Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[C:10]3[S:12][C:13]([NH2:15])=[N:14][C:9]3=[CH:8][CH:7]=2)[CH:3]=[N:2]1.[CH:16]1([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[CH2:18][CH2:17]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C>[NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:23](=[O:24])[C:22]4[CH:26]=[CH:27][C:19]([CH:16]5[CH2:18][CH2:17]5)=[CH:20][CH:21]=4)=[N:14][C:9]3=[CH:8][CH:7]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1ccc(C2CC2)cc1
Reactant: Nc1nc2ccc(-c3cn[nH]c3)nc2s1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc(-c3cn[nH]c3)nc2s1)c1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5B (25.0 mg, 1.0 equivalent) and 4-cyclopropylbenzoic acid (1.1 equivalent) were dissolved in DMF, followed by addition of HOBt (1.0 equivalent), EDC (1.0 equivalent), Et3N (2.0 equivalents). The mixture was stirred for 12 h at room temperature. The crude mixture was filtered and purified by LCMS to give the titled compound 5 as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.77-0.87 (m, 2H) 1.04-1.13 (m, 2H) 2.01-2.10 (m, 1H) 7.28 (d, J=8.34 Hz, 2H) 7.68 (t, J=7.58 Hz, 1H) 7.82-7.91 (m, 3H) 7.99 (d, J=8.34 Hz, 2H) 8.47 (s, 1H) 9.03 (s, 1H); ESI-MS: m/z 362.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][OH:14])=[CH:5]2.[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])(=O)C.[K+]>CC#N.O>[Cl:12][C:7]1[C:6]([CH2:13][OH:14])=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH3:24])[CH:3]=2)[N:8]=1
Reactant: Cc1ccccc1B(O)O
Reactant: OCc1cc2cc(Br)ccc2nc1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccccc1-c1ccc2nc(Cl)c(CO)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (6-bromo-2-chloroquinolin-3-yl)methanol (19.8 g, 72.5 mmol, prepared as in example 2, step 2), o-tolylboronic acid (10.4 g, 76.1 mmol), potassium acetate (21.3 g, 217.4 mmol) and dichlorobis(4-(di-tert-butylphosphino)-N,N-dimethylaniline)palladium (II) (0.51 g, 0.72 mmol) in CH3CN (300 ml) and water (100 ml) was heated in to reflux. After 2 h, the reaction was allowed to cool to RT and the aqueous phase was discarded. The organics were washed with 2×50% brine/water, and then 2× brine. The organics were concentrated to ˜100 mL, at which point the precipitate was filtered off to afford a pale yellow solid of (2-chloro-6-o-tolylquinolin-3-yl)methanol. Step 2: (2-chloro-6-o-tolylquinolin-3-yl)methanol (13.9 g, 49.0 mmol) was treated with DCM (100 ml) and thionyl chloride (106 ml, 1456 mmol) at ambient temperature. After 15 min, the solution was concentrated and azeotroped with 2×100 mL toluene, to afford a yellow solid of 2-chloro-3-(chloromethyl)-6-o-tolylquinoline.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[N:8][C:6]=2[N:7]=1.O.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.O>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])=[N:8][C:6]=2[N:7]=1
Reactant: COc1ccncc1B(O)O
Reactant: Clc1nc(N2CCOCC2)c2sc(I)nc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ccncc1-c1nc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
5-Chloro-2-iodo-7-morpholinothiazolo[4,5-d]pyrimidine, 4-methoxypyridine-3-boronic acid hydrate, and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 100° C. for 10 minutes. Water was added and the solution was filtered to give the product 5-chloro-2-(4-methoxypyridin-3-yl)-7-morpholinothiazolo[4,5-d]pyrimidine.
Reaction SMILES: N[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:10]([O-])=O.[Na+].C1(S(O)(=O)=O)C=CC=CC=1.C=CC1C=CC=CC=1>C(O)C.O>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[CH2:2])=[CH:5][CH:6]=1
Reactant: NC=Cc1ccccc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na+]
Solvent: C=Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C=Cc1ccc(N)cc1

