Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([N+:13]([O-])=O)=[CH:11][N:10]=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd]>[NH2:13][C:12]1[C:7]([NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:8][C:9]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)=[CH:19][CH:18]=2)=[N:10][CH:11]=1
Reactant: CN1CCN(c2ccc(Nc3ncc([N+](=O)[O-])c(NC4CCCC4)n3)cc2)CC1
Agent: [Pd]
Product: CN1CCN(c2ccc(Nc3ncc(N)c(NC4CCCC4)n3)cc2)CC1

Procedure:
Hydrogenation of 4-(cyclopentylamino)-2-[[4-(4-methylpiperazin-1-yl)phenyl]amino]-5-nitropyrimidine (from Example 2(5) above) over Pd/C gave the title compound: mp (i-Pr2O/CH2Cl2) 212° C. (dec).
Reaction SMILES: C([Li])CCC.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[C:15](=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1)([CH3:17])[CH3:16]>O>[CH:6]1([C:15]([CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19]2)([CH3:17])[CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: C1=Cc2ccccc2C1
Reactant: CC(C)=C1C=Cc2ccccc21
Agent: [Li]CCCC
Solvent: O
Product: CC(C)(C1C=Cc2ccccc21)C1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.7 %

Procedure:
18.8 cm3 (47.0 mmol) of n-butyllithium were added at 0° C. to a solution of 5.93 g (47.0 mmol) of indene (industrial, 91% pure) filtered over Al2O3. After the mixture had been stirred at room temperature for 15 minutes, the solution was slowly added dropwise to a solution of 7.40 g (47.0 mmol) of 1-isopropylideneindene. After the mixture had been stirred at room temperature for 2 hours, 50 cm3 of water were added and the mixture was extracted with diethyl ether. The yellow organic phase was dried over MgSO4. The residue which remained after the solvent had been stripped off was chromatographed on silica gel 60. 1.5 g (13%) of the product (2 isomers) could be isolated with hexane/methylene chloride (10:1).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.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>[CH3:10][N:6]1[C:5]2[CH:11]=[CH:12][C:2]([C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)=[CH:3][C:4]=2[S:8][C:7]1=[O:9]
Reactant: Cn1c(=O)sc2cc(Br)ccc21
Reactant: OB(O)c1cccnc1
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: Cn1c(=O)sc2cc(-c3cccnc3)ccc21
Yield: 131 %

Procedure:
A suspension of 6-Bromo-3-methyl-3H-benzothiazol-2-one (200 mg, 0.82 mmol), 3-pyridyl boronic acid (78 mg, 0.63 mmol), polymer-supported Pd(PPh3)4 (0.11 mmol/g, 115 mg, 0.0126 mmol) and Na2CO3 (2 M in water, 0.65 mL, 1.3 mmol) in DME (7 mL) was heated to reflux for overnight. After filtration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-4%) and yielded the title compound (200 mg). MS (ESI) m/z 243.0 (M+H, 1H NMR (400 MHz, CD2Cl2) δ ppm 3.52 (s, 3H), 7.23 (d, J=8.4 Hz, 1H), 7.43-7.46 (m, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.93-7.96 (m, 1H), 8.62 (m, 1H), 8.88 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH2:12][OH:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([O:10][CH2:11][CH2:12][O:13][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(OCCO)CC1
Reactant: NC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCC(OCCOc2ccc(C(N)=O)cc2)CC1
Yield: 44 %

Procedure:
N-Acetyl-4-(2-hydroxyethoxy)piperidine (1.0 g.), 4-hydroxybenzamide (0.82 g.), diethyl azodicarboxylate (1.12 g.) and triphenylphosphine (1.68 g.) in tetrahydrofuran (30 ml.) were stirred at room temperature for 66 hours. The precipitated solid was collected and dried to give 4-[2-(N-acetyl-4-piperidyloxy)ethoxy]benzamide (0.72 g.), m.p. 154°-155° C.
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:41]=[CH:40][C:14]([CH:15]([OH:39])[CH2:16][N:17]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:18]([CH3:31])[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)=[CH:13][C:12]=1[N+:42]([O-])=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.CCCCCC>C1C=CC=CC=1.[Fe]>[NH2:42][C:12]1[CH:13]=[C:14]([CH:40]=[CH:41][C:11]=1[O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:15]([OH:39])[CH2:16][N:17]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH:18]([CH3:31])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1
Reactant: COc1ccc(CCC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)cc1OC
Agent: [Fe]
Agent: Cl
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc(CCC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(N)c2)cc1OC

