Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:30])=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>Cl.O1CCOCC1>[CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]3=[O:30])=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C1CCCC1
Reaction time: 12 h

Procedure:
At RT, 695 mg (1.71 mmol) of tert-butyl(+/−)-cyclopentyl{4-[(1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}acetate were dissolved in 11 ml of a 4 N solution of hydrogen chloride in dioxane, and the mixture was stirred for 12 h. The reaction mixture was then frozen and freeze-dried under high vacuum. This gave 700 mg of product, which was not purified any further.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([Cl:8])[C:5]([CH3:7])=[O:6].[H-].[Na+].[Li]CCCC.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][C:28]([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>C1COCC1>[CH3:1][O:2][C:3](=[O:9])[CH:4]([Cl:8])[C:5](=[O:6])[CH2:7][C:28]([CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)([OH:29])[CH2:27][CH2:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([Cl:17])[CH:19]=1
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: COc1ccc(CCC(=O)C2CCCC2)cc1Cl
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(Cl)C(=O)CC(O)(CCc1ccc(OC)c(Cl)c1)C1CCCC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Methyl-2-chloroacetoacetate (2.5 g, 16.9 mmol) was added to a cooled 0° C. suspension of NaH (0.68 g, 16.9 mmol, 60% dispersion in mineral oil) in THF (30 ml). After 15 min the solution was cooled to −40° C. and n-BuLi (10.6 mL, 16.9 mmol, 1.6M in hexanes) was added. The resulting dianion was stirred for an additional 30 min and then treated with a solution of 3-(3-Chloro-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one (1.5 g, 5.6 mmol, prepared from Heck route) in THF (10 ml). After stirring for 1H at −40° C., the reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The organic layers were washed with brine, dried with Na2SO4 and concentrated to an orange oil that was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]1[CH3:14].[ClH:15].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:17]1.S1C2C=CC=CC=2C(N2CCNCC2)=N1.[Na+].[I-]>C(#N)C>[ClH:15].[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH:7]3[CH3:14])[CH2:29][CH2:30]2)=[N:17]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC1SC(C)(C)C(=O)N1CCCCBr
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC1SC(C)(C)C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 65 °C
Yield: 61.3 %

Procedure:
A mixture of 3-(4-bromobutyl)-2,5,5-trimethyl-4-thiazolidinone (4.70 g), 1-(1,2-benzisothiazol-3-yl)piperazine 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (4.72 g), K2 CO3 (8.13 g) and NaI (300 mg) in acetonitrile (200 ml) was heated at 65° C. for 16 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.77 g of crystals, m.p. 209°-214° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[N:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[CH:4][CH:3]=2)=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Yield: 87.9 %

Procedure:
1,1-Dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (6.87 g, 88%) was prepared as a gray solid from 1,1-dimethylethyl 4-{[(6-chloro-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 73, Step 1, 5.73 g, 17.5 mmol), [4-(methylsulfonyl)phenyl]boronic acid (3.85 g, 17.53 mmol), Pd(PPh3)4 (10.13 g, 8.76 mmol), 2M Na2CO3 (26 mL) in DME (170 mL) in a manner similar to Example 1, Step 1. 1H NMR (400 MHz, CDCl3): δ 8.40 (d, 1H, J=2.9 Hz), 8.15-8.12 (m, 2H), 8.02-7.99 (m, 2H), 7.73 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, Ja=8.7 Hz, Jb=3.0 Hz), 4.19 (bs, 2H), 3.91 (d, 2H, J=6.4 Hz), 3.08 (s, 3H), 2.81-2.71 (m, 2H), 2.07-1.96 (m, 1H), 1.87-1.82 (m, 2H), 1.47 (s, 9H), 1.36-1.24 (m, 2H); LRMS (APCI), m/z 447 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O:19]=[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[N:21]1[C@@H:30]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:31]([N:33]1[CH:38]=[CH:37][CH2:36][CH:35]=[CH:34]1)=[O:32].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CCCCCC>[O:29]=[C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](=[O:19])[N:21]1[C@H:30]1[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH:34]2[CH2:35][CH2:36][CH:37]=[CH:38][N:33]2[C:31]1=[O:32]
Reactant: O=C([C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)N1C=CCC=C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)Cc2ccccc2C2CCC=CN12
Reaction time: 0.5 h