Procedure:
The diazonium salt of 4-aminostyrene is prepared as described above from 3.6 g aminostyrene, 2.1 g sodium nitrite, and 150 g water. Ethanol, 10 g, is added to completely dissolve the diazonium salt. A solution of SA-treated MMC is added to the diazonium salt solution, and it is allowed to react for 18 hours under mixing. The solution is filtered to provide MMC solution at about 11 wt %. This MMC contains both benzenesulfonic acid and styrene functionalities covalently attached to the MMC particle.
Reaction SMILES: [Na+].[N+:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([O-:19])=[S:18])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].Cl[C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[O:28][CH3:29].O1CCOCC1.[I-].[Na+]>O.P([O-])([O-])([O-])=O>[N+:2]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([S:18][C@H:23]2[NH:26][C:25](=[O:27])[C@@H:24]2[O:28][CH3:29])=[O:19])=[O:12])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: CO[C@H]1C(=O)N[C@@H]1Cl
Reactant: O=C(NCCCC([O-])=S)OCc1ccc([N+](=O)[O-])cc1
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CO[C@H]1C(=O)N[C@@H]1SC(=O)CCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 350 mg of 4-p-nitrobenzyloxycarbonylaminothiobutyric acid sodium salt in 4 ml of water is added dropwise to a solution of 135 mg of (3S,4R)-4-chloro-3-methoxy-2-oxoazetidine in 6 ml of a phosphate buffer of a pH of 7 and 0.4 ml of dioxan in the presence of 150 mg of sodium iodide.
Reaction SMILES: [C:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)(=[O:3])[CH3:2].[Br:9][CH2:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1>C(#N)C>[Br-:9].[C:1]([N+:4]1[CH:8]=[CH:7][N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)COc1ccc(CBr)cc1
Reactant: CC(=O)n1ccnc1
Solvent: CC#N
Product: CCOC(=O)COc1ccc(Cn2cc[n+](C(C)=O)c2)cc1
Product: [Br-]
Temperature: 60 °C
Yield: 98 %

Procedure:
2.2 g of 1-acetylimidazole and 5.46 g of ethyl 4-bromomethylphenoxyacetate were added to 5 ml of dry acetonitrile, and the mixture was heated at 60° C. for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was triturated with an adequate amount of dry diethyl ether and the resulting powder was collected by filtration and dried to obtain 7.5 g of 1-acetyl-3-[4-(ethoxycarbonylmethoxy)benzyl]imidazolium bromide. (98.6% yield). Colorless hygroscopic amorphous.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[Cl:10][O-].[Na+].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Cl:10][C:7]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:4][NH:5][CH:6]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: [O-]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1n[nH]cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 3-trifluoromethyl-1H-pyrazole (500 mg, 3.67 mmol) in glacial acetic acid (5 ml) was added a 10% solution of sodium hypochlorite in water (2188 μl, 3.67 mmol). The reaction mixture was stirred at RT overnight and then neutralized with sat. sodium carbonate, and extracted with DCM. The organic layers were combined washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give the desired product (480 mg, 77%) as a white solid which did not require further purification. MS (ISP) 169.0 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH2:17][O:18][CH3:19])[NH:11][C:10](=[O:20])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:20])[NH:11][C:12]=2[CH2:17][O:18][CH3:19])=[O:16])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCCc1ccccc1
Reactant: COCC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COCC1=C(C(=O)NCCCc2ccccc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60.0 mg (0.225 mmol) of 4-(3-chlorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 36.5 mg (0.270 mmol) of 3-phenylpropylamine were dissolved in 10 ml of dichloromethane. 64.7 mg (0.338 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=100/1 to 10/1) to obtain the title compound.
Reaction SMILES: N[CH:2]([OH:4])[CH3:3].[CH2:5]([O:12][C:13](Cl)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([N:18](CC)CC)C>C(Cl)Cl>[CH2:5]([O:12][C:13](=[O:14])[NH:18][CH2:3][CH2:2][OH:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(N)O
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of aminoethanol (2.0 g, 32.7 mmol) in methylene chloride (60 ml) were added chloroformic acid benzyl ester (5.6 ml, 41.3 mmol) and triethylamine (5.5 ml, 39.5 mmol) in an ice bath. The mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (3:2) as the eluant to afford (2-hydroxyethyl)carbamic acid benzyl ester (5.37 g, yield 840%) as a white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=1)[OH:20]>>[OH:20][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:32])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=1)[CH2:18][NH:17][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(C(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example 151) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 179 as a white solid; mp>85° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.80–1.95 (m, 2 H), 2.60–3.00 (m, 5 H), 2.92 (s, 3 H), 3.75–3.85 (m, 2 H), 4.53 (dd, J=8.3, 4.0 Hz, 1 H), 6.82 (d, J=8.3 Hz, 1 H), 6.92 (d, J=8.9 Hz, 2 H), 7.01 (dd, J=8.3, 2.0 Hz, 1 H), 7.19 (d, J=2.0 Hz, 1 H), 7.73 (d, J=8.9 Hz, 2 H); MS (ES) m/z: 449.9 (MH+); HRMS Calcd. for C21H26N3O6S(M−H)−: 448.1549: Found: 448.1541.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[O:9].[C:10]1([C:16]2[C:18](=[O:19])[C:17]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18](=[O:19])[O:9]1
Reactant: O=c1c(-c2ccccc2)c1-c1ccccc1
Reactant: O=Nc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: O=C1ON(c2ccccc2Cl)C(c2ccccc2)C1c1ccccc1