Procedure:
In 50 ml. of methanol there was dissolved 5 g. of 4-benzyloxy-3-nitro-α-[N-benzyl-N-{3-(3,4-dimethoxyphenyl)-1-methylpropyl}aminomethyl]benzyl alcohol and after adding to the solution 2.5 g. of iron powder and 5 ml. of 2N hydrochloric acid, the mixture was refluxed for 50 minutes. After cooling the reaction mixture, the insoluble materials were filtered off, and 5 ml. of a 2N potassium hydride methanol solution and 20 ml. of ethyl acetate were added to the filtrate. The insoluble materials were filtered off and the filtrate was concentrated under a reduced pressure. The residue was extracted with benzene, and the extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under a reduced pressure to provide a yellowish brown viscous product. The product thus obtained was dissolved in benzene and after adding n-hexane until the solution became slightly muddy, the solution was allowed to stand whereby 2.7 g. of yellowish brown crystals of 3-amino-4-benzyloxy-α-[N-benzyl-N-{3-(3,4-dimethoxyphenyl)-1-methylpropyl}aminomethyl] benzyl alcohol [A]were obtained. The product was recrystallized from a mixture of benzene and n-hexane and was characterized by a melting point of 115° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:15][CH2:16][CH2:17][C:18]1[C:19]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[N:20][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[N:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[O:35][C:36]=3[CH3:37])=[CH:26][CH:25]=2)[CH:22]=1.Cl>O1CCCC1>[CH3:37][C:36]1[O:35][C:34]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[N:33][C:32]=1[CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:21]2[CH:22]=[C:18]([CH2:17][CH2:16][CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:19]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[N:20]2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCCI)c(-c3ccccc3)n2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1)C(=O)OCC
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
Sodium hydride (60%, oily, 476 mg) was added to a solution of diethyl malonate (2.37 g) in tetrahydrofuran (50 ml) at 0° C., and the mixture was stirred for 30 minutes. A solution of 1-iodo-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propane (1.75 g) in tetrahydrofuran (15 ml) was added dropwise to the above mixture, which was stirred at room temperature for 13 hours. The reaction mixture was acidified with diluted hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and diethyl 2-[3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propyl]malonate (1.63 g, yield: 88%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([O:4][C:5]([NH:7][C@H:8]([C:27]([OH:29])=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17](=[O:26])[N:18]([CH3:25])[C:19](=[O:24])[N:20]([CH3:23])[C:21]=2[CH3:22])=[CH:12][CH:11]=1)=[O:6])[CH3:3].C(=O)(O)[O-].[Na+].[C:36]([O:39][CH:40](Cl)[CH3:41])(=[O:38])[CH3:37].O>CN(C=O)C>[C:36]([O:39][CH:40]([O:28][C:27](=[O:29])[C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17](=[O:26])[N:18]([CH3:25])[C:19](=[O:24])[N:20]([CH3:23])[C:21]=2[CH3:22])=[CH:12][CH:11]=1)[NH:7][C:5]([O:4][C:2]([CH3:30])([CH3:1])[CH3:3])=[O:6])[CH3:41])(=[O:38])[CH3:37]
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reactant: CC(=O)OC(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 77 %

Procedure:
To a suspension of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine (1.006 mmol, 420 mg) and sodium bicarbonate (5.03 mmol, 422 mg) in DMF (8 mL) was added 1-chloroethyl acetate (5.03 mmol, 616 mg) at room temperature. The reaction mixture was stirred for 48 h. Then, it was poured into water (50 mL) and was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with water (2×50 mL) and brine solution (100 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate gave the crude product which was purified by silica gel chromatography using a Biotage (40s) column to obtain 390 mg (77% yield) of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester as an amorphous white solid. ES-HRMS m/e calcd for C25H33N3O8 (M+Na) 526.2160, found 526.2143.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Pd](Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:25])([F:24])[F:13])[CH:20]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(Br)cc1C
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 87.2 %

