Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[C@H:5]1[O:32][C@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:16]([O:17][CH2:18][CH:19]=[CH2:20])[C@@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:46]([O:53][C@H:54]1[C@H:67]([O:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C@@H:66]([CH2:76][O:77][CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[O:65][C@H:56]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C@H:55]1[OH:85])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.CCN(CC)CC>ClCCCl>[CH2:18]([O:17][C@H:16]1[C@H:21]([O:22][C:23](=[O:30])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:31]([CH2:33][O:34][C:35](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:32][C@H:5]([O:85][C@H:55]2[C@@H:54]([O:53][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:67]([O:68][CH2:69][C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)[C@@H:66]([CH2:76][O:77][CH2:78][C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=3)[O:65][C@@H:56]2[O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C@H:6]1[O:7][C:8](=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:19]=[CH2:20]
Reactant: C=CCO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](OC(=N)C(Cl)(Cl)Cl)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O[C@@H]1[C@@H](OCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: C=CCO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](O[C@@H]2[C@@H](OCc3ccccc3)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 3-O-allyl-2,4,6-tri-O-benzoyl-α-D-mannopyranosyl trichloroacetimidate [26] (902 mg, 1.21 mmol) and benzyl 3,4,6-tri-O-benzyl-α-D-mannopyranoside [27] (723 mg, 1.34 mmol) in 1,2-DCE (10 mL), was stirred in the presence of mol. sieves (1.0 g of 3 Å powder) under an atmosphere of argon (30 min). The mixture was cooled (0° C.) with continued stirring (10 min) prior to the addition of TMSOTf (219 μL, 1.21 mmol). After some time (10 min), Et3N (100 μL) was introduced and the mixture was filtered. The solvent was evaporated and the residue subjected to FC (10-50% EtOAc/hexane) to yield the tribenzoate (24) as, a colourless oil (1.14 g, 84%). 1H NMR (CDCl3) δ 3.67-3.81, 3.88-3.95, 4.06-4.15, 4.30-4.35 (4 m, 12 H; H-2I,-3I,-4I,-5I,-6aII,-6bII,-3II,-5II,-6aII,-6bII, OCH2), 4.94-4.70 (m, 7 H; CH2Ph), 4.84 (d, 1 H, JA,B 10.8 Hz; A of AB quartet), 4.93-4.96, 5.04-5.09 (2 m, 2 H; ═CH2), 5.02 (d, 1 H, J1,2 1.9 Hz; H-1I), 5.24 (d, 1 H; J1,2 1.9 Ha; H-1II), 5.59-5.69 (m, 1 H; ═CH), 5.72 (dd, 1 H, J2,3 3.1 Hz; H-2II), 5.75 (dd, 1H, J3,4 9.8, J4,5 9.9 Hz; H-4II), 7.09-7.58, 7.97-8.06 (2 m, 35 H; Ar). 13C NMR (CDCl3) δ 61.50, 63.49 (2C; C-6I,-6II), 68.63, 69.17, 69.31, 69.46, 69.64, 71.08, 72.04, 72.64, 73.60, 74.73, 75.30, 75.38 (13C; C-3I,-4I,-5I,-2II,-3II,-4II,-5II, OCH2, CH2Ph), 79.97 (C-2I), 98.52, 99.60 (C-1I,-1II), 117.67 (═CH2), 127.70-138.43 (43C; ═CH, Ar), 165.61, 165.69, 166.42 (3C; C═O).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:10])[C:8]=1[Br:9])[NH2:5].[N:11]([O-])=O.[Na+]>O.Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:11])[CH:6]=[C:7]([Br:10])[C:8]=1[Br:9]
Reactant: O=N[O-]
Reactant: Nc1cc(Br)c(Br)c(Br)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc(Br)c(Br)c(Br)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
3,4,5-Tribromoaniline was obtained by the procedure of L. F. Tietze and T. Eicher (L. F. Tietze, T. Eicher. Reaktionen und Synthesen im organisch-chemischen Praktikum und Forschungslaboratorium. (1991) Georg Thieme Verlag, Stuttgart, N.Y.). 