
A mixture of 5-(3-methylimidazo[1,2-a]pyridin-2-yl)-2-benzothiazolinone (2.8 g) and sodium hydride (50% suspension in oil, 0.96 g) in dry dimethylformamide (30 ml) was stirred at ambient temperature for 30 minutes. To the resultant mixture was added 2-bromoethyl acetate (3.34 g) at ambient temperature and stirred for 5 hours under the same condition. The reaction mixture was poured into water and adjusted to pH 7.0 with 10% hydrochloric acid. The neutrallized solution was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was subjected to column chromatography on silica gel eluting with a mixture of ethyl acetate and diisopropyl ether (8:2). The fractions containing the desired compound was combined and evaporated in vacuo. The crystalline residue was recrystallized from ethyl acetate to afford 5-(3-methylimidazo[1,2-a]pyridin-2-yl)-3-(2-acetoxyethyl)-2-benzothiazolinone (1.3 g). mp. 113°-115° C.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6].[H-].[Na+].[CH2:20](I)[CH3:21]>CN(C=O)C>[CH3:17][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:20][CH3:21])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CCI
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N-{3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl}acetamide 2 (12.7 g, 0.055 mol) and sodium hydride (60% in oil) (2.5 g) in DMF (150 ml) under nitrogen was stirred at room temperature for 30 minutes. The solution was then cooled to 0° C., and a solution of ethyl iodide (9.38 g, 0.063 mol) in DMF (50 ml) was added slowly dropwise. The mixture was then stirred at room temperature for one hour. The DMF was removed under high vacuum, water (200 ml) was added to the residue and the mixture was extracted with ethyl acetate (2×200 ml). The combined ethyl acetate extracts were washed with water (150 ml) and brine (100 ml), dried over sodium sulfate, filtered and concentrated to dryness to give the crude product. Compound 5 was obtained after recrystallization from hexane (7.9 g). M. P. (Hexane): 109-112° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([F:13])=[C:6]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH2:2][C:1]([C:4]1[C:5]([F:13])=[C:6]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:7]#[N:8])=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1cc(F)cc(C#N)c1F
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(F)cc(C(=O)CBr)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 6.85 g of 3-acetyl-2,5-difluorobenzonitrile and 220 mL of CHCl3 heated at reflux is added dropwise over 75 minutes a solution of 2.1 mL of Br2 in 50 mL of CHCl3. The mixture is boiled for another 15 minutes, cooled to 25° C., washed sequentially with saturated NaHCO3 and H2O (200 mL each), dried with Na2SO4 and stripped in vacuo to 10.26 g of brown oil. The oil which contains 78% of 3-bromoacetyl-2,5-difluorobenzonitrile by NMR analysis is satisfactory for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[N:6][CH2:7][C:8]1(C)[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]1)[CH3:2].[CH:16]1[CH2:20][CH:19]=[CH:18][CH:17]=1.[C:21](O)(C(F)(F)F)=O.O>CN(C=O)C>[C:8]1([CH:7]([N:6]2[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:20]3[CH2:16][CH:17]2[CH:18]=[CH:19]3)[CH3:21])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1=CCC=C1
Reactant: CCOC(=O)C=NCC1(C)C=CC=CC1
Reactant: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1C2C=CC(C2)N1C(C)c1ccccc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 58.9 %

Procedure:
To a mixture of N-[(1-methyl)phenylmethyl]imino-acetic acid ethyl ester (67.5 g; 328.9 mmol) and cyclopentadiene (43.48 g, 657.8 mmol) in dry DMF under argon cooled to 0° C., was added in portions (5 ml portion) 37.5 g (328.9 mmol) of TFA followed by water (0.057 ml) and the resulting mixture was allowed to stir at room temperature for 22 hours. The above reaction mixture was poured into ice, extracted with 80% hexane in ethyl acetate (to remove excess cyclopentadiene), and the aqueous layer was slowly neutralized with sodium bicarbonate (to pH=8). The aqueous layer was extracted with ethyl acetate and the organic layer was separated and dried over sodium sulfate. The organic solvent was concentrated in vacuo to afford 52.6 g (62%) of ethyl 2-(1-phenylethyl)-2 -azabicyclo [2,2,1 ]hept-5-en-3-carboxylate.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 74.1 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 3.3 g.), conc.hydrochloric acid (2.80 g.), tetrahydrofuran (20 ml.) and methanol (50 ml.) were treated in a similar manner to that of Example 15-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.3 g.)