Procedure:
To a degassed solution of 8.35 g (36.3 mmol) of 5-bromo-3-methyl-pyridine-2-carboxylic acid methyl ester [Wu, G. G.; Wong, Y.-S.; Poirier, M. Organic Letters (1999), 1(5), 745-747] in 180 ml of dioxane were added 13.79 g (72.6 mmol) of 3-(trifluoromethyl)phenyl boronic acid and 11.54 g (108.9 mmol) of sodium carbonate (dissolved in 55 ml of H2O). While stirring, 1.33 g (1.89 mmol) of (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) was added and the reaction mixture was stirred at RT for 4 hours, then heated up to 50° C. After 90 min, it was cooled down to RT, poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 9:1 to 1:1) to give 9.35 g (87%) of the title compound as light yellow solid. MS: 296.1 (MH+).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[C:5]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.[I-].[CH3:19][O-:20].[Na+]>CO.CN(C)C=O.O>[CH2:14]([CH:13]([C:5]1[C:6]2[N:7]([CH3:12])[C:8](=[O:11])[NH:9][C:10]=2[C:2]([O:20][CH3:19])=[CH:3][CH:4]=1)[CH2:16][CH3:17])[CH3:15]
Reactant: CCC(CC)c1ccc(Br)c2[nH]c(=O)n(C)c12
Reactant: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)c1ccc(OC)c2[nH]c(=O)n(C)c12
Yield: 91 %

Procedure:
A solution of 4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (250 mg, 0.841 mmol), anhydrous cuprus iodide (192 mg, 1.01 mmol) and 28% sodium methoxide in methanol (5.2 mL) in N,N-dimethylformamide (5 mL) was heated at 100° C. for 1 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (190 mg, 0.765 mmol, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:19]O)[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1
Reactant: OCc1cc(Cl)c(-c2ccc(O)cc2)c2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)c(-c2ccc(O)cc2)c2ccccc12
Yield: 25.1 %

Procedure:
190 mg of the alcohol obtained in Stage C of Example 8, 50 mg of palladium on carbon at 9.5% and 30 ml of ethyl acetate are mixed together for 15 minutes under a hydrogen atmosphere at ambient temperature. After filtration and evaporation under reduced pressure, the crude product is purified by chromatography eluting with a cyclohexane/ethyl acetate mixture 95/5. In this way 45 mg of expected product is obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][C:13]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].Cl>ClC1C=CC=CC=1Cl.C1(C)C=CC=CC=1>[CH3:22][C:20]1[CH:19]=[CH:18][C:14]([C:15](=[O:16])[C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)=[C:13]([CH3:12])[CH:21]=1
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(C(=O)c2ccc(F)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a suspension of anhydrous aluminum chloride (16.2 g) dispersed in 1,2-dichlorobenzene (150 ml) was added fluorobenzene (13 g), and thereto was added dropwise 2,4-dimethylbenzoyl chloride (17.0 g) at 0-20° C. The mixture was stirred at 10-30° C. for 1 hr and heated to 80° C. The mixture was stirred for 1 hr, cooled again and poured into 6N hydrochloric acid. The reaction mixture was diluted with a great excess toluene and partitioned. The obtained organic layer was washed successively with 5% aqueous sodium hydroxide solution and water, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane-ethyl acetate as eluent to give nearly pure 1,3-dimethyl-4-(4′-fluorobenzoyl)benzene (19.4 g, 85%) as pale-yellow oil. The spectrum data of this oil were the same as those confirmed in Example 7.
Reaction SMILES: [F:1][C:2]1[C:10]([CH2:11][S:12][CH3:13])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH:14]1([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)O)[CH2:16][CH2:15]1.ClC1C=C(F)C=CC=1C(C1CC1)C1C2C(=C(CSC)C(F)=CC=2)NC=1>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH:17]([CH:14]2[CH2:15][CH2:16]2)[C:6]2[C:5]3[C:9](=[C:10]([CH2:11][S:12][CH3:13])[C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)=[CH:20][CH:21]=1
Reactant: OC(c1ccc(Cl)cc1)C1CC1
Reactant: CSCc1c(F)ccc2cc[nH]c12
Agent: CSCc1c(F)ccc2c(C(c3ccc(F)cc3Cl)C3CC3)c[nH]c12
Product: CSCc1c(F)ccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 500 mg (2.56 mmol) of the compound from Example 9A and 468 mg (2.56 mmol) of the compound from Example 153A in analogy to the synthesis of the compound from Example 233. 411 mg (44% of theory) of the target compound were obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)noc1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1onc(-c2ccc(F)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 86 %