Procedure:
Combine sulfuric acid (3.0 mL, 96%) and trifluoroacetic anhydride (300 mL). Add (S)-N-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl]-1,4-dihydro-pyridine (1.0 mmol). After 30 minutes, pour the reaction mixture into mixture of saturated aqueous sodium bicarbonate and ice. Extract with ethyl acetate and then with methylene chloride. Combine the organic layers and filter through a plug of silica gel. Rinse the silica gel with dichloromethane. Evaporate the filtrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% ethyl acetate/hexane and then 25% ethyl acetate/hexane to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[CH2:13][OH:14].O.[OH-].[K+].S(OC)(O[CH3:22])(=O)=O>C1(C)C=CC=CC=1>[CH3:22][O:14][CH2:13][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([CH2:9][OH:10])=[C:5]([F:11])[C:4]=1[F:12]
Reactant: COS(=O)(=O)OC
Reactant: OCc1c(F)c(F)c(CO)c(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COCc1c(F)c(F)c(CO)c(F)c1F
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 100.8 %

Procedure:
Into a reaction vessel that was charged nitrogen, 5.00 g (23.1 mmol) of 2,3,5,6-tetrafluoro-1,4-benzenedimethanol, 15.00 g of water and 1.30 g (23.1 mmol) of potassium hydroxide were charged subsequently, and heated to 60° C. with stirring. At this time, solid 2,3,5,6-tetrafluoro-1,4-benzenedimethanol was completely dissolved to be a clear solution. Then, a mixture of 15.0 g of toluene and 3.07 g (23.1 mmol) of dimethyl sulfate was added at 55±5° C. After stirring at 50±5° C. for 1.5 hours, 0.64 g (11.4 mmol) of potassium hydroxide and 1.51 g (12.6 mmol) of dimethyl sulfate were added. After 1.5 hours, 0.66 g (11.7 mmol) of potassium hydroxide and 1.51 g (12.6 mmol) of dimethyl sulfate were further added and stirred at the same temperature for 1.5 hours. Allowing the reaction mixture to cool to room temperature, the layers of the reaction mixture were separated and the water layer was extracted with 30 ml of ethyl acetate. The organic layers were combined, washed with 30 ml of water, concentrated, and dried under reduced pressure to give 5.22 g of crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol. The crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol was subjected to content analysis by GC internal standard method (Analytical method 1 given later). GC area percentage of the crude product: 87% of the objective compound, 4% of the starting compound and 8% of the by-product compound Content analysis by GC internal standard method: 85% of the objective compound and 86% of the yield of pure compound
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[C:10]([O:17][CH3:18])(=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].C(Cl)Cl>O1CCOCC1.[Cu]Br>[CH3:15][O:14][C:12](=[O:13])[CH:11]([C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Br:9])[CH:3]=1)[C:10]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC(=O)OC
Reactant: Clc1cc(Br)cc(Br)c1
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)C(C(=O)OC)c1cc(Cl)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1,3-Dibromo-5-chlorobenzene (25 g, 93 mmol), dimethyl malonate (23.4 mL, 204 mmol), and copper(I) bromide (29.2 g, 204 mmol) were combined in 1,4-dioxane (300 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil; 8.2 g, 204 mmol) was added slowly, and the reaction was stirred at room temperature for 20 minutes, and then stirred at 105° C. for 4 hours. After cooling to room temperature, the mixture was worked-up with CH2Cl2 and aqueous Na4OH. The organic layer was concentrated, and the residue was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CCCCCC)=C=[O:17]>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][NH:10][C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:2]([C:1]([NH2:8])=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCN=C=O
Agent: O=C1CNC(=O)N1Cc1ccccc1
Product: CCCCCCC(N)=O

Procedure:
3-Benzylimidazolidine-2,4-dione (100 mg, 0.526 mmol) and 1-isocyanatohexane (80.2 mg, 0.63 mmol) were reacted in analogy to example 1. Yield: 19.3 mg (12%), M+H+: 318.15.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C@H:11]([CH3:15])[C@H:12]([OH:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([I:24])=[CH:19][N:18]=1.[Cl-].[Na+]>C(OCC)C.CCCCCC.C(OCC)(=O)C>[CH2:3]([O:10][C@H:11]([CH3:15])[C@@H:12]([CH3:13])[O:14][C:19]1[C:20]([I:24])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: C[C@@H](O)[C@@H](C)OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1I
Yield: 41 %

Procedure:
2.07 g sodium hydride (55%) was added in portions to 8.55 g (47.4 mmol) (2R,3R)-3-benzyloxy-butan-2-ol in 56 ml diethyl ether at 0° C. with stirring. After 10 minutes the ice bath was removed and it was stirred for a further 3 minutes at room temperature. The suspension formed was added at 0° C. to a solution of 6.52 g (23.7 mmol) of 2,4-dichloro-5-iodo-pyrimidine. The mixture was stirred for 4 hours at 40° C. and then dilute sodium chloride solution was added. It was then extracted with ethyl acetate (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was chromatographically (hexane/ethyl acetate 4:1). 4.12 g (9.8 mmol; yield: 41%) of the product was obtained.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][C:8]1=[O:9].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[NH:7][C:8](=[O:9])[CH2:10][CH2:11]2)=[O:4]
Reactant: O=C1CCc2ccccc2N1
Reactant: CC(Br)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc2c(c1)CCC(=O)N2
Temperature: 0 °C

