Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][CH3:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
To commercially available (R)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (4.5 g, 22.36 mmol) in 60 ml DMF at 0° C. was added NaH (1.3 g, 33.54 mmol, 55-65 in mineral oil) under stirring in three portions under an argon atmosphere. After 20 min methyl iodide (4.76 g, 33.54 mmol) was added and the reaction was warmed to RT and stirred for another 3 h. After quenching with sat. aq NaHCO3-solution the mixture was extracted with ethyl acetate. The organic layer was washed with 1N KHSO4 and brine. The organic layer was dried with MgSO4, filtered and evaporated. The crude material was purified by chromatography on silica gel. Yield: 4.6 g, 96
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][N:31]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([O:29][CH3:28])[CH:35]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: COc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.66 min, m/z=461.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.ClCC(C1CCC(CCCCC)CC1)=O.C([C@H]1CC[C@H](C(O)=O)CC1)CCCC>C1COCC1>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:6]([CH2:7][CH3:8])[CH3:9]
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CCCCCC1CCC(C(=O)CCl)CC1
Agent: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 25 %

Procedure:
Using the procedure described in Example 5, a solution of L-proline-L-isoleucine benzylamide (160 mg, 0.50 mmol), and triethylamine (352 uL, 2.53 mmol, 5.0 eq), in THF (2 mL), was treated with 232 mg (1.0 mmol) of 1-chloro-2-(4-pentylcyclohexyl)-2-oxoethane (prepared from trans-4-pentylcyclohexanecarboxylic acid using the procedure described in example 1) to provide 154 mg, (25%) of L-isoleucine, N-[1-(2-(4-pentylycyclohexyl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)([O-])=O>O1CCOCC1.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1ccc(N)cc1F
Yield: 104.3 %

Procedure:
[I] 2 g of 5% palladium carbon was added to a solution prepared by dissolving 10 g of 4-nitro-2-fluoroanisol in 150 ml of 1,4-dioxane, and the mixture was subjected to catalytic reduction under a hydrogen gas pressure of 4 kg/cm2 at room temperature for 30 minutes. After the completion of the reaction, palladium carbon was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 8.6 g of 4-amino-2-fluoroanisol.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:8][S:9]([O:7][CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature (r.t.) to a solution of cyclopentanemethanol (0.2 g, 2 mmol, Aldrich, Cat. No. 103985) in methylene chloride (5 mL, 80 mmol) was added methanesulfonyl chloride (180 uL, 2.4 mmol), followed by triethylamine (330 uL, 2.4 mmol), and 4-dimethylaminopyridine (24 mg, 0.20 mmol). The mixture was stirred at r.t. overnight. It was diluted with methylene chloride, washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 0.39 g of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]([F:31])([F:30])[S:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:27][C:26]4[CH:28]=[CH:29][C:23]([S:22][C:21]([F:31])([F:20])[F:30])=[CH:24][CH:25]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1ccc(SC(F)(F)F)cc1
Product: Fc1cnc(Nc2ccc(SC(F)(F)F)cc2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-(trifluoromethylthio)aniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(4-trifluoromethylthiophenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.73 (s, 1H), 9.47 (s, 1H), 8.13 (d, 1H, J=3.6 Hz), 7.79 (d, 2H, J=9.0 Hz), 7.51 (d, 2H, J=9.0 Hz), 7.28 (d, 1H, J=2.1 Hz), 7.12 (dd, 1H, J=2.4 and 9.0 Hz), 6.83 (d, 1H, J=8.7 Hz), 4.23 (s, 4H); 19F NMR (282 MHz DMSO-d6): −12306; LCMS: purity: 97%; MS (m/e): 439 (MH+).
Reaction SMILES: C1([OH:7])C=CC=CC=1.[CH:8]1([N:14]=[C:15]=[N:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH:17]1([NH:16][C:15]([NH:14][CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Oc1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
A solution of the alcohol or phenol (1.0 eq.), of the carboxylic acid (1.1 eq.), of N,N′-dicyclohexylcarbodiimide (Aldrich, purity 99%; about 1.1-1.7 eq.) and catalytic amounts of 4-pyrrolidinopyridine (Aldrich, purity 98%; about 0.01 eq.) is stirred in anhydrous dichloromethane until the reaction is complete. The N,N′-dicyclohexylurea formed is filtered off, the solvent is removed under reduced pressure, and the residue is purified as described.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(O[K])=O>C1COCC1.O.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Pd]
Agent: O=CO[K]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(O)cc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 72.3 %