7.8 g (24 mmol) of 3,4,5-tribromoaniline were stirred with a solution of 6.5 mL of concentrated hydrochloric acid and 6.5 mL of water. The mixture was cooled to about −10° C. and at this temperature the solution of 2.76 g of NaNO2 in 11 mL of water was added for 20 min with intensive stiffing. The reaction mixture was stirred for 30 min at −10° C. Then the cooled solution of 16.2 g of SnCl2-2H2O in 17 mL of concentrated HCl was added dropwise at −10° C. to the suspension of diazocompound. The reaction mixture was kept at −10° C. for one hour and at 5° C. overnight. The obtained precipitate was filtered off and washed with water. The residue was resuspended in 50 mL of water and concentrated aqueous solution of NaOH was added to get alkaline medium. The 3,4,5-tribromophenylhydrazine was extracted with ether. Organic layer was dried with MgSO4 and ether was evaporated. Yield: 5.5 g (67%). 1H-NMR (200 MHz, DMSO-d6), δ, ppm: 7.09 (2H, s, arom.), 7.34 (1H, s, NH), 4.19 (2H, d, NH2).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[C:22](=O)[C:21]2[C:20]([C:24]([O:26]C)=O)=[CH:19][CH:18]=[CH:17][C:16]=2[NH:15][CH:14]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:35][NH2:36]>CO>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[C:22]2=[N:35][NH:36][C:24](=[O:26])[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([C:21]=32)[NH:15][CH:14]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1nccn1Cc1ccccc1)C(c1ccccc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1nccn1Cc1ccccc1
Yield: 27 %

Procedure:
Methyl 3-(1-benzyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (3.7 g, 8.46 mmol) in hydrazine monohydrate (25 mL) and methanol (100 mL) was stirred at room temperature for 5 h. The resulting mixture was filtered to give 9-(1-benzyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a white solid (950 mg, yield 27%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.61-4.64 (d, J=11.2 Hz, 1H), 4.99-5.12 (m, 1H), 6.83-6.89 (m, 4H), 7.14-7.28 (m, 1H), 7.36-7.38 (d, J=7.6 Hz, 1H), 7.54-7.58 (t, J=8.0 Hz, 7H), 12.20 (s, 1H). LC-MS (ESI) m/z: 420 (M+1)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:30]C(=O)OC(C)(C)C)[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[N:25][CH:24]=[CH:23]4)[CH:19]=2)=[CH:2]1.C(O)(C(F)(F)F)=O>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH2:30])[CH2:12][O:13][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[N:25][CH:24]=[CH:23]4)[CH:19]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2ccc3cnccc3c2)c1)Cc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](COc1cncc(-c2ccc3cnccc3c2)c1)Cc1c[nH]c2ccccc12
Reaction time: 1 h

Procedure:
A solution of Example 27B (0.125 g, 0.25 mmol) in dichloromethane (3 mL) at room temperature was treated with TFA (400 μL), stirred for 1 hour, and concentrated. The concentrate was azeotropically distilled with diethyl ether two times and the residue was purified by reverse phase HPLC on a C18 column with 0-100% CH3CN/H2O/0.1% TFA to provide the desired product as the di-trifluoroacetate salt (0.110 g, 70%). MS (ESI) m/e 395 (M+H)+; 1H NMR (DMSO-d6, 300 MHz) δ 11.02 (br s, 1H), 9.52 (s, 1H), 8.76 (d, J=3 Hz, 1H), 8.62 (d, J=8 Hz, 1H), 8.44-8.46 (m, 2H), 8.38 (d, J=9 Hz, 1H), 8.11-8.20 (m, 3H), 8.04-8.08 (m, 1H), 7.83-7.86 (m, 1H), 7.62 (d, J=9 Hz, 1H), 7.37-7.40 (m, 1H), 7.31 (d, J=3 Hz, 1H), 7.08-7.12 (m, 1H), 6.99-7.03 (m, 1H), 4.37-4.41 (m, 1H), 4.18-4.23 (m, 1H), 3.86-3.91 (m, 1H), 3.16-3.20 (m, 2H); Anal. Calcd for C25H22N4O.2TFA.H2O: C, 49.35; H, 3.61; N, 7.43; F, 22.67. Found: C, 49.04; H, 3.55; N, 7.42; F, 22.28.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C@H:9]([CH3:12])[CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:13][C:14]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[CH:16][C:15]=1[C:29]1[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=1>>[NH2:35][C:32]1[N:33]=[CH:34][C:29]([C:15]2[CH:16]=[CH:17][C:18]([C:2]3[C:3]([O:8][C@H:9]([CH3:12])[CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=3)=[CH:19][C:14]=2[F:13])=[CH:30][N:31]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: C[C@H](CO)Oc1ncccc1Br
