Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[ClH:12].[CH2:13]([OH:15])[CH3:14]>>[ClH:12].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[NH:11])[O:15][CH2:13][CH3:14]
Reactant: N#CCc1ccc(F)cc1F
Reactant: CCO
Agent: Cl
Product: CCOC(=N)Cc1ccc(F)cc1F

Procedure:
Commercially available 2-(2,4-difluorophenyl)acetonitrile (Aldrich), HCl gas and ethanol were processed using the method described for Example 3A to obtain the titled compound except that the reaction time was 72 hours. MS (ESI+) m/z 200 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:32])([CH3:31])[CH2:12][C@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:14](O)[CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([CH3:31])([CH3:32])[CH2:12][C@@H:13]([C@H:14]1[O:18][C:17](=[O:19])[CH2:16][CH2:15]1)[NH:23][C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCC(O)[C@H](CC(C)(C)CCOCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(CCOCc1ccccc1)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CCC(=O)O1

Procedure:
5.52 g of the ethyl 9-benzyloxy-5(S)-tert-butoxycarbonylamino-4(R,S)-hydroxy-7,7-dimethyl-nonanoate obtained as the crude product are refluxed in 100 ml of toluene and 4 ml of glacial acetic acid at 110° C. under argon for 4.5 h. After the reaction mixture has cooled, it is diluted with ethyl acetate and worked up in the customary manner. The crude product is purified by chromatography over silica gel (mobile phase B), the two 5(S) and 5(R) stereoisomers being separated. This gives the pure title compound (diastereomer I) as a yellowish oil: Rf (B)=0.26; FAB-MS: (M+H)+ =406; and diastereomer II: Rf (B)=0.22.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Br[CH2:16][CH:17]1[CH2:22][CH2:21][Si:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(C2C=CC=CC=2)[CH2:19][CH2:18]1>>[F:1][C:2]1[CH:3]=[C:4]([O:14][CH2:16][C@H:17]2[CH2:22][CH2:21][Si@H:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:19][CH2:18]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(CBr)CC1
Reactant: Oc1ccc(OCC(F)(F)F)c(F)c1
Product: CCCCCCC[Si@H]1CC[C@H](COc2ccc(OCC(F)(F)F)c(F)c2)CC1

Procedure:
The general procedure of Example 9 was repeated using 3-fluoro-4-(2,2,2-trifluoroethoxy)phenol and 4-bromomethyl-1-n-heptyl-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[NH2:2].[CH3:9][C:10]([CH3:17])([CH3:16])[C:11](=O)[CH2:12][C:13]#[N:14]>>[C:10]([C:11]1[CH:12]=[C:13]([NH2:14])[N:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[N:2]=1)([CH3:17])([CH3:16])[CH3:9]
Reactant: NNc1cccnc1
Reactant: CC(C)(C)C(=O)CC#N
Product: CC(C)(C)c1cc(N)n(-c2cccnc2)n1
Yield: 77.3 %

Procedure:
Following the procedure in Example 161A Step 3, 3-hydrazinylpyridine (501 mg, 4.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (437 mg, 4.0 mmol) were reacted to give 3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-amine (667 mg, 3.09 mmol, 77%), LC-MS (ESI) m/z 217 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][OH:13])[CH2:10][C@H:9]([S:14][C:15]2[C@H:16]([CH3:39])[C@@H:17]3[C@@H:27]([C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH3:29])[C:26](=[O:38])[N:18]3[C:19]=2[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([NH3+])CC.C([NH3+])CC.C([NH3+])CC.C([NH3+])CC.[Ru]([O-])(=O)(=O)=O.[Ru]([O-])(=O)(=O)=O.[Ru]([O-])(=O)(=O)=O>[CH2:1]([O:4][C:5]([N:7]1[C@H:11]([CH:12]=[O:13])[CH2:10][C@H:9]([S:14][C:15]2[C@H:16]([CH3:39])[C@@H:17]3[C@@H:27]([C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH3:29])[C:26](=[O:38])[N:18]3[C:19]=2[C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CO)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[NH3+]
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
Tetrakis(n-propylammonium) perruthenate (VII) (45 mg) is added a solution of 871 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(hydroxymethyl)pyrrolidin-3-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate, 272 mg of N-methylmorpholine N-oxide, and 750 mg of 4A active molecular sieves (powder) in 3 ml of dry dichloromethane, and the mixture is stirred in an argon atmosphere at room temperature for 10 min. The reaction solution as such is purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give 719 mg of allyl(1R,5S,6S)-2-((3S,5S)-1-allyloxycarbonyl-5-formylpyrrolidin-3-yl)thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-methylcarbapen-2-em-3-carboxylate as a colorless viscous material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:24][N:25]3[CH2:30][CH2:29][C@@H:28]([NH2:31])[C@H:27](O)[CH2:26]3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:33]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([NH2:31])[CH2:29][CH2:30]3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:33]
Reactant: N[C@@H]1CCN(Cc2cccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)C[C@H]1O
Solvent: CO
Product: NC1CCN(Cc2cccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Yield: 81 %

