Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[C:13]2[S:12][C:11]([CH2:14]Br)=[CH:10][C:9]=2[C:8]([F:16])=[C:7]([F:17])[CH:6]=1>C1COCC1.C(#N)C>[Br:4][C:5]1[C:13]2[S:12][C:11]([CH2:14][N:2]([CH3:3])[CH3:1])=[CH:10][C:9]=2[C:8]([F:16])=[C:7]([F:17])[CH:6]=1
Reactant: CNC
Reactant: Fc1cc(Br)c2sc(CBr)cc2c1F
Solvent: CC#N
Solvent: C1CCOC1
Product: CN(C)Cc1cc2c(F)c(F)cc(Br)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetonitrile (1 mL) was added to a solution (0.5 mL) of 2.0 M dimethylamine in THF, and a solution (2 mL) of the compound (121 mg, 0.354 mmol) of Step 1 of Example 65 in acetonitrile was added dropwise under ice-cooling, and stirred at room temperature overnight. The solvent was distilled away under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to thus obtain the title compound.
Reaction SMILES: [N+](C1C=CC(O)=CC=1)([O-])=O.[CH3:11][NH:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]1[O:22][C:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=1>CN(C)C=O>[CH3:11][N:12]([CH3:13])[C:21]1[O:22][C:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=1
Reactant: CNC
Reactant: CCOC(=O)c1oc(Cl)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1oc(N(C)C)nc1C(F)(F)F
Temperature: 25 °C

Procedure:
A reaction vessel was charged with 4.17 g (0.03 mol) of para-nitrophenol, 50 ml of dry dimethylformamide containing dimethylamine as impurity, and potassium carbonate. After stirring of this mixture at ambient temperature, there was added 4.86 g (0.02 mol) of ethyl 2-chloro-4-trifluoromethyl-5-oxazolecarboxylate. The reaction mixture was stirred at ambient temperature for 24 hours. The resulting yellow mixture was extracted with ethyl ether and water. The organic phase was washed five times successively with 5% sodium hydroxide and five times with water, then dried with magnesium sulfate, and concentrated under reduced pressure to yield 2.2 g of a yellow solid which was recrystallized in methylcyclohexane to yield 1.7 g of a white powder. Chromatographic separation on silica gel using dichloroethane as eluent yielded 0.96 g of a light yellow powder product (m.p.=53°-55° C.) identified in Table I.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:50][C:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=[C:53]([NH2:61])[N:52]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([NH:61][C:53]2[N:52]=[C:51]([Br:50])[C:60]3[C:55]([CH:54]=2)=[CH:56][CH:57]=[CH:58][CH:59]=3)=[O:10])=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: Nc1cc2ccccc2c(Br)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Nc1cc2ccccc2c(Br)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
To a solution of 4-biphenylacetic acid (1.0 g, 4.7 mmol) in 10 ml of anhydrous DMF was added HBTU (2.1 g, 5.7 mmol) and 1.0 ml of DIEA. The mixture was stirred at room temperature for 10 min, and then 1-bromo-3-isoquinolinamine (0.68 g, 4.7 mmol) was added. After stirring over night, the mixture was poured into water, acidified with 10% citric acid, and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried over Na2SO4. After the condensation of the solvent, the residue was purified by flash column chromatography (SiO2, 1:1 hexane:ethyl aceate) to provide the title compound (1.7 g, 86%) as a light yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:26]=[CH:25][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20][CH3:21])=[O:19])[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1)=[O:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=3)[C:18]([O:20][CH3:21])=[O:19])[O:12][C:13]=2[CH3:14])=[CH:25][CH:26]=1