Procedure:
A suspension of 3-fluoro-4-nitrophenol (2.0 g, 12.73 mmol), 10% Pd/C (0.4 g) and HCOOK (8.75 g, 101.85 mmol) in THF/H2O (70 mL/20 mL) was stirred at 50° C. for 5 hours, then cooled to rt, and filtered through CELITE®. The filtrate was diluted with water (30 mL) and extracted with THF (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with DCM (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a brown solid (1.17 g, 72.3%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:20]([NH2:23])[CH2:21][CH3:22].Cl>C(O)C.C(O)(=O)C.O>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:23][CH2:20][CH2:21][CH3:22])[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: CCCN
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To a suspension of 4-fluoro-3-nitrobenzoic acid (2.0 g, 10.8 mmol) in ethanol (20 mL) was added potassium carbonate (2.34 mg, 16.2 mmol) and propylamine (1.27 g, 21.6 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, and water was added, this was adjusted to pH 5 with 10% hydrochloric acid and acetic acid, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (1.94 g, 80% yield).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][SH:6].[CH3:7][N:8]([CH2:10][C:11]1[O:17][C:14]([CH2:15]O)=[CH:13][CH:12]=1)[CH3:9].C(N)C.[Cl-].[Na+]>>[CH3:7][N:8]([CH2:10][C:11]1[O:17][C:14]([CH2:15][S:6][CH2:5][CH2:4][NH2:3])=[CH:13][CH:12]=1)[CH3:9]
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: NCCS
Agent: CCN
Agent: Cl
Agent: [Cl-]
Product: CN(C)Cc1ccc(CSCCN)o1
Reaction time: 0.5 h

Procedure:
In a mixture containing 38.5 g of an aqueous 36 wt% hydrochloric acid solution and 13.3 g of an aqueous 75 wt% cysteamine hydrochloride solution, 13.0 g of 5-(dimethylamino)methylfurfuryl alcohol was added dropwise and left reacting therein at 50° C. for 30 minutes. By gas chromatography, the yield of reaction of 2-[[[5-dimetylamino)methyl-2-furanyl]-methyl]thio]-ethane amine was found to be 89 mol% relative to 5-(dimethylamino)methylfurfuryl alcohol and the selectivity of the reaction to be 89 mol%. From the resultant reaction mixture in the presence of anhydrous sodium chloride added thereto in an excess amount, the product of the reaction was extracted with diethyl ether. The crude product was distilled under a vacuum to expel the solvent and isolate 14.3 g of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]-ethane amine (boiling at 134° C./1 mmHg).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH2:19][CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])=O.[Na+].[Br:27]Br.O>CC(O)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][O:17][C:11]=2[N:10]=[C:9]1[CH:19]([Br:27])[CH2:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1nc2onc(C)c2c(=O)n1Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC(Br)c1nc2onc(C)c2c(=O)n1Cc1ccccc1
Temperature: 55 °C
Reaction time: 72 h
Yield: 29.8 %

Procedure:
A solution of the compound of Example 1, Step 3 (525 mg, 1.85 mmol) in HOAc (20 mL) at room temperature was treated with NaOAc (182 mg, 2.22 mmol) followed by Br2 (296 mg, 1.85 mmol). The mixture was stirred at 55° C. for 72 h then cooled and poured into water. The resulting precipitate was collected and air dried to afford the desired product as a white solid (200 mg, 30%); 1H NMR (DMSO-d6) δ 7.35 (m, 5H), 5.71 (d, J=16.5 Hz, 1H), 5.21 (d, J=16.5 Hz, 1H), 5.16 (t, J=7.5 Hz, 1H), 2.51 (s, 3H), 2.49 (m, 1H), 2.28 (m, 1H), 0.78 (t, J=7.5 Hz, 3H); LC/MS (ESI): 284 (M+H)+.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25]>CO>[OH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: OCCCCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Temperature: 0 °C
Yield: 43 %

