Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:17]=[CH:16][N:15]([CH2:18][CH3:19])[C:11]=3[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:20][C:21]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1B(O)O>>[F:20][C:21]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]2[C:10]3[N:17]=[CH:16][N:15]([CH2:18][CH3:19])[C:11]=3[N:12]=[N:13][CH:14]=2)[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)c(F)c1
Reactant: CCn1cnc2c(-c3ccc(F)c(I)c3)cnnc21
Product: CCn1cnc2c(-c3ccc(F)c(-c4ccc(S(C)(=O)=O)cc4F)c3)cnnc21

Procedure:
Prepared according to the method described above for Example 1 using 4-(3-iodo-4-fluorophenyl)-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 11, 50 mg, 0.16 mmol) and 2-fluoro-4-(methylsulfonyl)phenylboronic acid (68 mg, 0.31 mmol).
Reaction SMILES: [CH2:1]([N:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[NH:7][C:6]1=[O:13])[CH2:2][CH2:3][CH3:4].[C:14]([O-])([O-])=O.[K+].[K+].CI.C(Cl)Cl.CCOC(C)=O>CN(C=O)C>[CH2:1]([N:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[N:7]([CH3:14])[C:6]1=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(C)cc(=O)[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CI
Product: CCCCn1c(C)cc(=O)n(C)c1=O
Temperature: 65 °C
Reaction time: 16.5 h
Yield: 82 %

Procedure:
To 2.3 g (12.62 mmol) of 1-butyl-6-methyl-1H-pyrimidine-2,4-dione in 100 mL DMF was added 3.49 (25.2 mmol) of K2CO3, 0.98 mL (2.24 g, 15.76 mmol) of MeI and the reaction mixture was heated to 65° C. After 16.5 h, TLC (8/1 CH2Cl2 /EtOAc) indicated the consumption of starting material (Rf =0.15). After cooling to 23° C., the resulting slurry was filtered through Celite, and evaporated to a yellow. This oil was dissolved in 100 mL EtOAc, extracted with 100 mL brine, 3×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered and evaporated to a yellow oil. Flash chromatography on silica gel, eluting with CH2Cl2 /EtOAc (20/1 to 4/1), gave 2.03 g (10.34 mmol, an 82% yield) of the title compound as a white crystalline solid. mp: 181-182° C.; 1H NMR (300 MHz, CDCl3): δ 0.95 (t, J=7.3 Hz, 3H), 1.38 (hex, J=7.3 Hz, 2H), 1.57-1.67 (m, 2H), 2.25 (s, 3H), 3.32 (s, 3H), 3.81 (t, J=7.4 Hz, 2H), 5.59 (s, 1H); IR (KBr, cm-1): 3083w, 2955w, 2876w, 1702s, 1665s, 1614s, 1446s, 1435s, 1368w, 1043w; MS (ES) m/z (relative intensity): 197 (M+ +H, 100). Anal. Calcd. for C10H16N2O2 : C, 61.20; H, 8.22; N, 14.27. Found: C, 60.95; H, 8.19; N, 14.16.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:45])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[N:32]([CH3:33])[C:31](=[O:34])[C:30]([F:36])([F:35])[CH2:29][N:28]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:42]=3)=[C:18]([O:43][CH3:44])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:37]1([N:28]2[CH2:29][C:30]([F:35])([F:36])[C:31](=[O:34])[N:32]([CH3:33])[C:26]3[CH:25]=[N:24][C:23]([NH:22][C:19]4[CH:20]=[CH:21][C:16]([C:15]([NH:14][CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[O:45])=[CH:17][C:18]=4[O:43][CH3:44])=[N:42][C:27]2=3)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To the solution 0.17 g (0.27 mmole) of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-71) in 10 mL of dichloromethane was added 5 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour. After removal of the solvents under reduced pressure. Then dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane three times. The combined organic layers were washed three times with sodium carbonate, three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Dichloromethane and ether were added to the residue, followed by hexane to give a precipitate. The solid was collected by filtration, washing with hexane to give 0.125 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-piperidin-4-yl-benzamide (I-72) as a white solid.
Reaction SMILES: [CH:1]([C:3]([C:5]1[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:6]=1[O:13]C)=[O:4])=[CH2:2]>C(#N)C.O>[C:3]([C:5]1[C:6](=[O:13])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)(=[O:4])[CH:1]=[CH2:2]
Reactant: C=CC(=O)c1cc(OC)ccc1OC
Solvent: O
Solvent: CC#N
Product: C=CC(=O)C1=CC(=O)C=CC1=O

