Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C[N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(NCCO)C>O.C(OCC)(=O)C.CC(N(C)C)=O>[CH2:52]([N:47]([CH2:48][CH2:49][OH:50])[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:14]([C:11]3[CH:12]=[N:13][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)=[O:15])[CH2:22][CH2:21]2)=[N:24][CH:25]=1)[CH3:51]
Reactant: CN1CCOCC1
Reactant: O=C(O)c1ccc(N2CCC(NC(=O)c3ccc(-c4cccc(F)c4)nc3)CC2)nc1
Agent: CCNCCO
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: CCN(CCO)C(=O)c1ccc(N2CCC(NC(=O)c3ccc(-c4cccc(F)c4)nc3)CC2)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a vial containing 6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]nicotinic acid (63.07 mg, 0.15 mmol) was added 0.375 mL of DMA, EDC (31.6 mg, 0.16 mmol), HOBt (20.3 mg, 0.15 mmol), NMM (0.04 mL, 0.37 mmol) and 2-(ethylamino)ethanol (13.4 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 12 hours and then diluted with water and ethyl acetate. The layers were separated and the organic layer collected and concentrated to give an oil, which was purified by RP-HPLC to give N-ethyl-6-[4-({[6-(3-fluorophenyl)pyridin-3-yl]carbonyl}amino)piperidin-1-yl]-N-(2-hydroxyethyl)nicotinamide
Reaction SMILES: O.Cl.[OH:3][CH:4]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:22]([CH2:23][N:24]([CH3:26])[CH3:25])=[N:21][C:20]([C:27]([NH2:29])=[O:28])=[N:19]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>S(=O)(=O)(O)O.CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[ClH:17].[C:4]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:22]([CH2:23][N:24]([CH3:26])[CH3:25])=[N:21][C:20]([C:27]([NH2:29])=[O:28])=[N:19]1)(=[O:3])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN(C)Cc1nc(C(N)=O)nn1-c1ccc(Cl)cc1C(O)c1ccccc1
Agent: [Cr+6]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CN(C)Cc1nc(C(N)=O)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.50 ml (corresponding to 0.0067 mole of chromium trioxide) of an oxidation solution according to Jones (preparation of 250 ml by dissolving of 66.8 g of chromium trioxide in 57.5 ml of concentrated sulphuric acid and making up with water to 250 ml) is added dropwise at room temperature, with stirring, to a solution of 4.22 g (0.01 mole) of 1-[2-(α-hydroxybenzyl)-4-chlorophenyl]-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxamide-hydrochloride in 800 ml of acetone. The reaction mixture, gradually assuming a green colour, is stirred for 18 hours at room temperature, and then concentrated in vacuo to 100 ml. Ice and saturated sodium carbonate solution are added until the pH-value has reached 10, and extraction is performed twice with ethyl acetate. The organic phase is washed twice with water and once with saturated sodium chloride solution and dried over magnesium sulphate. The drying agent is filtered off, and there is added to the filtrate ethereal hydrogen chloride solution until the pH-value has reached 3. The hydrochloride, precipitating in crystalline form, is filtered off with suction and washed with ethyl acetate and ether. After drying in vacuo, there is obtained 1-(2-benzoyl-4-chlorophenyl)-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-carboxamide-hydrochloride, m.p. 250° (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:15]#N)=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[Mg]Br.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:17]([F:19])([F:18])[F:20])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N#Cc1c(C(F)(F)F)cnn(-c2ccc(Cl)cc2)c1=O
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(C(F)(F)F)cnn(-c2ccc(Cl)cc2)c1=O