Procedure:
To 800 ml of a methanol solution having dissolved therein 34 g (0.514 mol) of potassium hydroxide were added 100 g (0.512 mol) of 4-hydroxy-4'-cyanobiphenyl and 93 g (0.512 mol) of 6-bromo-1-hexanol, and the mixture was heated at reflux for 13 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was concentrated under reduced pressure by the use of an evaporator, and the residue was purified by column chromatography using Wakogel C-200 as a carrier and hexane/THF, i.e., tetrahydrofuran as a developing solution to obtain 65 g (yield: 40%) of 4-(6-hydroxyhexyloxy)-4'-cyanobiphenyl.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:26]([OH:29])[C:27]#[CH:28].C(N(C(C)C)CC)(C)C>[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O.O1CCCC1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[C:28]#[C:27][CH2:26][OH:29]
Reactant: Ic1cccs1
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: OCC#Cc1cccs1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-iodothiophene(5.00 g), copper(I) iodide (91 mg), triphenylphosphine (315 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (497 mg), propargyl alcohol (1.54 ml), diisopropylethylamine (16.6 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 20 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-2:1) to give the object product (1.45 g) as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+]>C(O)C>[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[O:20])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(S)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cc3)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A mixture of the product of Example 49A (1.00 g, 2.816 mmol), 4-aminothiophenol (529 mg, 4.224 mmol) and anhydrous sodium acetate (1.155 g, 14.08 mmol) in anhydrous ethanol (30 mL) was heated at reflux under a nitrogen atmosphere for 19 hours. The reaction was cooled to room temperature and the ethanol removed by rotary evaporation. The residue was taken up in water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration of the solid with 4% ethyl acetate/methylene chloride (25 mL) afforded the title compound as a yellow solid (1.091 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C([O:13]C(N(C)C)N(C)C)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1>[F:1][C:2]1[N:3]=[C:4]([CH:8]=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cccc(F)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=Cc1cccc(F)n1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
30 g of 2-fluoro-6-methylpyridine (270 mmol) and 70 g of tert-butoxybis(dimethylamino)methane (405 mmol) are mixed under a nitrogen atmosphere. The mixture is heated at 140° C. for 24 hours. The mixture is diluted with 50 ml of tetrahydrofuran and the solution obtained is added dropwise to an aqueous solution of 115 g of sodium periodate (538 mmol). The mixture is stirred overnight at room temperature, the precipitate formed is removed by filtration and then the tetrahydrofuran is evaporated off. The residue is extracted with dichloromethane, the organic phase is dried over magnesium sulfate, filtered and then the solvent is evaporated under vacuum. The title product is isolated by distillation in a bulb oven, b.p.77 : 70-80° C. 34 g of a yellow oil containing about 20% of N,N-dimethylformamide are recovered.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Li+]>ClC1C=CC=CC=1Cl>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Agent: [Br-]
Agent: [Li+]
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 160 °C
Yield: 88.66 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in o-dichlorobenzene (70 mL) respectively and heated to 160° C. Then lithium bromide (0.15 g, 1.74 mmol) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.46 g, yield: 88.66%).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Cl-].[Mg+2].[Cl-]>C(OCCC(C)C)(=O)C>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC(=O)OCCC(C)C
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 120 °C
Yield: 95.5 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (4.56 g, 22.46 mmol, 1.3 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in isoamyl acetate (70 mL) respectively, and heated to 120° C. Then magnesium chloride (0.12 g, 1.28 mmol) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.97 g, yield: 95.5%).
Reaction SMILES: C([O:3][C:4](=[O:10])[CH:5](Cl)[C:6]([CH3:8])=O)C.[CH:11]([NH2:13])=[O:12].[OH-].[Na+].Cl>CCOC(C)=O>[CH3:8][C:6]1[N:13]=[CH:11][O:12][C:5]=1[C:4]([OH:3])=[O:10]
Reactant: NC=O
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ncoc1C(=O)O
Temperature: 120 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
Ethyl-2-chloroacetoacetate (1 wt; 1 eq., 1000 g) was aged with formamide (0.68 vol; ca. 2.8 eq.) and the resulting solution was heated to 120° C. After 5 hours the mixture was allowed to cool to room temperature and allowed to age under nitrogen over night. The mixture was treated with NaOH (3 M, 6 vol, reaction moderately exothermic) and stirred at room temperature for 4 hours. Ethyl acetate (6 vol) was added and the phases allowed to separae. The organic layer was discarded while the aqueous was acidified with conc. (32%) aqueous HCl to pH 2 (ca. 2.0 vol). A precipitate started to form. The suspension was treated with AcOEt (8 vol) and vigorously stirred until the bulk of the precipitate had dissolved. The aqueous phase was further extracted with AcOEt twice (6 vol each) and the combined organic layers distilled to low volume (again a suspension was observed at low volume). Fresh AcOEt (8 vol) was added and the mixture evaporated to dryness. The collected solid was placed in the oven at 40° C. over night under reduced pressure to give 4-methyl-1,3-oxazole-5-carboxylic acid (498 g, 64.5%).
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([NH:28][C:29]1[S:30][CH:31]=[C:32]([C:34](=[N:38][O:39][CH2:40][CH:41]=[CH2:42])[C:35](O)=[O:36])[N:33]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN1CCOCC1.[CH3:50][C:51]([O:53][CH2:54][C:55]1[CH2:64][S:63][C@@H:58]2[C@H:59]([NH2:62])[C:60](=[O:61])[N:57]2[C:56]=1[C:65]([OH:67])=[O:66])=[O:52]>C(N(CC)CC)C.C(Cl)Cl.O1CCCC1>[C:51]([O:53][CH2:54][C:55]1[CH2:64][S:63][C@@H:58]2[CH:59]([NH:62][C:35](=[O:36])[C:34]([C:32]3[N:33]=[C:29]([NH:28][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[S:30][CH:31]=3)=[N:38][O:39][CH2:40][CH:41]=[CH2:42])[C:60](=[O:61])[N:57]2[C:56]=1[C:65]([OH:67])=[O:66])(=[O:52])[CH3:50]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: C=CCON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -20 °C
Reaction time: 0.05 h