Procedure:
The preparation was carried out from 20A (68 mg) in a similar way as described in example 21B in 81% yield. It has an analytical HPLC retention time=2.40 min (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA over 4 minutes, 4 mL/min, monitoring at 254 nm) and a LC/MS M++H=492+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][N:8](C(=O)C3C(Cl)=CC=CC=3Cl)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[C:48]3[C:52](=[CH:53][CH:54]=2)[NH:51][N:50]=[CH:49]3)O1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.C(O)C>[F:27][C:14]1[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:46]4[CH:47]=[C:48]5[C:52](=[CH:53][CH:54]=4)[NH:51][N:50]=[CH:49]5)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:22])=[O:23]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(Br)cc23)c1F
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc5[nH]ncc5c4)cc23)c1F
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
Into a microwave vial, propane-1-sulfonic acid {3-[5-bromo-1-(2,6-dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (11, 0.100 g, 0.158 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (12, 0.080 g, 0.33 mmol) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.07 g, 0.086 mmol, 1:1 complex with dichloromethane) are combined with 2.0 mL of toluene and 2.0 mL of ethanol. The mixture is stirred for 5 minutes, then potassium carbonate (0.475 mL, 1.0 M aqueous) is added and the reaction heated at 110° C. for 60 minutes in a microwave, followed by 140° C. for 45 minutes. The reaction is added to silica and the solvents are removed under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of ethyl acetate (with 2% acetic acid):hexanes. Appropriate fractions are combined and concentrated under vacuum, then washed with acetonitrile to provide the desired compound (P-0001). MS (ESI) [M+H+]+=496.0.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH3:29])[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([Cl:27])=[CH:21][C:22]=3[Cl:26])[NH:17][C:16]2=[O:28])=[CH:11][C:10]=1[Br:30])C1C=CC=CC=1.B(Br)(Br)Br.CCCCCC>CCOC(C)=O>[Br:30][C:10]1[CH:11]=[C:12]([C:15]2([CH3:29])[C:24](=[O:25])[C:23]3[C:18](=[CH:19][C:20]([Cl:27])=[CH:21][C:22]=3[Cl:26])[NH:17][C:16]2=[O:28])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CC1(c2ccc(OCc3ccccc3)c(Br)c2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(c2ccc(O)c(Br)c2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Yield: 78.3 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 3-(4-benzyloxy-3-bromo-phenyl)-5,7-dichloro-3-methyl-1H-quinoline-2,4-dione (0.10 g, 0.20 mmol) and BBr3 (0.59 mL, 1.0 M dichloromethane solution). After normal workup, the pure objective compound (65 mg, 78%) was obtained as white solid by a flash column chromatography (n-hexane:EtOAc=2:1): 1H NMR (200 MHz, CDCl3) δ 1.70 (s, 3H, CH3), 5.51 (br s, 1H, OH), 6.76 (d, J=1.6 Hz, 1H, ArH), 6.94 (d, J=8.6 Hz, 1H, ArH), 7.02 (d, J=2 Hz, 1H, ArH), 7.28 (dd, J=8.6, 2.4 Hz, 1H, ArH); m.p. 228-229° C.; MS(EI) m/e 413 [M+], 381, 336, 299, 226; HRMS m/e cacld. for C16H10NO3Br1Cl2 412.9221, found 412.9195.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.[NH4+].[Cl-].CC[N:18]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([NH2:18])=[O:13])[NH:6]2
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc2c(F)cccc2[nH]1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc2c(F)cccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
To a solution of 34 (179 mg, 1.00 mmol) in anhydrous DMF (2.0 mL) were added NH4Cl (160 mg, 3.00 mmol), EDCI (395 mg, 2.20 mmol), HOBt (297 mg, 2.20 mmol) and TEA (303 mg, 3.00 mmol) at RT. After stirring at RT for 3 h, the mixture was quenched with H2O (10 mL) the resulting mixture was extracted with EtOAc (3×6 mL). The combined extracts were dried and concentrated. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (5:1 to 3:1) to afford 130 mg (73%) of 4-fluoro-1H-indole-2-carboxamide (36) as a white solid. LCMS (ESI) m/z: 179.1 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)=[CH:16][C:15]([C:28]([F:31])([F:30])[F:29])=[N:14]2)=[CH:9][CH:8]=1>C(OC(=O)C)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)=[CH:16][C:15]([C:28]([F:31])([F:29])[F:30])=[N:14]2)=[CH:11][C:12]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To acetic anhydride (20 ml) was added 70% nitric acid (2 ml) dropwise in an ice-bath. During the addition, the internal temperature of the mixture temporarily rose to 25° C. and dropped to 0° C. To the mixture was added 1-(4-methoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (2.0 g) portionwise. The reaction mixture was allowed to stir for 5 hours and poured into ice-water. The precipitate formed was collected by filtration and dried to give 1-(4-methoxy-3-nitrophenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (2.15 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:15][C:9]2[N:10]=[CH:11][N:12]=[C:13](O)[C:8]=2[CH:7]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:13]1[C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:15][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1cc2c(O)ncnc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc2c(Cl)ncnc2[nH]1
Temperature: 120 °C