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][C:14]=1F)(=[O:12])=[O:11])(C)C.[OH:30][C:31]1[CH:32]=[C:33]([CH:43]=[C:44]([O:46][C@@H:47]([CH3:60])[CH2:48][O:49][Si](C(C)C)(C(C)C)C(C)C)[CH:45]=1)[C:34]([NH:36][C:37]1[CH:41]=[CH:40][N:39]([CH3:42])[N:38]=1)=[O:35].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[O:12]=[S:10]1(=[O:11])[C:13]2[CH:14]=[CH:15][C:16]([O:30][C:31]3[CH:32]=[C:33]([CH:43]=[C:44]([O:46][C@@H:47]([CH3:60])[CH2:48][OH:49])[CH:45]=3)[C:34]([NH:36][C:37]3[CH:41]=[CH:40][N:39]([CH3:42])[N:38]=3)=[O:35])=[CH:17][C:18]=2[O:6][CH2:7][CH2:8][N:9]1[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)S(=O)(=O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@@H](CO)Oc1cc(Oc2ccc3c(c2)OCCN(Cc2ccccc2)S3(=O)=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 150 °C
Yield: 117.8 %

Procedure:
N-(2-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}ethyl)-2,4-difluoro-N-(phenylmethyl)benzenesulfonamide (291 mg, 0.66 mmol) was added to 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-{(s)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzamide (296 mg, 0.66 mmol) and potassium carbonate (183 mg, 1.31 mmol) in dry DMA (4 mL). The mixture was heated in a Smith Creator microwave at 150° C. for 45 mins. Water (25 mL) was added to the reaction mixture and extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated. Purification by column chromatography on silica, eluting with 80-90% ethyl acetate in isohexane, afforded the title compound as a colourless oil (450 mg). 1H NMR δ (CDCl3): 1.25 (d, 3H), 2.16-2.19 (m, 1H), 3.53 (t, 2H), 3.68-3.71 (m, 2H), 3.74 (s, 3H), 4.14 (t, 2H), 4.18 (s, 2H), 4.50 (ddd, 1H), 6.70 (d, 1H), 6.72 (d, 1H), 6.75 (t, 1H), 6.78 (dd, 1H), 7.09 (t, 1H), 7.22 (ddd, 1H), 7.24-7.26 (m, 1H), 7.28-7.29 (m, 5H), 7.78 (d, 1H), 8.45 (s, 1H). m/z 579 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:28])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].I[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCCCC)CCC.[Cu]>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:28])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([S:18]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:16][CH:17]=2)=[C:2]([NH:1][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:7]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(CCC(=O)c3ccc(Cl)cc3N)cc2)CC1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOCCCC
Product: CN1CCN(S(=O)(=O)c2ccc(CCC(=O)c3ccc(Cl)cc3Nc3ccccc3)cc2)CC1
Temperature: 160 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of 1-(2-amino-4-chlorophenyl)-3-[4-(4-methylpiperazine-1-sulfonyl)-phenyl]-propan-1-one (1.268 g), copper powder (38 mg), KI (99 mg), K2CO3 (829 mg) and iodobenzene (1.35 mL) in dibutyl ether (25 mL) was heated to 160° C. (oil bath temperature) overnight. Additional copper powder (38 mg), KI (99 mg), K2CO3 (829 mg) and iodobenzene (1.35 mL) were added, and the resulting mixture was again stirred at 160° C. overnight. The reaction mixture was then cooled and concentrated under reduced pressure. The residue was partitioned between water and EtOAc, the organic layer was separated, and the aqueous layer was extracted 2× with EtOAc (50 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/MeOH, 100/0 for 5 minutes, 98/2 from minute 8 to 20) to give 1-(4-chloro-2-phenylaminophenyl)-3-[4-(4-methylpiperazine-1-sulfonyl)-phenyl]-propan-1-one (1.02 g; 68% yield). MS=498.0 [M+H]+.