Procedure:
After 3.0 g of 2-(4-chlorophenyl)-4-cyano-5-trifluoromethylpyridazin-3-one (The present compound 1-15) is dissolved in 30 mL of anhydrous tetrahydrofuran, 4.0 mL of methylmagnesium bromide (3.0M diethyl ether solution) is dropped to the tetrahydrofuran solution at 0° C. and stirred for hour. Afterwards, the reaction solution is poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed, in order, with water and aqueous saturated sodium chloride. After drying over anhydrous magnesium sulfate and concentrated, the residue is subjected to silica gel column chromatography to afford 2-(4-chlorophenyl)-4-methyl-5-trifluoromethylpyridazin-3-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=1.CC1(C)C(C)(C)OB([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:10]1([C:4]2[N:3]=[C:2]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:29]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CCc1cc(Cl)nc(C2CCCC2)n1
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(Cc2ccc(CC(=O)OC)cc2)nc(C2CCCC2)n1
Temperature: 90 °C
Reaction time: 48 h
Yield: 8.4 %

Procedure:
A mixture of 4-chloro-2-cyclopentyl-6-ethylpyrimidine (0.275 g, 0.95 mmol), methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (0.200 g, 0.95 mmol), Pd(dppf)Cl2 (0.078 g, 0.095 mmol), and powdered Na2CO3 (0.302 g, 2.85 mmol) in dioxane (5 mL) and water (3 mL) was stirred under an argon atmosphere at 90° C. for 48 h. After this time, the mixture was cooled and filtered through celite washing with ethyl acetate. The filtrate was washed with brine (3×15 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, hexane/ethyl acetate) to afford the title compound (0.027 g, 14%) as a brown oil. MW=338.44. 1H NMR (DMSO-d6, 500 MHz) δ 7.28-7.22 (m, 2H), 7.21-7.17 (m, 2H), 7.01 (s, 1H), 3.96 (s, 2H), 3.63 (s, 2H), 3.59 (s, 3H), 3.21 (quin, J=8.1 Hz, 1H), 2.63 (q, J=7.6 Hz, 2H), 2.01-1.90 (m, 2H), 1.88-1.79 (m, 2H), 1.78-1.70 (m, 2H), 1.69-1.57 (m, 2H), 1.17 (t, J=7.6 Hz, 3H); APCI MS m/z 339 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]1([C:25]2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][NH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C)C=O>O>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:27]2[CH:28]=[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:26]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1c[nH]nc1-c1ccccc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Reaction time: 1.5 h
Yield: 80.2 %

Procedure:
Sodium hydride (60%, oily, 1.85 g) was added to a mixture of 4-benzyloxybenzyl chloride (10.8 g), ethyl 3-phenyl-1H-pyrazole-4-carboxylate (10.0 g) and N,N-dimethylformamide (50 ml) at 0° C., and the mixture was stirred for 1.5 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield ethyl 1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylate (15.3 g, yield: 80%). This was crystallized from ethyl acetate-diisopropyl ether. Melting point: 102–103° C.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O[C@H:33]1[CH2:37][NH:36][C@H:35]([C:38](O)=O)[CH2:34]1>CS(C)=O.[Cu]I>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:22]=[CH:23][C:2]([N:36]5[CH2:37][CH2:33][CH2:34][C@H:35]5[CH2:38][N:36]5[CH2:37][CH2:33][CH2:34][CH2:35]5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@H]3CN3CCCC3)cc1OCC2
Temperature: 90 °C
Yield: 89.4 %

