Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([S:9][C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])[S:7][CH:8]=1.C1C=C2N=NN(O)C2=CC=1.O.C(N=C=NC(C)C)(C)C.[CH3:36][CH:37]([CH3:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45]>CN(C)C=O>[CH3:14][C:10]([S:9][C:6]1[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH:37]([CH3:36])[CH3:47])[N:5]=1)([CH3:15])[C:11]([OH:13])=[O:12]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: CC(C)(Sc1nc(CCN)cs1)C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCCCCCC(=O)NCCc1csc(SC(C)(C)C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin (0.30 g) synthesized in Example 483-3 in dimethylformamide (4.0 mL) were added HOBT monohydrate (0.092 g), diisopropylcarbodiimide (0.10 mL) and 8-methylnonanoic acid (0.10 g), and the mixture was stirred at room temperature overnight. The resin was collected by filtration from the reaction mixture, washed three times each with dimethylformamide, tetrahydrofuran and methanol, and vacuum dried to give 2-methyl-2-[(4-{2-[(8-methylnonanoyl)amino]ethyl}-1,3-thiazol-2-yl)thio]propionic acid resin.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:13][NH:14][CH3:15]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([N:14]([CH3:15])[CH3:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: CNC
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1S(=O)(=O)N(C)C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of 5-fluoro-2-methyl-benzenesulfonyl chloride (4.18 g, 20 mmol) in tetrahydrofuran (25 mL) was added, dropwise, a solution of dimethylamine in tetrahydrofuran (2M, 25 mL, 50 mmol) over 15 min. and the mixture stirred for 5 min. The insoluble materials were filtered and the filtrate concentrated. The residue was purified by column chromatography (SiO2, 5% ether in CH2Cl2) to provide 4.3 g (Yield 90%) of the title compound as a clear oil: 1H NMR (500 MHz, CDCl3) δ ppm: 2.57 (3H, s) 2.82 (3H, s) 2.82 (3H, s) 7.12-7.18 (1H, m) 7.28 (1H, dd, J=8.2, 5.5 Hz) 7.59 (1H, dd, J=8.2, 2.1 Hz); LC/MC m/z 218 (M+H).
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[N:7]=[C:8]([CH2:16][CH2:17][CH3:18])[NH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:5])[CH3:4].CC(C)=O>C(O)C>[OH:5][CH:3]([C:6]1[N:7]=[C:8]([CH2:16][CH2:17][CH3:18])[NH:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:4]
Reactant: CCCc1nc(C(C)=O)c(C(=O)OCC)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCCc1nc(C(C)O)c(C(=O)OCC)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
125 mg of sodium borohydride were added to a solution of 1.50 g of ethyl 4-acetyl-2-propylimidazole-5-carboxylate [prepared as described in step (ii) above] in 15 ml of ethanol, and the resulting mixture was stirred at room temperature for 30 minutes. 2 ml of acetone were added, and the mixture was stirred for a further 10 minutes. The reaction mixture was then concentrated by evaporation under reduced pressure, and the concentrate was dissolved in methanol. The solution was again concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using 1:20 and 1:10 by volume mixtures of methylene chloride and methanol as the eluent, to give 1.32 g of the title compound as crystals, melting at 151°-153° C.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:9]2[CH:4]([NH:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C1COCC1>[N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:9]2[CH:4]([N:5]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC2NCCCC21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2C1CCCN2C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
The product of Step 4 (HOAc salt; 3.49 g, 12.2 mmol) was added to a flask, followed by THF (55 mL). Aqueous sodium carbonate (2M; 30.5 mL, 60.9 mmol) was added, and the resulting biphasic mixture was cooled to 0° C. Benzyl chloroformate (2.61 mL, 18.3 mmol) was added and the reaction mixture was allowed to stir while the bath naturally warmed to ambient temperature. After 30 minutes the reaction mixture was partitioned between EtOAc and water (100 mL each) and the layers were separated. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to a crude oil that was purified by column chromatography on silica gel eluting with EtOAc/hexane (5-30%) (TLC was visualized with CAM staining) to afford the title product as a colorless oil. LRMS calc'd for C20H28N2O4Na [M+Na]+, 383; found 383. 1H NMR (500 MHz, CDCl3) δ 7.39-7.30 (br m, 5H), 5.15 (br s, 2H), 4.70-4.45 (br m, 1H), 4.15-3.95 (br m, 1H), 3.82-3.62 (br d, 1H), 3.50-3.21 (br m, 2H), 2.79 (br pentet, 1H), 2.30-1.90 (br m, 3H), 1.72-1.58 (br m, 1H), 1.45 (s, 9H), 1.40 (br m, 1H), 1.28-1.14 (br m, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26])(=[O:14])=[O:13])=[CH:7]2.[CH3:27][O:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:30]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:27][O:28][C:29]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:30]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26])(=[O:13])=[O:14])=[CH:7]2
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)cccc2c1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(C(F)(F)F)ccc1-c1cccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: 90 °C
Yield: 65.9 %