Product: C[C@H](CO)Oc1ncccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (R)-2-((3-bromopyridin-2-yl)oxy)propan-1-ol and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C18H17FN4O2, 340.13; m/z found, 340.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J=1.4, 2H), 8.17 (dd, J=4.9, 1.9, 1H), 7.85 (dd, J=7.4, 1.9, 1H), 7.67-7.54 (m, 3H), 7.09 (dd, J=7.4, 4.9, 1H), 6.89 (s, 2H), 5.35-5.23 (m, 1H), 4.86 (t, J=5.4, 1H), 3.62-3.51 (m, 2H), 1.25 (d, J=6.3, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][C:17](=[O:19])[C:16]3[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:15]=3[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:18][CH:17]([OH:19])[C:16]3[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:15]=3[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(O)ccc1O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)c1cc(O)ccc1O2
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
A solution of the product from step 1 (4.51 g, 13.5 mmol) in methanol (50 mL) was cooled to 15° C. and sodium borohydride was added slowly and the mixture was further stirred for 30 min and then concentrated. The crude residue was partitioned between methylene chloride and water and the aqueous layer was extracted twice with methylene chloride. The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated to produce the product of step 2 (4.1 g, 90%), mp 171-173° C. (ethyl acetate, ether and hexane), MS m/z=334 (M−H).
Reaction SMILES: [C:1]([CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10]C(C)(C)C)=O)#[N:2].[CH2:15]([C:23]1[CH:31]=[CH:30][C:26](C(O)=O)=[CH:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:15]([C:23]1[CH:24]=[CH:25][C:26]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][CH:3]2[C:1]#[N:2])=[O:10])=[CH:30][CH:31]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C#N
Product: CCCCCCCCc1ccc(C(=O)N2CCCC2C#N)cc1

Procedure:
General procedure D was used to deprotect 19 (1.2 mmol, 0.24 g). The product was immediately carried on and coupled to 2 (1.2 mmol, 0.281 g) using general procedure F. After standard work up procedures the title product was recovered from flash chromatography to yield 0.238 g (0.76 mmol) after two steps. 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J=8.1, 2H), 7.21 (dd, J=7.9, 14.6, 2H), 4.91 (s, 0.5H), 4.66 (s, 0.5H), 3.67 (s, 1H), 3.56 (s, 1H), 2.66-2.60 (m, 2H), 2.32 (s, 1H), 2.17 (s, 1H), 2.01 (s, 1H), 1.88 (s, OH), 1.60 (d, J=7.5, 2H), 1.28 (dd, J=7.5, 14.4, 10H), 0.87 (t, J=6.8, 3H). 13C NMR (126 MHz, CDCl3) δ 173.09, 146.33, 133.26, 132.60, 128.43, 128.21, 127.64, 127.44, 118.72, 59.24, 52.28, 50.05, 46.85, 35.84, 31.85, 31.19, 29.41, 29.22, 25.42, 22.64, 14.11.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:13][C:14](N)=[O:15]>O>[CH3:12][O:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:14]([OH:15])[N:13]=[C:4]2[OH:6]
Reactant: NC(N)=O
Reactant: COc1ccc(N)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2nc(O)nc(O)c2c1
Yield: 71.6 %

Procedure:
2-Amino-5-methoxybenzoic acid (5.090 g, 30.45 mmol) was heated with urea (18.300 g, 304.50 mmol) to 150° C. for 24 h. Water (150 mL) was cautiously added to the melt and allowed to cool. The resulting precipitate was filtered off and dried to give a solid (4.189 g, 72%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([OH:11])=O)[CH2:4][CH2:3]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:27]1([C@@H:33]([NH2:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([CH2:8][C:9]([NH:35][C@H:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:34])=[O:11])[CH2:6][CH2:7]1
Reactant: O=C(O)CC1CCC(=O)CC1
Reactant: C[C@H](N)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)CC1CCC(=O)CC1)c1ccccc1
Reaction time: 0.25 h
Yield: 143.2 %

Procedure:
A solution of 4-oxocyclohexaneacetic acid (28.39 g) (Example H) and triethylamine (30.4 ml) in 800 ml of dichloromethane at -10° C. is treated dropwise with isobutyl chloroformate (26.0 ml). The reaction mixture is stirred at this temperature for 15 minutes and 1(S)-phenylethylamine (26.51 g) is added via syringe. After 30 minutes at -10° C., the mixture is stirred at room temperature for another 30 minutes. The reaction is concentrated in vacuo and the residue partitioned between ethyl acetate (1000 ml) and 1 N hydrochloric acid solution (400 ml). The organic extract is washed with 1 N sodium hydroxide solution and brine, dried (magnesium sulfate), and concentrated in vacuo to leave 67.5 g of crude (S)-4-oxo-N-(1-phenylethyl)cyclohexaneacetamide as a white solid; mp 110°-151° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:23][C:24](=[O:26])[CH3:25])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccccc2)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccccc2)c1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-cyano-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (206 mg), acetic anhydride (0.127 mL), and triethyl amine (0.187 mL) in dichloromethane (2 mL) was stirred at room temperature for 1 h; then the mixture was concentrated, the residue was purified with column to give the title compound (201 mg). The title compound, ESI MS (m/z): 350 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH:23]([C:25]3[CH:26]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:28]=[C:29]4[C:33]=3[NH:32][C:31](=[O:34])[CH2:30]4)[CH3:24])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH:23]([C:25]3[CH:26]=[C:27]([C:35]([F:37])([F:36])[F:38])[CH:28]=[C:29]4[C:33]=3[NH:32][C:31](=[O:34])[CH2:30]4)[CH3:24])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2c1NC(=O)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(C(F)(F)F)cc2c1NC(=O)C2
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of tert-butyl 4-(4-fluorophenyl)-4-((1-(2-oxo-5-(trifluoromethyl)indolin-7-yl)ethoxy)methyl)piperidine-1-carboxylate (13 mg, 0.024 mmol) in dichloromethane (1.5 mL) at ice bath temperature was added TFA (200 μL, 2.60 mmol). The mixture was stirred at this temperature for 1 hour. TLC (30% ethyl acetate/hexanes) indicated complete conversion of starting material. The mixture was concentrated and the crude residue was loaded onto an SCX cartridge (Phenomenex Strata X-C 200mg) with methanol then the resin was washed with methanol and the compound eluted with 2N NH3 in methanol to give the product (10.2 mg, 0.023 mmol, 96%) as a clear pale yellow film. 1H-NMR (CDCl3, 400 MHz) δ 7.57-7.88 (m, 1H), 7.32 (s, 1H), 7.21-7.29 (m, 2H), 7.11 (s, 1H), 7.03 (t, J=8.69 Hz, 2H), 4.28 (q, J=6.55 Hz, 1H), 3.42 (s, 2H), 3.31-3.36 (m, 1H), 3.24-3.30 (m, 1H), 2.83-2.96 (m, 2H), 2.63-2.80 (m, 2H), 2.17 (ddd, J=13.72, 2.27 Hz, 1H), 2.06 (dt, J=13.60, 2.27 Hz, 1H), 1.74-1.91 (m, 2H), 1.29 (d, J=6.55 Hz, 3H). Mass spec. (M-H)−: 435.5, (MH)+: 437.3.
Reaction SMILES: [C:1]([N:4]([CH3:47])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]4[N:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]3[C:28]=2[C:29]2[CH:34]=[CH:33][C:32]([C:35]3([NH:39]C(=O)OC(C)(C)C)[CH2:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[ClH:48].O1CCOCC1>CO>[ClH:48].[ClH:48].[ClH:48].[NH2:39][C:35]1([C:32]2[CH:33]=[CH:34][C:29]([C:28]3[N:14]4[C:15]5[CH:27]=[CH:26][CH:25]=[N:24][C:16]=5[NH:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[C:13]4=[N:12][C:11]=3[C:8]3[CH:7]=[CH:6][C:5]([N:4]([CH3:47])[C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=3)=[CH:30][CH:31]=2)[CH2:38][CH2:37][CH2:36]1
Reactant: CC(=O)N(C)c1ccc(-c2nc3n(c2-c2ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)N(C)c1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 93 %

Procedure:
tert-Butyl {1-[4-(2-{4-[acetyl(methyl)amino]phenyl}-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (30 mg, 0.048 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 20.5 hours. The mixture was concentrated to afford the desired product (28 mg, 93%) as a yellow solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.68 (br s, 2H), 8.62 (s, 1H), 8.10 (dd, J=4.9 Hz and 1.4 Hz, 1H), 7.96 (dd, J=7.7 Hz and 1.4 Hz, 1H), 7.56 (d, J=8.6 Hz, 3H), 7.37 (d, J=8.6 Hz, 2H), 7.31-7.26 (m, 2H), 7.13 (t, J=8.6 Hz, 1H), 6.88 (dd, J=8.0 Hz and 1.1 Hz, 1H), 6.73 (dd, J=8.0 Hz and 4.6 Hz, 1H), 3.73-3.65 (m, 1H), 3.51-3.45 (m, 1H), 3.17-3.13 (m, 2H), 2.59-2.47 (m, 3H), 2.23-2.15 (m, 2H), 1.88-1.75 (m, 3H). LCMS: 527 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=1.[CH3:17][O:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH2:28][CH2:29][NH2:30])=[CH:24][NH:25]2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][C:6]1[O:10][N:9]=[C:8]([C:11]([NH:30][CH2:29][CH2:28][C:23]2[C:22]3[C:26](=[CH:27][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[NH:25][CH:24]=2)=[O:13])[CH:7]=1