Procedure:
A mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 95 from Example 95 (100 mg, 0.27 mmol), (S)-pyrrolidinylmethylpyrrolidine (206 mg, 1.34 mmol), K3PO4 (114 mg, 0.53 mmol), trans-4-hydroxyproline (14 mg, 0.11 mmol) and CuI (10 mg, 0.05 mmol) in DMSO (0.5 mL) was heated at 90° C. for 23 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was dissolved in DCM and washed with 10% citric acid, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-6% MeOH in DCM) then Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was freeze-dried from MeCN/H2O to afford 133 (22 mg, 19%) as a white solid. LCMS: RT 2.81 min [M+H]+ 448.4. 1H NMR (DMSO, 400 MHz): δ 8.19 (1H, d, J=8.93 Hz), 7.88 (1H, d, J=0.63 Hz), 7.77 (1H, s), 6.45 (1H, dd, J=9.00, 2.43 Hz), 6.13 (1H, d, J=2.38 Hz), 5.93-5.92 (1H, m), 4.48-4.36 (4H, m), 3.89-3.81 (1H, m), 3.42-3.35 (1H, m), 3.15-3.05 (1H, m), 2.64-2.57 (2H, m), 2.43-2.40 (4H, m), 2.00-1.98 (4H, m), 1.74-1.66 (4H, m), 1.47 (6H, d, J=6.61 Hz)
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(=O)([O-])[O-].[Ag+2]>[CH2:13]([O:8][C:5]1[CH:4]=[C:3]([C:2]([Br:1])=[CH:7][N:6]=1)[C:9]([O:11][CH3:12])=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(=O)[nH]cc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Product: COC(=O)c1cc(OCc2ccccc2)ncc1Br
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To 2 mL of methyl 5-bromo-2-oxo-1,2-dihydropyridine-4-carboxylate (232 mg, 1.00 mmol)(commercially available from Combi-Blocks) was added benzyl bromide (205 mg, 1.20 mmol) and silver carbonate (413 mg, 1.50 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA). The resulting mixture was stirred at 50° C. overnight. After reaction completion, the mixture was loaded onto a solid silica gel cartridge and purified by chromatography with 10% EtOAc/hexane to afford the desired product H6.1 (293 mg, 91%). MS ESI (pos.) m/e: 322.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:9]([C:10]#[CH:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:12])[CH:3]=1.CC([O-])(C)C.[K+]>C1COCC1>[Cl:12][C:4]1[CH:3]=[C:2]2[C:9]([CH:10]=[CH:11][NH:1]2)=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: C#Cc1cc(C#N)c(Cl)cc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cc2cc[nH]c2cc1Cl
Temperature: 75 °C
Yield: 85.7 %

Procedure:
To a solution of 240 (50 mg, 0.284 mmol) in THF (100 mL) was added t-BuOK (160 mg, 1.42 mmol). The mixture was heated at 75° C. for 3 h during which the color of the reaction mixture changed from yellow to brown. After the mixture was cooled, it was partitioned between EtOAc (200 mL) and H2O (50 mL). The organic layer was separated, washed with brine, dried and concentrated in vacuo to afford 43 mg (86%) of 6-chloro-1H-indole-5-carbonitrile (242) as white solid: 1H NMR (500 MHz, DMSO-d6) (511.80 (s, 1H), 8.21 (s, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 6.61 (d, 1H); MS (ESI) m/z=177.0 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].I[C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>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].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(O)(C)C>[OH:32][C:28]1[CH:27]=[C:26]([NH:1][C:2]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH:12]=[CH:11][C:3]=2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:31]=[CH:30][CH:29]=1
Reactant: COc1cccc(CCc2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Reactant: Oc1cccc(I)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CC(C)(C)O
Product: COc1cccc(CCc2ccc(C(=O)OC(C)(C)C)c(Nc3cccc(O)c3)c2)c1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To 2-methyl-2-propanol 3.0 mL solution of tert-butyl 2-amino-4-(2-(3-methoxyphenyl)ethyl)benzoate 0.13 g were added 3-iodophenol 0.22 g, cesium carbonate 0.26 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg at room temperature, and it was stirred at 70° C. for 12 hours. Tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 70° C. for 7 hours. Cesium carbonate 0.26 g, tris(dibenzylideneacetone)dipalladium(0) 3.7 mg, palladium acetate 1.8 mg and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl 9.5 mg were added to it, and it was stirred at 70° C. for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=4:1] to give tert-butyl 2-((3-hydroxyphenyl)amino)-4-(2-(3-methoxyphenyl)ethyl)benzoate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].B(OB=O)=O.[Cl:23][C:24]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:25]=1[CH:26]=O.B(OCCCC)(OCCCC)OCCCC.C(N)CCC.Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[Cl:23][C:24]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:25]=1/[CH:26]=[CH:15]/[C:14](=[O:16])[CH2:13][C:12](=[O:17])/[CH:11]=[CH:10]/[C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([OH:1])[CH:3]=1
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: COc1ccc(C=CC(=O)CC(C)=O)cc1O
Agent: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: O=BOB=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCN
Product: COc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2Cl)cc1O
Reaction time: 1 h
Yield: 23.4 %