Procedure:
0.78 ml of isobutyl chloroformate were added at -20° C. to a mixture of 2.82 g of the product of Step B, 24 ml of dry tetrahydrofuran and 24 ml of methylene chloride to which 0.66 ml of N-methyl-morpholine had been added and the mixture was stirred at -20° C. for 3 minutes. The mixture was then cooled to -35° C. and a solution of 1.63 g of 7-aminocephalosporanic acid, 30 ml of methylene chloride and 1.68 ml of triethylamine was added thereto. The mixture was returned to room temperature during 3 hours and was evaporated to dryness. The residue was taken up in methylene chloride, and 50 ml of water and 15 ml of N hydrochloric acid were added. The mixture was stirred, decanted, and washed with water. The mixture was extracted with methylene chloride and the extracts were dried and vacuum filtered. The filter was rinsed with methylene chloride and the filtrate was evaporated to dryness. The residue was taken up in ethyl acetate and the solution was diluted with isopropyl ether, was stirred and was vacuum filtered. The recovered precipitate was rinsed with isopropyl ether to obtain 3.08 g of the anti isomer of 3-acetoxymethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-(2-propenyloxyimino)-acetamido]-ceph-3-eme-4 -carboxylic acid. 3.59 g of the said product were dissolved in 15 ml of ethyl acetate and the solution was diluted with isopropyl ether, was stirred and was vacuum filtered to obtain 3.33 g of the said purified product.