Procedure:
A mixture of 179.5 g (0.72 mol) of 3-(4-Fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester in 880 g of ethanol 95% was stirred at 20-30° C. for 40 minutes and then treated with 78.5 g of solid sodium hydroxide. The resulting mixture was stirred for 5 h at 20-30° C. Ethanol was removed in vacuum at 45-50° C. and the residue was subsequently treated with 500 g of water at 20-30° C. to afford a clear solution. The solution was stirred for 40 minutes and filtered. To the filtrate was added 235 g of methyl tert-butyl ether and 600 g of water and the resulting mixture stirred for 20 min and then stood for 20 min. The layers were separated and the aqueous layer was acidified to pH<1 with hydrochloric acid. The crystals were filtered and washed with water to provide 147 g crude wet product. The crude wet product was suspended in 680 g of toluene and the mixture was heated at 75-85° C. for 7 h. The mixture was cooled to 20-30° C. and stirred for 1 hour at this temperature. The crystals were filtered off and dried at 50-55° C. in vacuum over night to afford 137 g (86% yield) of the title acid as a white to slightly yellow solid with a purity of 99.9% (HPLC).
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Br:33])=[C:7]([C:9](=[N:30][O:31][CH3:32])[C:10]([NH:12][CH:13]2[C:28](=[O:29])[N:15]3[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:34]>>[ClH:34].[NH2:3][C:4]1[S:5][C:6]([Br:33])=[C:7]([C:9](=[N:30][O:31][CH3:32])[C:10]([NH:12][CH:13]2[C:28](=[O:29])[N:15]3[C:16]([C:25]([OH:27])=[O:26])=[C:17]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1nc(NC=O)sc1Br
Agent: Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1nc(N)sc1Br

Procedure:
7-[2-(2-Formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer, 0.9 g.) was treated with conc. hydrochloric acid (0.34 ml.) in a similar manner to that of Example 1-(2) to give 7-[2-(2-amino-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 850 mg.).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.[S:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH2:38][NH2:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:39][CH2:38][C:34]1[S:33][CH:37]=[CH:36][N:35]=1)=[O:5]
Reactant: NCc1nccs1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1nccs1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 62.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 23 mg, 0.053 mmol), thiazol-2-ylmethanamine-HCl (12.05 mg, 0.080 mmol), 4-methylmorpholine (21.57 mg, 0.213 mmol), and HATU (26.4 mg, 0.069 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (YMC S5 20×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.8 min) to provide (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(thiazol-2-ylmethyl)acetamide (19 mg, 0.033 mmol, 62.3% yield): LCMS=528.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.22 (2 H, m), 7.46-7.78 (9 H, m), 5.22 (1 H, s), 4.67-4.82 (2 H, m); HPLC peak RT=9.5 min (Method A).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)O1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]4)=[CH:33][CH:32]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc(N3CCC(O)CC3)cc2)OC1(C)C
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(N5CCC(O)CC5)cc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedure analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-ol. LCMS calculated for C27H31N4O3(M+H)+: m/z=459.2. Found 459.3.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])[CH:14]=1)OCCC)#[N:2].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([NH:15][CH:16]([CH3:17])[CH3:18])[CH:14]=1)=[N:28][CH2:27][CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[Cl:19])#[N:2]
Reactant: CCCOC(=NC#N)c1cncc(NC(C)C)c1
Reactant: NCCc1ccccc1Cl
Solvent: CO
Product: CC(C)Nc1cncc(C(=NCCc2ccccc2Cl)NC#N)c1
Reaction time: 1.75 h
Yield: 81 %

Procedure:
To a solution of propyl N-cyano-5-isopropylamino-3-pyridinecarboximidate (98 mg, 0.42 mmol) in methanol (3 ml) was added 2-(2-chlorophenyl)ethylamine (79 mg, 0.51 mmol), and the mixture was stirred for 105 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (Wako Gel C-200, 30 g; eluted with chloroform:methanol=100:1) and further crystallized from diethyl ether to give the title compound (110 mg, 0.34 mmol) as colorless crystals in the yield of 80%.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:5]=1.Br[CH2:28][CH2:29][CH:30]1[O:34][CH2:33][CH2:32][O:31]1>>[O:31]1[CH2:32][CH2:33][O:34][CH:30]1[CH2:29][CH2:28][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH:14]2[CH2:15][CH2:16][N:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:26])[CH2:12][CH2:13]2)=[CH:18]1
Reactant: COC(=O)c1cccc(CN2CCC(c3c[nH]c4ccccc34)CC2)c1
Reactant: BrCCC1OCCO1
Product: O=C(O)c1cccc(CN2CCC(c3cn(CCC4OCCO4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.046 g (0.13 mmol) of 3-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid methyl ester and 0.019 mL (0.16 mmol) of 2-(2-bromo-ethyl)-[1,3]dioxolane. After the described purification, 0.023 g (40% of yield) of the expected acid was obtained.