Procedure:
6-(3-Hydroxy-4-methoxyphenyl)hex-5-ene-2,4-dione (20 mg, 85 μmol) and boron trioxide (11 mg, 0.16 mmol) was placed in a 20 mL reaction vessel, and dissolved in 0.4 mL of ethyl acetate. To the stirring mixture at 80° C. was added a solution of 2-chloro-4-hydroxybenzaldehyde (17 mg, 0.11 mmol) and tri-n-butyl borate (25 μL, 93 μmol), sequentially. After the reaction mixture was stirred for 2 h at the same temperature, n-butylamine (10 μL, 0.10 mmol) was added with additional stirring for 1 h. The reaction mixture was treated with a 1:1 solution (1 mL) of 1N HCl and brine at room temperature, and was stirred at 50° C. for 5 min to 1 h (if necessary, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution). The organic layer was purified directly by silica gel column chromatography (eluting with hexane/ethyl acetate or chloroform/methanol) to obtain the title compound (7.4 mg, 23%) as a solid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:13]([NH:15][C:16]1[S:17][C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)=[O:14])(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:13]([NH:15][C:16]1[S:17][C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1)=[O:14]
Reactant: CCOC(=O)c1sc(NC(=O)c2cc3ccccc3n2C(C)=O)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc(NC(=O)c2cc3ccccc3[nH]2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
By carrying out the procedure according to Example 10 which is described above, the compound 2-[(1-acetyl-2-indolyl ) carbonylamino]-4-phenyl-5-ethoxycarbonylthiazole (1.5 g) is prepared and dissolved in 100 ml of ethanol in the presence of 0.6 g of Na2CO3. The mixture is stirred at room temperature for 48 hours and then concentrated under vacuum. The residue is triturated in water and then in a minimum amount of dichloromethane, filtered and dried.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[N:5][CH:4]=1)=[O:2].[NH2:16][C@@H:17]([CH3:38])[C:18]([NH:20][C@@H:21]([CH3:37])[C:22]([NH:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:26]([NH2:28])=[O:27])=[O:23])=[O:19].C(Cl)CCl.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(O)(C(F)(F)F)=O>CN(C=O)C>[NH2:28][C:26](=[O:27])[C@@H:25]([NH:24][C:22](=[O:23])[C@@H:21]([NH:20][C:18](=[O:19])[C@@H:17]([NH:16][C:10](=[O:12])[CH:9]([NH:8][C:6]1[S:7][C:3]([CH:1]=[O:2])=[CH:4][N:5]=1)[CH:13]([CH3:15])[CH3:14])[CH3:38])[CH3:37])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1
Reactant: CC(C)[C@H](Nc1ncc(C=O)s1)C(=O)O
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C(Nc1ncc(C=O)s1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
Yield: 74.4 %

Procedure:
Following the procedure described in Example 4, except using the material from Example 20 (77 mg, 0.169 mmol), (S)-2-amino-N-((S)-1-((S)-1-amino-3-(4-hydroxyphenyl)-1-oxopropan-2-ylamino)-1-oxopropan-2-yl)propanamide (61.2 mg, 0.19 mmol), EDC (56.2 mg, 0.293 mmol), 1-hydroxy-7-azabenzotriazole (19.2 mg, 0.141 mmol), anhydrous DMF (2 mL) and N-methylmorpholine (104 μL, 0.946 mmol), 67 mg (54.5%) of the title compound is obtained as a yellow solid as a TFA salt. Purification is done by preparative HPLC (Condition A) using a PHENOMENEX® Luna Axia 30×100 mm S10 column from 15% Solvent B to 90% Solvent B over 1 min, ret. T=6.98 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]([NH2:27])=[N:25][OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].O>C(OCC)(=O)C>[CH2:20]([O:19][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:24]3[NH:27][C:34](=[O:35])[O:26][N:25]=3)[CH:16]=2)[C:11](=[O:28])[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:9]=1[CH2:8][NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(N)=NO)cc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3noc(=O)[nH]3)cc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a solution of tert-butyl[6-[amino(hydroxyimino)methyl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.78 g, 1.7 mmol) in ethyl acetate (10 ml) tetrahydrofuran (10 ml) was added 1,1′-carbonyldiimidazole (0.83 g, 5.1 mmol) and the mixture was stirred at 80° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give tert-butyl [4-butoxy-2-isobutyl-1-oxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.54 g, 65.9%) as crystals.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[N+:2]=[N-:3].S(Cl)([Cl:14])=O>>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([Cl:14])=[O:11])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Product: [N-]=[N+]=NCCCCCC(=O)Cl
Yield: 65.7 %