Reactant: COC(=O)c1cccc(-c2nc(COc3ccc(C=O)cc3)c(C)o2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(-c2nc(COc3ccc(CO)cc3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of methyl 3-{4-[(4-formylphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (2.12 g) in tetrahydrofuran (30 mL)-ethanol (5 mL) was gradually added sodium borohydride (0.23 g) at room temperature. After stirring the reaction mixture at room temperature for 1 hr, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 3-(4-{[4-(hydroxymethyl)phenoxy]methyl}-5-methyl-1,3-oxazol-2-yl)benzoate as colorless crystals (1.93 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 105-106° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+].Cl>O1CCCC1.O>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cc(F)ccc2F)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cc(F)ccc2F)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A mixture of (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.38 g, 1.11 mmol) in tetrahydrofuran (8.4 mL) and water (2.8 mL) was treated with lithium hydroxide monohydrate (56 mg, 1.34 mmol). The reaction was stirred at 25° C. overnight. At this time, the reaction was diluted with water (100 mL), acidified with a 2N aqueous hydrochloric acid solution and then extracted with 10% methanol/dichloromethane (3×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-[4-(2,5-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.36 g, 99%) as a light yellow foam: HR-ES-MS m/z calculated for C16H17NO4F2 [M+Na]+ 348.1018, observed 348.1018; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.5 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H), 1.38-1.52 (m, 1H), 1.62 (ddd, J=14.0, 9.7, 4.4 Hz, 1H), 1.77-1.84 (m, 1H), 4.17 (d, J=18.2 Hz, 1H), 4.28 (d, J=18.2 Hz, 1H), 4.63 (dd, J=11.6, 4.4 Hz, 1H), 5.05 (s, 1H), 7.21-7.33 (m, 1H), 7.46-7.62 (m, 2H), 12.83 (br. s., 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]2=[O:16])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].O>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:11](=[O:16])[CH2:12][CH2:13][C:14]2=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1C=CC(=O)N1c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Product: Nc1cccc(N2C(=O)CCC2=O)c1
Yield: 55 %

Procedure:
To a solution of N-(3-nitrophenyl)maleimide (26.3 g) in methanol-dioxane (1:1) was added suspension of palladium on carbon (2 g) in water. The reaction mixture was hydrogenated for 4 hours at 3 atm. (White crystal was precipitated.) The mixture was added 1N hydrochloric acid (ca. 300 ml) to dissolve the crude product. The mixture was filtrated and evaporated. Obtained residue was dissolved in water and basified by aqueous sodium hydrogencarbonate. Precipitate was collected by suction to give N-(3-aminophenyl)succinimide (12.6 g).
Reaction SMILES: [OH-].[Na+].[CH:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]([CH2:13][CH:14]([NH2:18])[C:15]([OH:17])=[O:16])=[O:12])=[CH:5][CH:4]=1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30].Cl>O1CCOCC1>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29]([NH:18][C@@H:14]([C:15]([OH:17])=[O:16])[CH2:13][C:11]([O:10][CH2:9][C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1)=[O:12])(=[O:30])=[O:31]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: NC(CC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(C[C@@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)O)OCc1ccccc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
22.4 ml of 2N NaOH are added dropwise at 10° C. to a solution of 5 g of D-aspartic acid β-benzyl ester and 5.07 g of 2-naphthylsulphonyl chloride in 80 ml of dioxan cooled to 10° C. The reaction mixture is subsequently stirred at room temperature for 2 hours and then treated with 25 ml of 1N hydrochloric acid. After evaporation of the dioxan the residue is taken up in ethyl acetate and washed with water. After drying and evaporation of the ethyl acetate phase there are obtained 9.1 g of 4-benzyl 1-hydrogen N-(2-naphthylsulfonyl)-D-aspartate, Rf=0.53 (ethyl acetate/glacial acetic acid 0.97:0.03).