Procedure:
A mixture of α-bromopropionyl chloride (50 g) in methylene chloride (350 ml) is added to a stirred mixture of 3,4-dihydrocarbostyril (21.8 g) and aluminum chloride (44.8 g). The reaction mixture is stirred under reflux for four hours, poured into an ice water mixture, stirred for 30 minutes and the solid filtered, washed with water, dried, and recrystallized from isopropanol affording the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[C:7]([CH3:19])[CH:6]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1>[CH3:19][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18]
Reactant: COC(=O)c1ccc(-c2ccccc2OC)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc(C(=O)O)cc1C
Yield: 89.2 %

Procedure:
The (2-methyl-2′-methoxy-[1,1′-biphenyl]-4yl)carboxylic acid methyl ester of Step A (1.9 g, 7.4 mmol) was dissolved in tetrahydrofuran (30 mL) and 1 N sodium hydroxide (15 mL, 15 mmol) was added. The reaction mixture was heated at reflux overnight, then cooled and acidified with 2 N hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.6 g of product as a white solid, m.p. 160–162° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[N:4][C:5]([CH3:9])=[C:6]([Br:8])[CH:7]=1.[CH2:11]([N:14]([CH3:16])[CH3:15])[C:12]#[CH:13]>C(NCC)C.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+].[Cu](I)I.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>[Br:8][C:6]1[CH:7]=[C:2]([C:13]#[C:12][CH2:11][N:14]([CH3:16])[CH3:15])[C:3]([CH3:10])=[N:4][C:5]=1[CH3:9]
Reactant: Cc1nc(C)c(Br)cc1Br
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Solvent: CCNCC
Solvent: CCOC(C)=O
Product: Cc1nc(C)c(C#CCN(C)C)cc1Br
Temperature: 50 °C
Reaction time: 15 h
Yield: 46.9 %

Procedure:
To a mixture of 3,5-dibromo-2,6-dimethylpyridine (605 mg, 2.54 mmol), copper iodide (22 mg, 0.11 mmol) and bis(triphenylphosphine)palladium(II) chloride (41 mg, 0.058 mmol) in diethylamine (3.0 mL) was added propargyl(dimethylamine) (0.27 mL, 2.50 mmol). The reaction mixture was allowed to stir for 15 h at 50° C. and was then allowed to cool to rt. The resulting mixture was diluted with EtOAc (30 mL) and 1M aqueous Na2CO3 (20 mL). After stirring for 30 min, the organic solution was separated and the aqueous solution was extracted with EtOAc (2×15 mL). The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3-(5-bromo-2,6-dimethylpyridin-3-yl)-N,N-dimethylprop-2-yn-1-amine (313 mg, 51%) as a dark oil. LCMS (AA): Rt=1.47 min, m/z=267.1 (M−H), 269.1 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH2:6].[N:18]([CH2:21][CH2:22][C:23]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1)=[N+:19]=[N-:20].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl.O.C(OCC)(=O)C.CCCCCC>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[NH:6][C:28]([C:23]1([CH2:22][CH2:21][N:18]=[N+:19]=[N-:20])[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:29]
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=NCCC1(C(=O)O)CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)C1(CCN=[N+]=[N-])CCCC1
Yield: 95.1 %