Procedure:
A vial was charged with perfluorophenyl 5-bromonaphthalene-2-sulfonate (285.84 mg, 0.631 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (277 mg, 1.261 mmol), potassium phosphate (402 mg, 1.892 mmol), and Pd(AmPhos)2Cl2 (22.33 mg, 0.032 mmol). The vial was flushed with Ar (g), then dioxane (1577 μl) and water (526 μl) was added. The vial was sealed and heated in a microwave for 20 min at 90° C. The mixture was diluted with water and extracted with EtOAc (three times). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The product was purified by chromatography on silica gel (0 to 20% EtOAc/Heptane) to give perfluorophenyl 5-(2-methoxy-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonate (228.1 mg, 0.416 mmol) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.62 (d, J=1.9 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.85 (dd, J=2.0, 9.0 Hz, 1H), 7.79-7.71 (m, 2H), 7.64 (dd, J=1.3, 7.1 Hz, 1H), 7.47-7.38 (m, 2H), 7.29 (s, 1H), 3.77 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][C:34]=2[F:40])[C:29]([F:32])([F:31])[F:30])[N:3]=1.[CH3:41][O:42][C:43]1[CH:44]=[N:45][CH:46]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:48]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36]([C:47]3[CH:46]=[N:45][CH:44]=[C:43]([O:42][CH3:41])[CH:48]=3)=[CH:35][C:34]=2[F:40])[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(OC(c3ccc(Br)cc3F)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
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: COc1cncc(-c2ccc(C(Oc3cc(-c4ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc4)nc(N)n3)C(F)(F)F)c(F)c2)c1
Temperature: 150 °C
Yield: 38.8 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (130 mg, 0.2 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (70 mg, 0.3 mmol) 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg (5 mol %) of dichlorobis(triphenylphosphine)palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and purified with Prep HPLC to give 51 mg of (S)-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[2-fluoro-4-(5-methoxy-pyridin-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)=[CH:4][C:3]=1[OH:20].[CH2:21](Br)[C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:23]([O:20][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)[C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[C:22]#[CH:21]
Reactant: C#CCBr
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2F)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2ncc(C(F)(F)F)cc2F)c(F)cc1Cl
Temperature: 67.5 °C
Reaction time: 2 h

Procedure:
A mixture of 0.25 g (0.808 mmol) of the compound of Example 7, 0.12 g (0.97 mmol) of propargyl bromide and 0.22 g (1.62 mmol) of potassium carbonate powder in 10 ml of DMF was stirred for 2 h at 65-70° C. After cooling, 50 ml of water were added and the mixture was extracted 3 times with methyl tert-butyl ether, and the extracts were dried and concentrated, affording 0.28 g (100% of theory) of the title compound of mp. 68-70° C.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]([N:19]2[CH2:23][CH:22]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:21]3([C:36]4[C:31](=[CH:32][C:33]([Cl:37])=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:38])[CH:20]2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:40]=2[F:46])=[O:18])[CH2:10][CH2:9]1.C(N(CC)CC)C.C(Cl)(=O)C>O1CCCC1>[C:3]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]([N:19]2[CH2:23][CH:22]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:21]3([C:36]4[C:31](=[CH:32][C:33]([Cl:37])=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:38])[CH:20]2[C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:40]=2[F:46])=[O:18])[CH2:10][CH2:9]1)(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)CC1CN(C(=O)NCCC2CCNCC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(CCNC(=O)N2CC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)CC1