Reaction SMILES: O(C([N:8]1[CH2:39][CH2:38][CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:9]1[C:10]([N:12]1[CH2:36][CH2:35][CH2:34][C@H:13]1[C:14]([NH:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[CH2:25][NH:26]C(OC(C)(C)C)=O)=[O:15])=[O:11])=O)C(C)(C)C.Cl>CO.CCOCC>[C:40]1([CH:37]2[CH2:38][CH2:39][NH:8][C@@H:9]2[C:10]([N:12]2[CH2:36][CH2:35][CH2:34][C@H:13]2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[CH2:25][NH2:26])=[O:15])=[O:11])[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@@H]1C(c2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)[C@H]1NCCC1c1ccccc1

Procedure:
To a stirred solution of diastereomer A of 1-(tert-butoxylcarbonyl)-3-phenylprolyl-N-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)-L-prolinamide (60 mg, 0.09 mmol) from the previous step in approx. 2 mL MeOH at room temperature was added excess of a solution of 1.0 M HCl in ether. The reaction was monitored for completeness by LCMS. The solvent was removed in vacuo to give the HCl salt of the title compound as a white solid. LCMS RT=0.94 min. LCMS (M+H)=441.1. 1H NMR (CD3OD, 500 MHz): δ 7.50-7.23 (m, 8H), 4.58-4.51 (m, 1H), 4.41-4.24 (m, 3H), 4.08-3.96 (m, 1H), 3.80-3.74 (m, 1H), 3.49-3.43 (m, 1H), 3.39-3.31 (m, 3H), 3.05-2.92 (m, 1H), 2.57-2.37 (m, 2H), 2.06-1.64 (m, 2H), 1.56-1.26 (m, 2H). Diastereomer B (73 mg, 0.11 mmol) was deprotected in similar fashion to afford the HCl salt of the title compound as a white solid. LCMS RT=0.98 min. LCMS (M+H)=441.2. 1H NMR (CD3OD, 400 MHz): δ 8.90 (m, 1H), 7.49-7.32 (m, 8H), 4.49 (d, J=15.6 Hz, 1H), 4.31 (d, J=15.6 Hz, 1H), 4.23 (s, 2H), 4.02-3.95 (m, 1H), 3.90-3.87 (m, 1H), 3.79-3.75 (m, 1H), 3.48-3.30 (m, 2H), 3.13-3.03 (m, 1H), 2.91-2.85 (m, 1H), 2.50-2.43 (m, 1H), 2.39-2.28 (m, 1H), 1.73-1.59 (m, 3H), 1.18-1.12 (m, 1H).
Reaction SMILES: [CH2:1]([C@H:4]1[C:8]2=[N:9][CH:10]=[C:11]([N:14]([CH2:25][CH:26]=[CH2:27])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[C:12](=[O:13])[N:7]2[C@H:6]([C:28](O)=[O:29])[CH2:5]1)[CH:2]=[CH2:3].Cl.[CH2:32]([O:39][C:40](=[O:52])[NH:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([CH2:50][NH2:51])=[CH:46][CH:45]=1)=[NH:43])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1C=NC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[CH2:25]([N:14]([C:11]1[C:12](=[O:13])[N:7]2[C@H:6]([C:28](=[O:29])[NH:51][CH2:50][C:47]3[CH:46]=[CH:45][C:44]([C:42]([NH:41][C:40]([O:39][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:52])=[NH:43])=[CH:49][CH:48]=3)[CH2:5][C@@H:4]([CH2:1][CH:2]=[CH2:3])[C:8]2=[N:9][CH:10]=1)[C:15](=[O:16])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:26]=[CH2:27]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Reactant: C=CC[C@@H]1C[C@@H](C(=O)O)n2c1ncc(N(CC=C)C(=O)OCc1ccccc1)c2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CC[C@@H]1C[C@@H](C(=O)NCc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)n2c1ncc(N(CC=C)C(=O)OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 64 h
Yield: 20.8 %

Procedure:
To a solution of 28d (172 mg, 0.420 mmol) and [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester hydrochloride (180 mg, 0.504 mmol) in 3.6 mL CH2Cl2/DMF (5:1) at 0° C., was added HOAT (113 mg, 0.588 mmol), NaHCO3 (141 mg, 1.68 mmol), and EDCI (113 mg, 0.588 mmol). The mixture was allowed to warm to rt and stir for 64 h. The reaction was diluted with EtOAc and the organic phase was washed with H2O, 1N HCl, H2O, and brine. The organic phase was dried (Na2SO4) and concentrated. The residue obtained was purified by flash chromatography (75% EtOAc/hexanes) to afford 59 mg of intermediate 28e.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C=C(C=C(C(F)(F)F)C=1)C=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)[CH:12]=[O:13]
Reactant: OCc1cc(Br)cc(C(F)(F)F)c1
Agent: O=Cc1cc(Cl)cc(C(F)(F)F)c1
Product: O=Cc1cc(Br)cc(C(F)(F)F)c1
Yield: 85 %

Procedure:
The title compound was prepared from (3-bromo-5-(trifluoromethyl)phenyl)methanol (Reference Example 38) by a procedure similar to the one described for 3-chloro-5-(trifluoromethyl)benzaldehyde (Reference Example 31) to provide 3-bromo-5-(trifluoromethyl)benzaldehyde (22.03 g, 85%) as a pale yellow oil.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:1]([C:3]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: Fc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccn2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (220 mg, 1.05 mmol) and 2-fluoropyridine (0.094 mL, 1.10 mmol) was dissolved in 5.2 mL of THF. The reaction was purged with a stream of nitrogen and cooled to −78° C. To this reaction was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 1.47 mL, 1.47 mmol), which was stirred for 1 h. The reaction was warmed to ambient temperature, stirred for 1 hour, and quenched with a saturated ammonium chloride solution. The mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography eluting with 0-20% ethyl acetate in hexanes to provide tert-butyl 4-cyano-4-pyridin-2-ylpiperidine-1-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:59]1[CH:64]=[C:63]([NH:65][CH2:66][C:67]2([F:80])[CH2:72][CH2:71][N:70]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:69][CH2:68]2)[C:62]([C:81]2[CH:86]=[CH:85][C:84]([O:87][CH3:88])=[CH:83][CH:82]=2)=[CH:61][N:60]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:59]2[CH:64]=[C:63]([NH:65][CH2:66][C:67]3([F:80])[CH2:72][CH2:71][N:70]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:69][CH2:68]3)[C:62]([C:81]3[CH:86]=[CH:85][C:84]([O:87][CH3:88])=[CH:83][CH:82]=3)=[CH:61][N:60]=2)=[N:3][CH:4]=1)#[N:9]
Reactant: N#Cc1cnc(N)cn1
Reactant: COc1ccc(-c2cnc(Cl)cc2NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 150 °C
Yield: 7.4 %

Procedure:
5-Aminopyrazine-2-carbonitrile (5.45 mg, 0.045 mmol), Xantphos (1.749 mg, 3.02 μmol), tris(dibenzylideneacetone)dipalladium(0) (1.384 mg, 1.511 μmol), and cesium carbonate (24.62 mg, 0.076 mmol) were added to tert-butyl 4-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (17 mg, 0.038 mmol) in a 0.2 mL microwave reaction vial. The vial was sealed and an inert atmosphere was introduced before dry dioxane (291 μL) was added. Nitrogen was bubbled through the mixture for 5 min. The mixture was heated at 150° C. for 1 hr by microwave irradiation. After cooling the mixture was diluted with 20% dichloromethane in MeOH and loaded onto a preparative thin layer chromatography plate. Elution with 50% EtOAc in hexane gave tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (1.5 mg, 2.81 μmol, 7% yield) as a light yellow powder. LCMS (4) Rt=2.35 min; m/z (ESI+) 534 (MH+). Trifluoroacetic acid (0.1 mL, 1.298 mmol) was added to tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)-4-fluoropiperidine-1-carboxylate (1.5 mg, 2.81 μmol) dissolved in dichloromethane (0.5 mL) and the solution was stirred for 1 hr. The volatiles were removed in vacuo and the crude product was purified by ion exchange on Isolute SCX II acidic resin (1 g), followed by preparative thin layer chromatography, eluting with 10% MeOH/1% NH3/89% dichloromethane, to give 5-(4-((4-fluoropiperidin-4-yl)methylamino)-5-(4-methoxyphenyl)pyridin-2-ylamino)pyrazine-2-carbonitrile (1 mg, 2.307 μmol, 82% yield) as a yellow powder.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[S:9]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:2]1([N:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[S:9]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(S(=O)(=O)N(CCC(=O)O)c3ccccc3)ccc21
Yield: 24 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 24% of theory, C25H26N6O4S (506.6); Rf value: 0.55 (Reverse-Phase RP-18 silica gel; methanol/5% saline solution=3:2); EKA mass spectrum: (M+H)+=507; (M+Na)+=529; (M+2Na)++=276.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:18]2[C:23]([O:24][CH3:25])=[C:22]([CH3:26])[C:21]([CH3:27])=[C:20]([CH:28]([OH:30])[CH3:29])[C:19]=2[CH3:31])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[C:28]([C:20]1[C:19]([CH3:31])=[C:18]([C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:23]([O:24][CH3:25])=[C:22]([CH3:26])[C:21]=1[CH3:27])(=[O:30])[CH3:29]