Procedure:
To a stirred solution of 2,5-dimethoxyphenyl vinyl ketone (2.5 g, 0.013 mole) in 25 ml of acetonitrile at 0° C. was added dropwise over 3 minutes an aqueous solution of (NH4)2Ce(NO2)6 (17.9 g, 0.033 mole) in 30 ml of water. After the addition, the dark brown mixture turned to yellowish-brown within 5 minutes. At that point, the mixture was poured into water and extracted with methylene chloride. The methylene chloride portion was washed twice with water and then with brine. After drying (MgSO4), the solvent was removed to give a brown oil, which was purified by column chromatography on silica gel, using diethyl ether/hexane (1/1) as eluant. The product was obtained as a reddish/orange, semi-solid residue; 0.8 g; IR (neat) 1670 cm-1 ; NMR (CDCl3) δ5.95 (d,1H); 6.5-7.2 (m5H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[N+:22]([O-])=O)[CH:10]=1>CO.[Pd]>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][NH:7][C:8](=[O:25])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[NH2:22])[CH:10]=1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide 14d (200 mg, 0.48 mmol, 1.00 equiv) in methanol (5 mL). The solution was treated with Pd/C (0.2 g), and stirred under an atmosphere of hydrogen for 2 h at room temperature. The reaction progress was monitored by LCMS. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 200 mg of crude product as a yellow oil.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([O:19][CH2:20][C@H:21]([C@H:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH3:25])[CH2:22][OH:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][C@@H:21]([CH2:20][O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH3:25])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CO)COCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](COCc2ccccc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
p-Toluenesulfonyl chloride (1.4 g. 7.4 mmol) was added in one portion to a cold (ice/water bath) stirred solution of 4 (2.0 g, 6.16 mmol) in anhydrous pyridine (25 ml). The reaction was allowed to warm up to room temperature and stirred for 6 hrs until no starting material was found by HPLC analysis. Ethyl acetate (100 ml) and 10% citric acid (enough to neutralize pyridine) were added. The organic phase was washed with saturated NaCl, saturated NaHCO3 and dried over MgSO4. The crude tosylate 9 (2.9 g) was used in the next step without additional purification. 1H NMR (CDCl3): δ 7.80 (d, J=8.1 Hz, 2H). 7.40-7.25 (m, 7H), 4.41 (d, J=3.6 Hz, 2H), 4.25 (m, 1H), 4.11 (m, 1H), 3.98 (m, 1H), 3.45 (m, 2H), 2.45 (s, 3H), 1.96 (m, 1H), 1.12 (d, J=6.3 Hz, 3H), 0.83 (s, 9H), 0.036 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[C:10]=1[CH3:18])=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:6][NH:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[C:10]=1[CH3:18]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(C)c(C)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1cc(C)c(O)c(C)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
A solution of 15 g of N-t-butoxycarbonyl-4-hydroxy-2,3,5-trimethylaniline [prepared as described in step (d) above] in 200 ml of dehydrated tetrahydrofuran was added to a suspension of 6.8 g of lithium aluminum hydride in 300 ml of dehydrated tetrahydrofuran, whilst ice-cooling, and the resulting mixture was stirred at room temperature for 3 hours, after which it was heated under reflux for 2 hours. At the end of this time, a mixture of 10 ml of water and 30 ml of tetrahydrofuran was added to the reaction mixture in order to destroy any excess of lithium aluminum hydride. The reaction mixture was then stirred at room temperature for 1.5 hours, after which insoluble materials were filtered off with the aid of a Celite (trade mark) filter aid. These materials were washed with ethyl acetate, and the ethyl acetate washings were combined and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 5.1 g of the title compound, melting at 120°-122° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]([CH2:14][NH2:15])[OH:13]>O1CCCC1>[OH:13][CH2:12][CH2:14][NH:15][C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCO
Solvent: C1CCOC1
Product: O=C(NCCO)OCc1ccccc1
Reaction time: 8 h
Yield: 41.6 %