Procedure:
The above compound was prepared by a literature procedure [V. M. Rothe and K. Gehrke, Makromol Chem. 83, 1 (1965)] as follows: To 6-azidohexanoic acid (7.5 g, 47.7 mmol) previously cooled to 0° C. was added 10 ml (16.3 g, 137 mmol) of thionyl chloride and the solution was stirred in cold until the evolution of gas had subsided (5-10 min) and then refluxed for 1 h. The reaction mixture was evaporated and the residue distilled to give 5.5 g (65.6%) of title compound bp 110°-111° C./12 Tor (lit. bp 73°-75° C./0.1 tor); ir (neat) νmax : 2097 (N3), 1795 cm-1 (C=O); 1Hmr (CDCl3) δ: 1.1-2.0 (m, 6H, 3CH2), 2.9 (m, 2H, CH2CO), 3.27 (m, 2H, CH2N3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>[C-]#N.[C-]#N.[Zn+2].[Zn]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: Cc1ccc(Br)nc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Product: Cc1ccc(C#N)nc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
2-Bromo-5-methylpyridine ((8.6 g, 50 mmol) was mixed with Zn(CN)2 (4.1 g, 35 mmol), Pd(dppf)2C12 (0.89 g, mmol) and zinc dust (0.14 g, mmol) in DMF (86 ml) at 155° C. for 15 minutes. The reaction mixture was cooled down to room temperature and quenched with water and ethyl acetate. The mixture was filtered through celite and the organic layer was separated and dried with sodium sulfate. The product was purified by column chromatography with 10˜25% ethyl acetate in hexanes to give 3.4 g of 5-methyl-pyridine-2-carbonitrile (yield: 57.6%). 1H NMR (CDCl3), δ(ppm): 8.52 (s, 1H), 7.59 (m, 2H), 2.42 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[CH3:11].[CH:12]([B-](F)(F)F)=[CH2:13].[K+]>CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[CH3:11])=[CH2:13]
Reactant: C=C[B-](F)(F)F
Reactant: Cc1c(Br)ccc(C#N)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCO
Product: C=Cc1ccc(C#N)c(F)c1C

Procedure:
A mixture of 4-bromo-2-fluoro-3-methylbenzonitrile (7.00 g, 32.7 mmol), potassium vinyltrifluoroborate (5.3 g, 39 mmol) and Pd(dppf)Cl2 (0.5 g, 0.7 mmol) in 70 mL of EtOH and 30 mL of TEA was refluxed under Ar for 4 hours. Concentrated, the residue was purified by column chromatography (petrol ether:EtOAc=10:1) to afford 4-ethenyl-2-fluoro-3-methylbenzonitrile.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]=2[C:8]1=[O:27].[N:37]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:45]3[CH2:46][CH2:47][CH:42]([N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH2:43][CH2:44]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]=2[C:8]1=[O:27]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C1c2c(-c3ccccc3F)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C1c2c(-c3ccccc3F)cc(N3CCC(N4CCCC4)CC3)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 51.9 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-fluorophenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (100 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (70.2 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-7-(2-fluorophenyl)-6-oxo-9-[4-(pyrrolidine-1-yl)piperidine-1-yl]-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (63.4 mg, 52%).