Procedure:
Under a N2 atmosphere, 32.0 g (154 mmol) of 6-ethoxycarbonyl-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine are suspended in 308 ml (338 mmol) of POCl3 at RT and warmed to 120° C. with stirring; the solid dissolves in the course of this. After stirring at 120° C. for 3 h, the excess POCl3 is distilled off (65° C. external temperature; 15 mbar). Suspension of the residue in 50 ml of ice-cold toluene, filtration and washing with toluene yields 4-chloro-6-ethoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine; m.p. 219-221° C.; 1H-NMR (DMSO-d6) 8.77 and 7.24 (2s, 2H), 4.39 (q, J=7, 2H), 1.36 (t, J=7, 3H). Further product can be obtained from the evaporated filtrate by stirring in ethyl acetate/water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:27]3[O:28][C:29](=[O:32])[NH:30][N:31]=3)=[O:26])[CH2:16][C@@H:17]([CH3:23])[C:18]([O:20]CC)=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:27]3[O:28][C:29](=[O:32])[NH:30][N:31]=3)=[O:26])[CH2:16][C@@H:17]([CH3:23])[C:18]([OH:20])=[O:19])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1n[nH]c(=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1n[nH]c(=O)o1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a solution of (2R,4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoate (91 mg, 0.198 mmol) in MeOH (2 mL) is added aqueous 1N NaOH (4 mL, 4 mmol). After stirring at room temperature for 2 hours, the crude is quenched with 1N HCl and concentrated under reduced pressure to remove MeOH and is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN), and then lyophilized to give (2R,4S)-5-(3′-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoic acid (62 mg). HPLC retention time=1.60 minutes (condition B); MS (m+1)=430.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.12 (d, J=7.1 Hz, 3 H) 1.60 (ddd, J=13.8, 9.9, 4.3 Hz, 1 H) 1.85 (ddd, J=13.6, 9.6, 4.0 Hz, 1 H) 2.35-2.47 (m, 1 H) 2.79 (dd, J=13.7, 7.8 Hz, 1 H) 2.86 (dd, J=13.7, 7.8 Hz, 1 H) 4.11-4.28 (m, 1 H) 7.28 (d, J=8.3 Hz, 2 H) 7.35-7.43 (m, 1 H) 7.47 (t, J=7.8 Hz, 1 H) 7.57-7.65 (m, 3 H) 7.70 (t, J=1.8 Hz, 1 H) 8.84 (d, J=8.8 Hz, 1 H) 12.05 (br. s., 1 H) 12.92 (s, 1 H).
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15](O)[CH3:16])[CH:10]=1)([O-:5])=[O:4].[F:18]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C>C1COCC1.CCN(CC)CC>[F:18][CH:15]([CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11][N:9]1[CH:10]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[N:8]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(O)CCCCn1cc([N+](=O)[O-])cn1
Agent: F
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(F)CCCCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 6-(4-nitro-pyrazol-1-yl)-hexan-2-ol (213 mg, 1.00 mmol) in THF (3.0 mL) was treated at rt with perfluoro-1-butanesulfonyl fluoride (0.36 mL, 2.00 mmol), triethylamine trihydrofluoride (0.33 mL, 2.00 mmol) and Et3N and the reaction mixture was stirred at rt overnight. Purification of the residue by FC (80:10 hept-EA) gave the title compound. TLC: rf (80:20 hept-EA)=0.28. LC-MS-conditions 02: tR=0.97 min; [M+H]+=216.20.
Reaction SMILES: C([NH:4][C@@H:5]([C:15]([OH:17])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)(=O)C.O.[ClH:19]>CN(C=O)C>[ClH:19].[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([C:15]([OH:17])=[O:16])[NH2:4])=[CH:12][CH:11]=1
Reactant: COc1ccc(C[C@@H](NC(C)=O)C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C[C@@H](N)C(=O)O)cc1
Temperature: 25 °C