Procedure:
In a manner similar to the method described in Example 26, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (piperidin-4-ylethyl)-amide trifluoroacetic acid prepared in Example 51 (30 mg, 0.04 mmol) was reacted with triethylamine and acetyl chloride (3.8 mg, 0.05 mmol) in tetrahydrofuran to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (1-acetyl-piperidin-4-ylethyl)-amide as a white solid (Yield, 23 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][C@H:9]2[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[O:23][N:22]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O>[C:24]([C:21]1[CH:20]=[C:19]([NH:18][C:15]([C@@H:9]2[CH2:10][CH2:11][CH2:12][C:13](=[O:14])[N:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:17])[O:23][N:22]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(O)[C@@H]1CCCC(=O)N1c1ccc(Cl)cc1
Reactant: CC(C)(C)c1cc(N)on1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCC(=O)N2c2ccc(Cl)cc2)on1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold slurry of (S)-1-(4-Chloro-phenyl)-6-oxo-piperidine-2-carboxylic acid (0.2 g; 0.788 mmol) and 5-amino-3-tert-butylisoxazole (0.110 g; 0.788 mmol) in pyridine (0.956 mL; 11.820 mmol) is added phosphorous oxychloride (0.088 mL; 0.946 mmol). The mixture is stirred at 0° C. for 30 minutes and then diluted with water and extracted with ethyl acetate several times. The organics are combined and washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. Purification by preparative HPLC affords title compound, m/z 376 [M+H+].
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC(C)CCN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: CC(C)CCNS(=O)(=O)c1ccc(Br)cc1
Yield: 98 %

Procedure:
Starting materials: isoamylamine and 4-bromobenzenesulfonyl chloride. Yield 98% as a white solid: 1H NMR (CDCl3) δ 7.71 (d, J=9 Hz, 2H), 7.62 (d, J=9 Hz, 2H), 4.26 (br s, 1H), 2.82 (t, J=7 Hz, 2H), 1.52 (m, 1H), 1.30 (q, J=7 Hz, 2H), 0.86 (s, 3H), 0.84 (s, 3H); 13C NMR (CDCl3) δ 139.3, 132.6, 128.8, 127.7, 41.7, 38.6, 25.6, 22.8, 22.4; MS (ESP) m/z 306, 308 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH:9]2[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:3]=1[NH2:4].N(OC(C)(C)C)=O.[Si]([N:23]=[N+:24]=[N-])(C)(C)C.C([O-])(O)=O.[Na+]>O>[N:4]([C:3]1[CH:5]=[CH:6][C:7]([CH:9]2[CH2:11][CH2:10]2)=[CH:8][C:2]=1[Cl:1])=[N+:23]=[N-:24]
Reactant: Nc1ccc(C2CC2)cc1Cl
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)(C)ON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(C2CC2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-4-cyclopropylaniline (70 g, 418 mmol) was dissolved in Me-THF (2090 mL) and cooled to 0° C. in an ice bath. t-Butyl nitrite (59.8 mL, 501 mmol) was added slowly and TMSN3 (66.5 mL, 501 mmol) dropwise. The mixture was stirred at 0° C. for 30 min and gradually allowed to warm up to RT and stirred for 2 hrs. To the resulting mixture was added sat. NaHCO3 (aq) (250 mL) slowly under cooling, followed by water (250 mL). The mixture was transferred to a separating funnel and washed with water (1.5 L), dried over Na2SO4 and filtered to give the title compound which was used in the next step without further purification; HPLC Method D: Rt 5.63 mins;
Reaction SMILES: [C:1]([C:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:8]([C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])=[C:7]([CH3:26])[NH:6][C:5]=1[CH3:27])(=[O:3])[CH3:2].Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C.[Pt]>[C:1]([C:4]1[C:5]([CH3:27])=[N:6][C:7]([CH3:26])=[C:8]([C:19]([O:21][CH2:22][CH2:23][C:24]#[N:25])=[O:20])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)C1c1cccc([N+](=O)[O-])c1
Agent: [Pt]
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: CC(=O)c1c(C)nc(C)c(C(=O)OCCC#N)c1-c1cccc([N+](=O)[O-])c1

Procedure:
A solution of 10 g (27 mmols) of 2-cyanoethyl 3-acetyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-5-carboxylate in an electrolyte of 5 g of lithium perchlorate in 250 ml of acetonitrile was electrolyzed on a platinum anode at an electrode potential of +1.2 V vs. SCE. After passing through 2 Faraday equivalents, the electrolysis was stopped, the anolyte was evaporated in vacuo, the residue was taken up in a sodium bicarbonate solution and extracted several times with methylene chloride. The organic extracts were washed with water, dried over sodium sulphate and then evaporated in vacuo. The resulting oil crystallized completely, and the solid product was thoroughly stirred in petroleum ether, filtered off with suction and dried, melting point 85° C., yield: 7.5 g (75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:19][OH:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].[OH2:21].N1[CH:27]=[CH:26]C=CC=1>C(OC(=O)C)(=O)C>[C:26]([OH:17])(=[O:21])[CH3:27].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:19][OH:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: c1ccncc1
Reactant: O
Agent: O=[N+]([O-])c1ccccc1CC(=NO)c1ccccc1F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O