Procedure:
Benzyl chloroformate (63 mL, 443 mmol) was added dropwise to a solution of ethanolamine (60 g, 984 mmol) in tetrahydrofuran (300 mL). After being stirred overnight, the mixture was concentrated in vacuo, and partitioned between methylene chloride and dilute aqueous HCl. The separated organic layer was washed with dilute aqueous NaHCO3, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound (36 g) which was used without further purification in the next step.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21](COCC[Si](C)(C)C)[C:22](=[O:23])[C:17]=4[C:16]=3[CH3:33])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH3:33])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.6 %

Procedure:
To 1.10 g (2.30 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 4-(b) were added 30 ml of dichloromethane and 6 ml of trifluoroacetic acid, and the mixture was stirred under room temperature for 2.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 20 ml of methanol and 2 ml of 28% aqueous ammonia were added to the obtained solid, and the mixture was stirred under room temperature for 12 hours. Then, water was added to the solution, precipitated solid was collected by filtration, washed with water, and then, dried under reduced pressure. To the obtained dried material was added ethyl acetate to dissolve therein, diisopropyl ether was added to the solution and precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain 0.54 g of the title compound as a white solid. (Yield: 67%)
Reaction SMILES: C[O:2][C:3](=[O:27])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:5][C:6]1[C:9](=[O:10])[C:8](=[O:11])[C:7]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Li+].[OH-]>C1COCC1>[CH2:13]([NH:12][C:7]1[C:8](=[O:11])[C:9](=[O:10])[C:6]=1[NH:5][C@H:4]([C:3]([OH:27])=[O:2])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)Nc1c(NCc2ccccc2)c(=O)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H](Cc1ccccc1)Nc1c(NCc2ccccc2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of [2-(benzylamino)-3,4-dioxo-cyclobut-1-enyl]-L-phenylalanine methyl ester (0.16 mmol, 60 mg) in THF (5 mL) was added aqueous LiOH (1.0 M; 0.16 mmol; 160 μL) and the resulting solution was stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue partitoned between 0.1M acetic acid and EtOAc. The organics were dried (Na2SO4) and concentrated in vacuo to afford the title compound as a white solid, mp=215-216° C. (33 mg; 59%).
Reaction SMILES: C(OC1C=CC=CC=1)=CC.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.C1(O)C=CC=CC=1.[CH2:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1/[CH:38]=[CH:39]/[CH3:40])[CH:29]=[CH2:30]>CC(C)=O>[CH2:28]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]=[CH:39][CH3:40])[CH:29]=[CH2:30]
Reactant: C=CCOc1ccccc1/C=C/C
Agent: CC=COc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: C=CCOc1ccccc1C=CC

Procedure:
O-propenylphenol (67 g) was added to a stirred suspension of potassium carbonate (138 g) in dry acetone. Allyl bromide (67 g) was then added dropwise over about 20 minutes and the stirred mixture was heated under reflux for 4 hours. After this time, gas liquid chromatography indicated that the phenol had been converted to about 95% of a mixture of cis and trans 2-allyloxy-1-propenylbenzene. The mixture was filtered and the solvent removed under reduced pressure. The residue was vacuum distilled and yielded 58.9 g of almost pure 2-allyloxy-1-propenylbenzene which was identified spectroscopically. [b.p. 64-88° C. at 0.6 mbar].
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[CH3:19][O-:20].[Na+]>CO>[CH3:19][O:20][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: O=C1CC(c2ccccc2)Cc2nccc(Cl)c21
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccnc2c1C(=O)CC(c1ccccc1)C2
Yield: 92.9 %