Procedure:
N-Acetyl-O-methyl-D-tyrosine, 24 g. is heated in 100 ml. of water and 100 ml. of concentrated hydrochloric acid for seven hours on a steam bath and let cool to room temperature overnight. The flask is swirled gently and the product crystallizes. It is separated by filtration, washed with a small amount of isopropanol, then with ether and dried to give 16.1 g. of the above named compound, [α]D23 +7.4° (c 2.02, DMF).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:19]3=[C:20]4[C:10](=[CH:11][CH:12]=[C:13]([C:21]5[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=5)[C:14]4=[CH:15][CH:16]=[C:17]3[CH:18]=1)[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CO.[Br-:30].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.O>ClCCl>[Br:30][C:11]1[C:10]2[C:20]3=[C:19]4[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:18]=[C:17]4[CH:16]=[CH:15][C:14]3=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)[CH:12]=1
Reactant: Cc1ccc(-c2ccc3ccc4cc(C(C)(C)C)cc5ccc2c3c45)cc1
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2cc(Br)c3ccc4cc(C(C)(C)C)cc5ccc2c3c45)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 180.6 %

Procedure:
Next, a mixed solution of 1.5 g of 7-t-butyl-1-(4-methylphenyl)pyrene, 25 ml of dichloromethane and 8 ml of methanol was cooled to 0° C. under a nitrogen gas stream and then 1.7 g of benzyltrimethylammonium tribromide dissolved in 5 ml of dichloromethane was added dropwise. This mixed solution was stirred at room temperature for 2 hours and 20 ml of water was poured into the solution, followed by extraction with 20 ml of dichloromethane. The organic layer was washed twice with 20 ml of water, dried over magnesium sulfate and then evaporated. To the resulting solid, 10 ml of methanol was added, followed by standing overnight. The precipitated solid was filtered and then vacuum-dried to obtain 1.9 g of 1-bromo-7-t-butyl-3-(4-methylphenyl)pyrene.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[C:17]([F:24])[CH:16]=1>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[S:23][C:2]3=[N:3][CH:4]=[CH:5][CH:6]=[C:7]3[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:17]([F:24])[CH:16]=1
Reactant: CCOC(=O)Cc1cccnc1Cl
Reactant: Fc1cc(Br)ccc1N=C=S
Product: CCOC(=O)c1c(Nc2ccc(Br)cc2F)sc2ncccc12