Reactant: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C(C)O)c(C)c(C)c1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(C)c(C(C)=O)c(C)c(C)c1OC
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A solution of methyl (R)-7-(4-fluorophenyl)-7-[3-(1-hydroxyethyl)-6-methoxy-2,4,5-trimethylphenyl]heptanoate (4.1 g, 9.5 mmol) in dichloromethane (10 ml) was added to a solution of pyridinium chlorochromate (3.3 g, 15.2 mmol) in dichloromethane (20 ml) at room temperature. The mixture was stirred for 2 hours at the same temperature. To the mixture was added diethyl ether. Insolubles were filtered off, and the liltrate was concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography to give methyl (R)-7-(3-acetyl-6-methoxy-2,4,5-trimethylphenyl)-7-(4-fluorophenyl)heptanoate (3.9 g). Physico-chemical properties and spectral data are shown in [Table 5].
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:38]/[O:39][C:40]([C:43]([O:45]C(C)(C)C)=[O:44])([CH3:42])[CH3:41])/[C:8]([NH:10][C@@H:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH2:18]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[I-].[Na+].C(OC([NH:59][CH2:60][C:61]1[CH:62]=[N:63][N:64]([CH2:86][CH2:87][O:88]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:65]=1[NH:66]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)(C)(C)C.O>CN(C)C=O>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:38]/[O:39][C:40]([C:43]([OH:45])=[O:44])([CH3:41])[CH3:42])/[C:8]([NH:10][C@@H:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][N+:63]4[N:64]([CH2:86][CH2:87][OH:88])[C:65]([NH2:66])=[C:61]([CH2:60][NH2:59])[CH:62]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Reactant: CC(C)(C)OC(=O)NCc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(CN)c(N)n3CCO)CS[C@H]12)c1nsc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
To a solution of benzhydryl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (5.82 g) in N,N-dimethylformamide (12 ml) was added sodium iodide (1.44 g). After stirring at room temperature for 1 hour, 4-(tert-butoxycarbonylaminomethyl)-5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazole (14.8 g) was added to the mixture. The stirring was continued at 35° C. for 24 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and added to diisopropyl ether (500 ml) dropwise. The resulting precipitate was collected by filtration. The filter cake was washed with diisopropyl ether and dried over phosphorous pentoxide in vacuo. The solid (15.6 g) was dissolved in dichloromethane (47 ml), and to the solution were added anisole (16 ml) and trifluoroacetic acid (32 ml) successively. After stirring at room temperature for 3 hours, the reaction mixture was poured into diisopropyl ether (500 ml). The precipitate was collected by filtration, washed with diisopropyl ether and dried over phosphorous pentoxide in vacuo. The crude product was dissolved in a phosphate buffer (pH 7.0) and purified by preparative HPLC (eluent: pH 7.0 phosphate buffer and acetonitrile). The eluate was subjected to column chromatography on Diaion® HP-20 (Mitsubishi Chemical Corporation) and freeze-dried to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-aminomethyl-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (940 mg).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:19][O:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:14][C:13]2[CH:12]=[C:11]([C:10]#[C:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:18]=[CH:17][CH:16]=2)[CH2:23][CH2:22]1
Reactant: COC1CCNCC1
Reactant: O=Cc1cccc(C#CCCN2CCOCC2)c1
Product: COC1CCN(Cc2cccc(C#CCCN3CCOCC3)c2)CC1

Procedure:
May be prepared analogously to Example 15 using the product of Example 10 and 4-methoxypiperidine.