Procedure:
To a solution of 4-chloro-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.23 g) in methanol (20 ml) was added sodium methoxide (0.096 g), and the mixture was refluxed for 1 hour and cooled. The solvent was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give crystals of 4-methoxy-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.21 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:22]([CH:25]=[C:26]=[O:27])(=[O:24])[CH3:23]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:26](=[O:27])[CH2:25][C:22](=[O:24])[CH3:23])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(=O)C=C=O
Reactant: CCCCCCN(CCCCCC)c1ccc(N)cc1Br
Solvent: CCOC(C)=O
Product: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 2-bromo-N1,N1-dihexylbenzene-1,4-diamine (4.40 g, 12.4 mmol) in EtOAc (120 mL) was added acetyl ketene (1.57 g, 18.7 mmol), and the mixture was stirred at 80° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as colorless oil (5.10 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][C@@H:13]([O:34][C:35]([N:37]2[CH2:42][CH2:41][CH:40]([N:43]3[CH2:49][CH2:48][C:47]4[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=4[NH:45][C:44]3=[O:54])[CH2:39][CH2:38]2)=[O:36])[C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][C@H:17]2[C:29]([O:31]CC)=[O:30])=[O:15])=[CH:4][C:3]=1[Cl:55].[Li+].[OH-]>>[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][C:5]([CH2:12][C@@H:13]([O:34][C:35]([N:37]2[CH2:38][CH2:39][CH:40]([N:43]3[CH2:49][CH2:48][C:47]4[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=4[NH:45][C:44]3=[O:54])[CH2:41][CH2:42]2)=[O:36])[C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)[CH2:18][C@H:17]2[C:29]([OH:31])=[O:30])=[O:15])=[CH:4][C:3]=1[Cl:55]
Reactant: CCOC(=O)[C@@H]1CN(C2CCN(C)CC2)CCN1C(=O)[C@@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)[C@H](C(=O)O)C2)CC1

Procedure:
Prepared analogously to Example 22.1 from 80.0 mg (0.10 mmol) ethyl(S)-1-{(R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyloxy]-propionyl}-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate and 0.46 mL (0.23 mmol) 0.5 M LiOH solution.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].C(N(C(C)C)CC)(C)C.Br[CH2:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:19][CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(CCBr)cc1
Reactant: NCc1ccccn1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(CCNCc2ccccn2)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Commercially available 2-picolylamine (0.625 ml) was dissolved in toluene (15 ml) and diisopropylethylamine (0.715 ml) was added. After the addition of the compound obtained in Example 9-1 (499.7 mg), the mixture was stirred for two days at 80° C. After the reaction, toluene was added. The solution was washed with distilled water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed by istillation under reduced pressure, and the residue was purified by silica gel column chromatography (25 g, chloroform/methanol=25/1) to obtain the title compound (400.1 mg) as light brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10]COC)[CH:4]=1)#[CH:2].Cl>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(COCOC)c1
Agent: Cl
Solvent: CO
Product: C#Cc1cccc(CO)c1
Temperature: 70 °C
Reaction time: 0.42 h
Yield: 101.9 %