Procedure:
Prepared from ethyl (2-chloropyridin-3-yl)acetate (D. H. Bremner et al., Synthesis, 1997, 949) (500 mg, 2.5 mmol) and 4-bromo-2-fluorophenyl isothiocyanate (580 mg, 2.5 mmol) by the method of Example 1. Title compound obtained as an off-white solid (390 mg, 40%). δH (DMSO-d6) 10.37 (1H, br s), 8.25 (1H, dd, J 1.4, 8.1 Hz), 8.19 (1H, d, J=4.8 Hz), 7.69 (1H, dd, J 1.8, 10.2 Hz), 7.56-7.45 (2H, m), 7.32 (1H, dd, J 4.5, 8.1 Hz), 4.35 (2H, q, J=7.1 Hz), 1.37 (3H, t, J=7.1 Hz). LCMS (ES+) RT 4.66 minutes, 395 (M(79Br)+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][N:9](C)[CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6].ClC(OC(Cl)C)=O>ClCCl>[CH3:1][O:2][N:3]=[C:4]([C:7]1[CH2:8][NH:9][CH2:10][CH2:11][CH:12]=1)[C:5]#[N:6]
Reactant: CON=C(C#N)C1=CCCN(C)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: CON=C(C#N)C1=CCCNC1
Temperature: 0 °C
Yield: 69.8 %

Procedure:
α-(Methoxyimino)-α-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)acetonitrile (D7) (0. 047 g, 0.00026 moles) was dissolved in dry dichloromethane (1 ml) and cooled to 0° C. under a nitrogen atmosphere. α-Chloroethyl chloroformate (0.041 g, 0.00029 moles) was added with stirring and the mixture allowed to warm to room temperature. The mixture was stirred for a further 4 h and then evaporated to dryness. Methanol (5 ml) was added and the mixture was heated under reflux for 1 h. Evaporation of the solvent gave an oil which was partitioned between saturated aqueous potassium carbonate and chloroform. The organic phase was separated and dried (Na2SO4) then evaporated to dryness. Column chromatography on silica-gel eluting with 0-2% methanol/chloroform gave the title compound (D8) as a crystallising oil (0.03 g, 69%). Treatment with anhydrous oxalic acid afforded a white crystalline solid m.p. 180°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:43])[CH2:34][NH:35][C:36](OC(C)(C)C)=[O:37])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].Cl.CCN(C(C)C)C(C)C.[C:55]([O:59][C:60]([N:62]1[CH2:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]1C(O)=O)=[O:61])([CH3:58])([CH3:57])[CH3:56].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1.CN(C=O)C.CCOC(C)=O>[C:55]([O:59][C:60]([N:62]1[CH2:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]1[C:36](=[O:37])[NH:35][CH2:34][C:33]([C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:23]=[CH:22][C:21]([C:19]3[N:20]=[C:16]([CH:12]4[CH2:13][CH2:14][CH2:15][N:11]4[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:44])[CH:6]([CH3:8])[CH3:7])[NH:17][CH:18]=3)=[CH:26][CH:25]=2)=[CH:28][CH:29]=1)=[O:43])=[O:61])([CH3:57])([CH3:58])[CH3:56]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C1C(=O)O
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(-c3ccc(C(=O)CNC(=O)OC(C)(C)C)cc3)cc2)c[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(-c3ccc(C(=O)CNC(=O)C4c5ccccc5CN4C(=O)OC(C)(C)C)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 111.5 %

Procedure:
[1-(2-{-4-[4′-(2-tert-Butoxycarbonylamino-acetyl)-biphenyl-4-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (107.0 mg, 0.177 mmol) was dissolved in DCM (1 mL) and HCl in dioxane (4M, 1 mL) was added and stirring at room temperature was continued. After 45 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (0.6 mL) and DIEA (68.4 mg, 0.531 mmol) was added. A solution of racemic 1,3-dihydro-isoindole-1,2-dicarboxylic acid 2-tert-butyl ester (46.6 mg, 0.177 mmol), HATU (67.3 mg, 0.177 mmol) and DIEA (22.8 mg, 0.177 mmol) in DMF (0.4 mL) was added. The reaction was stirred at room temperature. After 15 minutes, the reaction was diluted with EtOAc and was washed with brine, saturated sodium bicarbonate solution, brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material (147.8 mg), which was used in the next step without further purification.