Procedure:
A solution of 4-nitro-L-phenylalanine methyl ester hydrochloride (3.0 g, 11.5 mmol), 1-(2-azidoethyl)cyclopentane carboxylic acid (2.3 g, 12.7 mmol) and BOP (5.34 g, 12.1 mmol) in dichloromethane (6 mL) and DMP (4 mL) was treated with diisopropylethylamine (4.2 mL, 24.2 mmol). The mixture was stirred overnight at which time TLC (1:1 hexane:ethyl acetate) indicated no more starting material. The mixture was diluted with water, extracted with ethyl acetate. The extracts were washed with water and brine, then were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography over silica gel (3:1 hexane:ethyl acetate) to afford 4.26 g of N-[[1-(2-azidoethyl)cyclopentyl]carbonyl]-4nitro-L-phenylalanine methyl ester.
Reaction SMILES: COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O.[SH:19][C:20]1[S:24][C:23]([CH3:25])=[N:22][N:21]=1.CC(O[CH2:30][C:31]1[CH2:40][S:39][C@@H:34]2[C@H:35]([NH2:38])[C:36](=[O:37])[N:33]2[C:32]=1[C:41]([OH:43])=[O:42])=O.N>C(#N)C>[NH2:38][CH:35]1[C:36](=[O:37])[N:33]2[C:32]([C:41]([OH:43])=[O:42])=[C:31]([CH2:30][S:19][C:20]3[S:24][C:23]([CH3:25])=[N:22][N:21]=3)[CH2:40][S:39][C@H:34]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1nnc(S)s1
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Agent: N
Solvent: CC#N
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A 14.8 g quantity of DCPA was cooled at 14° C., and 1.59 g of 5-mercapto-2-methyl-1,3,4-thiadiazole was added to it, whereby the mixture reached at the temperature of 25° C. and dissolved. 6.0 ml of acetonitrile was added and the solution was cooled at 15° C., to which 2.72 g of 7-ACA and 10.0 ml of acetonitrile were added, followed by stirring at 25° to 27° C. for 30 minutes. The reaction solution was poured into 80 g of ice-water, which was placed in a refrigerator overnight, adjusted to pH 4.0 with 25% aqueous ammonia and stirred for 1.0 hour under ice-cooling. The resultant precipitate was recovered by filtration, washed with 50 ml each of cold water and acetone successively, and dried, thereby affording 2.40 g of 7-amino-3-[(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8].[CH2:10](I)[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])O.[Na+]>C(#N)C>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCI
Reactant: O=C(O)c1occc1Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1occc1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
3-Bromofuran-2-carboxylic acid (1.86 g, 9.75 mmol), ethyl iodide (3.1 mL, 38.8 mol) and cesium carbonate (4.80 g, 14.7 mmol) were suspended in acetonitrile (50 mL), followed by stirring at 80° C. for 3 hours. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=9:1) to afford ethyl 3-bromofuran-2-carboxylate (1.16 g, 54%).
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([F:13])[CH:5]=1)([OH:3])[OH:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.Cl>CN(C=O)C>[F:13][C:6]1[CH:5]=[C:4]([B:1]([OH:2])[OH:3])[CH:12]=[CH:11][C:7]=1[C:8]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:10]
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccc(B(O)O)cc1F)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To a solution of 4-borono-2-fluorobenzoic acid (1.0 g, 5.43 mmol) and HATU (2.0 g, 5.43 mmol) in DMF (20.0 mL) was added morpholine (0.9 g, 10.87 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into ice cold water, acidified with 1N HCl, extracted with EtOAc (2×50 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford 1.2 g of crude compound as a colourless gum. Crude compound was directly used for the next step without any further purification.
Reaction SMILES: [OH-].[K+:2].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1>C(O)C>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([O-:3])=[CH:5][CH:6]=1)=[O:9].[K+:2]
Reactant: O=Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1ccc([O-])cc1
Yield: 100.1 %

Procedure:
In 1.08 liter of ethanol was dissolved 81.3 g of potassium hydroxide (content 85%) under stirring. In the solution was dissolved 150 g of p-hydroxybenzaldehyde at room temperature, which was stirred further for one hour. The reaction mixture was concentrated under reduced pressure. To the concentrate was added 350 ml of ethanol, which was concentrated again. To the solid concentrate was added 200 ml of ethanol, to which was further added 2.1 liters of diisopropyl ether, then the mixture was stirred for one hour at room temperature. Resulting precipitates were collected by filtration under reduced pressure and washed with 150 ml of diisopropyl ether, followed by drying at 40° C. under reduced pressure to give 197 g (yield 100%) of potassium 4-formylphenolate.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Product: O=[N+]([O-])c1cccnc1NCc1ccccc1
Yield: 91 %

Procedure:
In accordance with the same procedures as in Step 1 of Preparation 4, except for using 2-chloro-3-nitropyridine and benzylamine, the titled compound was obtained as yellow solid. (Yield: 91%)
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:4]([NH:6][CH2:7][C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:3]>C1COCC1.[Pd]>[NH:1]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[C@H:2]([C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 6 h
Yield: 97.4 %

Procedure:
BOC-Ala-Gly-OBzl (101 g.) was dissolved in THF (500 ml.) and hydrogenized with 5% palladium/carbon (7 g.). After 6 hours, the catalyst was removed, concentrated, dissolved in THF (800 ml.), then again hydrogenized with 5% palladium/carbon. After 4 hours, the catalyst was removed and concentrated in vacuo, and the residue was solidified by treating with n-hexane. The solid residue was recrystallized by ethyl acetate - THF - n-hexane to obtain BOC-Ala-Gly-OH (72 g., Yield: 97.4%, m.p.: 129° - 132° C.). TLC: one spot (solvent system 3). [α]D28 = -8.87° (c=1, DMF).