Procedure:
To a mixture of 1-bromo-3-methoxymethoxymethyl-benzene (3.0 g, 13 mmol) described in Manufacturing Example 214-1-1, trimethylsilylacetylene (2.6 g, 26 mmol), N,N-diisopropylethylamine (3.4 g, 26 mmol), copper (I) iodide (500 mg, 2.6 mmol), and 1-methyl-2-pyrrolidone (30 mL) was added tetrakis(triphenylphosphine)palladium (0) (1.5 g, 1.3 mmol), which was stirred for 15 minutes at 60° C. This mixture was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=8:1) to obtain a mixture of (3-methoxymethoxymethyl-phenylethynyl)-trimethyl-silane and 1-bromo-3-methoxymethoxymethyl-benzene (3.0 g of mixture, including approximately 30% (3-methoxymethoxymethyl-phenylethynyl)-trimethyl-silane). Tetrabutylammonium fluoride (2 mL, 1 M tetrahydrofuran solution) was added to a tetrahydrofuran (20 mL) solution of this mixture, which was stirred for 15 minutes at room temperature. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=20:1) to obtain 1-ethynyl-3-methoxymethoxymethyl-benzene (470 mg). To a methanol (10 mL) solution of this 1-ethynyl-3-methoxymethoxymethyl-benzene (470 mg, 2.6 mmol) was added 5 N hydrochloric acid, which was stirred for 25 minutes at 70° C. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure to obtain the title compound (350 mg, 20%).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7](=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9]=1[NH2:23])C.[OH-].[Na+]>C(O)C>[NH2:23][C:9]1[C:10]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][C:8]=1[C:7](=[O:24])[CH2:6][CH2:5][C:4]([OH:25])=[O:3]
Reactant: CCOC(=O)CCC(=O)c1cccc(C(=O)c2ccc(Cl)cc2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c(C(=O)CCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Yield: 88.5 %

Procedure:
A solution of 3.3 g (0.0092 mole) of 2-amino-3-(4-chlorobenzoyl)-γ-oxobenzenebutanoic acid ethyl ester in 70 ml of hot 190 proof ethanol was treated with 40 ml of 4N aqueous sodium hydroxide solution and the mixture was heated at reflux for 18 hr. The hot mixture was filtered and the insoluble material was discarded. The filtrate was cooled and the precipitate collected by filtration. This precipitate was partitioned between dilute hydrochloric acid and methylene chloride. The organic layer was separated, dried over magnesium sulfate and concentrated to give 2.7 g (89%) of bright yellow crystals, m.p. 172°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:23]([CH3:27])[C:24]([OH:26])=O)=[N:13]2)=[O:10])=[CH:4][CH:3]=1.[CH3:28][C:29]([CH3:33])([CH3:32])[CH2:30][NH2:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:23]([CH3:27])[C:24]([NH:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH3:28])=[O:26])=[N:13]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C(=O)O)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: CC(C)(C)CN
Product: CC(C(=O)NCC(C)(C)C)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
A mixture of the product from Example 110 and 2,2-dimethylpropan-1-amine was processed using a method similar to that described in Example 112 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.59-11.62 (bs, 1H), 8.31 (dd, J=7.8, 1.4 Hz, 1H), 8.16-8.21 (m, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.93-8.00 (m, 1H), 7.85-7.91 (m, 1H), 7.41 (s, 4H), 4.38 (q, J=6.9 Hz, 1H), 3.68 (s, 2H), 2.94 (dd, J=13.1, 6.4 Hz, 1H), 2.85 (dd, J=13.1, 6.0 Hz, 1H), 1.44 (d, J=6.9 Hz, 3H), 0.81 (s, 9H); MS (ESI+) M/Z 455 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][NH:14][CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][O:30][C:31](=[O:33])[CH3:32]>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:12]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:13][NH:14][CH:15]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(C(CNCC(=O)N(C)C)C(=O)OC(C)(C)C)c1
Reactant: CC(=O)OCBr
Product: CCCCOc1cccc(C(CNC(COC(C)=O)C(=O)N(C)C)C(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from [2-[2-(3-butoxyphenyl)-(tert-butoxycarbonyl)ethylamino]-N,N-dimethylacetamide and acetic acid bromomethyl ester according to Step 1 of Example 3. Colourless oil (38% yield).