Procedure:
4.6 Parts of o-chloronitrosobenzene and 6.7 parts of diphenylcyclopropenone is refluxed in 60 parts of chloroform for 72 hours. The solvent is removed under reduced pressure and the residue remaining is triturated with ethyl ether. Recrystallization from ethyl acetate then affords as tan crystals, pure 2-(o-chlorophenyl)-3,4-diphenylisoxazolin-5-one, melting at about 178°-180°. That compound is represented structurally by the following formula. ##STR7##
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2C=N[N:15]([CH3:17])[CH:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1C=CC(B2OC(C)(C)C(C)(C)O2)=C(C=1)C(OC)=O.I[C:39]1C=NC=C[N:40]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:16]=[N:15][CH:17]=[CH:39][N:40]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: Ic1cnccn1
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Agent: COC(=O)c1cc(C)ccc1B1OC(C)(C)C(C)(C)O1
Product: COC(=O)c1cc(C)ccc1-c1cnccn1

Procedure:
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using methyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and using 2-iodopyrazine. ESI-MS (m/z): 229 [M+1]+.
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][N:4]2[C:13]([S:16][CH3:17])=[N:14][N:15]=[C:3]12.ClC1C=CC=C(C(OO)=[O:26])C=1>>[CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][N:4]2[C:13]([S:16]([CH3:17])=[O:26])=[N:14][N:15]=[C:3]12
Reactant: C=C1c2ccccc2C=Cn2c(SC)nnc21
Reactant: O=C(OO)c1cccc(Cl)c1
Product: C=C1c2ccccc2C=Cn2c1nnc2S(C)=O

Procedure:
By a procedure similar to that of Example 17, the reaction of 11-methylene-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine with m-chloroperbenzoic acid gave 11-methylene-3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from ethyl acetate yielded colorless prisms, m.p. 140°-142° C.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH3:4].[C:6]([C:9]1[CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1)(=[O:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:6]([C:9]1[CH:10]=[CH:11][C:12]([O:19][CH2:1][CH2:2][CH2:3][CH3:4])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])(=[O:8])[CH3:7]
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCOc1ccc(C(C)=O)cc1C(=O)OC
Temperature: 60 °C
Reaction time: 18 h

Procedure:
n-Butyl iodide (13.2 ml, 117 mmol) was added to a mixture of methyl 5-acetylsalicylate (15 g, 77 mmol) and potassium carbonate (16 g, 117 mmol) in acetonitrile (500 ml), and the reaction stirred at 60° C. for 18 hours. TLC analysis showed starting material remaining, so additional n-butyl iodide (26.4 ml, 234 mmol) and potassium carbonate (16 g, 117 mmol) were added and the reaction stirred at 60° C. for a further 72 hours. The cooled mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The phases were separated, the organic layer washed with brine, dried (MgSO4) and evaporated under reduced pressure to afford the title compound as a yellow oil that crystallised on drying in vacuo, 17.4 g.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:47][CH2:48][N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: OCCN1CCCC1
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of 1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (0.35 g, 0.09 mmol) in anhydrous THF (2 mL), triphenyl phosphine (70.8 mg, 0.27 mmol) and 1-(2-hydroxyethyl)-pyrrolidine (0.032 mL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (0.052 mL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was subjected to purification by preparative HPLC. The proper fractions were collected, neutralized with 1N NaOH and extracted with EtOAc four times. The solution was evaporated under reduced pressure to afford Compound 13 as an off-white solid in 52.8% yield. LCMS m/z (%)=476 (M+H35Cl, 100), 478 (M+H37Cl, 40). 1H NMR (400 MHz, DMSO-d6) δ: 9.10 (s, 1H), 8.55 (s, 1H), 8.17-8.09 (m, 1H), 7.69 (s, 1H), 7.61 (dd, J=8.97 and 2.72 Hz, 1H), 7.47 (d, J=2.70 Hz, 1H), 7.43-7.36 (m, 1H), 7.26 (d, J=9.04 Hz, 1H), 7.16-7.09 (m, 1H), 4.25-4.08 (m, 2H), 3.73 (s, 3H), 2.58-2.45 (m, 2H), 2.45-2.29 (m, 4H), 1.75-1.69 (m, 4H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[C:5]([CH2:8][C:9](=O)[CH3:10])(=[O:7])[CH3:6]>>[CH2:1]([N:4]=[C:9]([CH2:8][C:5](=[O:7])[CH3:6])[CH3:10])[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CC(=O)CC(C)=O
Product: CCCN=C(C)CC(C)=O