Procedure:
To a solution of 8 g of 1-(2-fluorophenyl)-2-(2-nitrophenyl)ethanone oxime in 20 ml of pyridine, 10 ml of acetic anhydride is added dropwise. The mixture is warmed (steam bath) for 31/2 hours, poured into water and extracted with methylene chloride. The methylene chloride extract is washed with 5% hydrochloric acid, dried over anhydrous sodium sulfate, filtered and evaporated. The residual oil is distilled at 5 mm to give 1-(2-fluorophenyl)-2-(2-nitrophenyl)ethanone oxime acetate, bp 133°-135° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]([NH:34][NH2:35])=[O:33])[CH2:27][CH2:26]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:34]([C:32](=[O:33])[CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[NH2:35])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: NNC(=O)CN1CCOCC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NN(C(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)C(=O)CN1CCOCC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.5 g, 1.0 eq.) was dissolved in CH2Cl2:EtOAc (20 mL, 2:1) and cooled to −60° C. where 2-morpholinoacetohydrazide (0.23 g, 1.0 eq.) was introduced dropwise. T3P (50% in EtOAc) (1.27 mL, 1.5 eq.) was added dropwise followed by DIPEA (0.96 mL, 2 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(2-morpholinoacetyl)acrylohydrazide (0.1 g, yield: 14%).
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[N:27]=[C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[O:29][C:30]=4[C:31]([F:34])([F:33])[F:32])=[O:25])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[Li+].[OH-]>C1COCC1.CO>[C:35]1([C:28]2[O:29][C:30]([C:31]([F:32])([F:34])[F:33])=[C:26]([C:24]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([N:14]4[CH2:13][CH2:12][N:11]([C:8]5[CH:9]=[CH:10][C:5]([C:4]([OH:41])=[O:3])=[CH:6][CH:7]=5)[CH2:16][CH2:15]4)=[N:18][CH:19]=3)=[O:25])[N:27]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cn3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(N2CCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-benzoic acid ethyl ester (130 mg, 0.23 mmol) dissolved in a 1:1 mixture of THF/methanol (2 mL) was added 1N LiOH (2.60 mL, 2.60 mmol). The mixture was stirred at rt overnight. The crude mixture was acidified to pH=1 and purified by HPLC to give 4-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-benzoic acid. The NMR spectrum obtained on the sample is compatible with its structure. LCMS calcd for C27H22F3N5O4 (m/e) 537, obsd 538 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[CH2:18]([N:25]1[CH2:26][CH2:27][N:28]([C:31]([NH:33][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[O:32])[CH2:29][CH2:30]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: NC(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1)N1CCN(Cc2ccccc2)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
A suspension of Example A1 (0.5 g, 1.987 mmol), 4-benzylpiperazine-1-carboxamide (0.741 g, 3.38 mmol), cesium carbonate (0.971 g, 2.98 mmol) and X-Phos (0.047 g, 0.099 mmol) in dioxane (20 mL) was purged 5 min with Ar. To the reaction mixture was added Pd2 dba3 (0.055 g, 0.060 mmol) and it was then heated to 120° C. After 16 h, the reaction was cooled to RT, diluted with EtOAc (100 mL) and filtered through diatomaceous earth. The filter cake was washed with additional EtOAc and the combined filtrates concentrated to afford crude product. This was purified by silica gel chromatography (0-8% MeOH/DCM) to afford 4-benzyl-N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide (0.574 g, 66%). 1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 8.56 (d, J=2.8 Hz, 1H), 8.40 (d, J=8.9 Hz, 1H), 8.23 (d, J=5.7 Hz, 1H), 7.94 (dd, J=8.9, 2.8 Hz, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.30-7.29 (m, 5H), 6.79 (dd, J=5.7, 2.4 Hz, 1H), 3.47 (s, 2H), 3.43 (t, J=4.7 Hz, 4H), 2.32 (t, J=4.7 Hz, 4H); MS (ESI) m/z: 435.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>C(NCC)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.[Cu]I>[Br:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:23]#[C:22][C:20]([OH:24])([CH3:21])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Br)c2C1=O
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)O)ncn2-c2cccc(Br)c2C1=O

Procedure:
3.74 g (8.95 mmol) of 7-bromo-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at the boiling temperature for 1.5 hours with 0.80 g (9.5 mmol) of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization of the residue, which remains behind upon evaporation of the eluate, from ethyl acetate there was obtained 7-bromo-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 207°-208°.