Procedure:
0.1 Mole (5.9 g.) n-propylamine is mixed with 0.1 mole (10 g.) acetylacetone. An exothermal reaction takes place in which a yellowish, liquid ketimine is obtained which, even after comparatively lengthy storage, does not give a precipitate.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:31]([OH:33])=[O:32])=[C:17]([CH2:20][O:21][C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[O:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.FC(F)(F)C([O-])=O.[ClH:43].C>CO.O1CCCC1>[ClH:43].[ClH:43].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:31]([OH:33])=[O:32])=[C:17]([CH2:20][O:21][C:22]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[O:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CN1CCN(C(=O)OCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4csc(NC=O)n4)[C@H]3SC2)CC1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OCC2=C(C(=O)O)N3C(=O)C(NC(=O)Cc4csc(N)n4)[C@H]3SC2)CC1

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylic acid.trifluoroacetate (1.25 g) and conc.hydrochloric acid (0.6 ml) in methanol (12 ml) and tetrahydrofuran (12 ml) was stirred for 1 hour and 15 minutes at ambient temperature. The reaction mixture was treated with activated charcoal and filtered. The filtrate was evaporated and to the residue was added isopropyl alcohol followed by evaporation. The residue was pulverized in diethyl ether, collected by filtration, washed with ethyl acetate and then dried under reduced pressure to give 7-[2-(2-aminothiazol-4-yl)acetamido]-3-(4-methyl-1-piperazinyl)carbonyloxymethyl-3-cephem-4-carboxylic acid.dihydrochloride (0.65 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16]1[N:17]=[C:18]([CH2:21][C:22]([CH3:24])=O)[S:19][CH:20]=1.[NH2:25]/[C:26](/[CH3:30])=[CH:27]\[C:28]#[N:29]>C(O)(C)C>[CH3:30][C:26]1[NH:25][C:22]([CH3:24])=[C:21]([C:18]2[S:19][CH:20]=[C:16]([CH3:15])[N:17]=2)[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:27]=1[C:28]#[N:29]
Reactant: CC(=O)Cc1nc(C)cs1
Reactant: C/C(N)=C/C#N
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)C(c2nc(C)cs2)=C(C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
181 mg (0.97 mmol) of the compound from example 11A, 150 mg (0.97 mmol) of the compound from example 4A and 79 mg (0.97 mmol) of 3-aminocrotononitrile are dissolved in 4 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, the crude material is taken up in 5 ml of ethyl acetate, and the precipitated product is then filtered off 240 mg (64% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][C:14](Br)=[CH:15][C:16]([CH3:17])=[C:11]2[N:10]=[C:9]1[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([Cu])#[N:22].O.[C-]#N.[K+]>N1C=CC=CC=1.CCOC(C)=O>[CH2:1]([N:8]1[C:12]2=[N:13][C:14]([C:21]#[N:22])=[CH:15][C:16]([CH3:17])=[C:11]2[N:10]=[C:9]1[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: CCc1nc2c(C)cc(Br)nc2n1Cc1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CCc1nc2c(C)cc(C#N)nc2n1Cc1ccccc1
Temperature: 50 °C
Yield: 93.9 %

Procedure:
A mixture of 620 mg(1.8 mmol) of the product of Step D and CuCN (806 mg, 9.0 mmol) was heated in pyridine (4 mL) at reflux for 10 hours under nitrogen. The reaction was cooled, then water (50 mL), KCN (1.17 g), and EtOAc (20 mL) were added and the mixture was heated to 50° C. for 5 min. Cooling and extraction with EtOAc (2×50 mL) gave 467 mg of the title compound as a tan solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(OC(C)C)(=O)C>O>[ClH:13].[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a 250 mL 3 neck flask equipped with mechanical stirring, condenser, and heating apparatus consisting of a RTD probe hooked via a temperature controller to a heating mantle and under nitrogen atmosphere, the following were added: 7.61 g methyl 4-hydroxybenzoate, 11.05 g β-chloroethylpiperidine hydrochloride, 16.59 g powdered potassium carbonate, and 60 mL isopropyl acetate. The mixture was heated slowly to 80° C. After 5 hours, high performance liquid chromatography showed reaction to be 90% complete. After being left overnight at 80° C., reaction was complete. The mixture was then cooled to ambient temperature, after which 60 mL deionized water was added. The mixture was stirred until all solids dissolved. The aqueous layer was separated and discarded.