Reactant: O=C(O)c1cc(Cc2cccc(F)c2)on1
Reactant: COc1ccc2c(CCN)c[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(CCNC(=O)c3cc(Cc4cccc(F)c4)on3)c[nH]c2c1
Yield: 34.6 %

Procedure:
A solution of the 5-(3-fluorobenzyl)isoxazole-3-carboxylic acid (0.057 g; 0.257 mmol), 2-(6-methoxy-1H-indol-3-yl)ethanamine (0.054 g; 0.284 mmol), HATU (0.108 g; 0.284 mmol) and N,N-diisopropylethylamine (0.112 mL; 0.649 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.035 g (38%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][N:10]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:26][CH:27]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CN(CCCCCCC(=O)OCC)S(C)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1ccc(CN(CCCCCCC(=O)O)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
To a solution of the title compound of Step A (379 mg, 0.95 mmol) in MeOH (6 mL) was added NaOH (1.0 mL, 5N). The reaction was stirred at room temperature for 24 h and was acidified with aqueous HCl (1N). The MeOH was removed in vacuo and the residue was dissolved in CH2Cl2. The organic solution was washed sequentially with HCl (1N, 1×), water (2×), and brine (1×). The organic solution was dried with MgSO4, filtered, and concentrated in vacuo. Purification by radial chromatography (CH2Cl2 to 6% MeOH/CH2Cl2) provided the title compound (356 mg). 1H NMR (400 MHz, CDCl3) δ 7.30–7.12 (m, 4H), 4.35 (s, 2H), 3.10–3.19 (m, 2H), 2.80 (s, 3H), 2.60 (t, 2H), 2.31 (t, 2H), 1.48–1.65 (m, 7H), 1.20–1.40 (m, 6H). 0.97 (t, 3H); MS 387 (M+18).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[N:14]=[N:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:4]=[N:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:15]([C:12]2[N:13]=[N:14][C:9]([O:8][CH2:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:10][CH:11]=2)=[O:17])[CH2:57][CH2:58]1
Reactant: NC1CCOCC1
Reactant: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)nn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)NC2CCOCC2)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
To a solution of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (98 mg, 0.31 mmol) and TBTU (111 mg, 0.35 mmol) in DMF (2 mL) was added DIPEA (270 μL, 1.57 mmol). Then 4-aminotetrahydropyran (35 mg, 0.35 mmol) was added and the mixture was stirred at room temperature under Ar for 16 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (101 mg, 81%) as an off white solid. MS: m/e=396.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1B(O)O.[CH2:17]([O:19][C:20](=[O:41])[C@H:21]([CH2:33][C:34]1[CH:39]=[CH:38][C:37](Br)=[CH:36][CH:35]=1)[NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31])[CH3:18]>>[CH2:17]([O:19][C:20](=[O:41])[C@H:21]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][CH2:10][OH:11])=[CH:6][C:5]=2[O:12][CH3:13])=[CH:36][CH:35]=1)[NH:22][C:23](=[O:32])[C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[Cl:30])[CH3:18]
Reactant: COc1cc(CCO)cc(OC)c1B(O)O
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CCO)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
2,6-Dimethoxy-4-(2-hydroxyethyl)benzeneboronic acid was coupled with N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine ethyl ester according to the procedure described in Example 8-3) to yield 1.3 g of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-(2-hydroxyethyl)phenyl]-L-phenylalanine ethyl ester. ESMS: m/z 546 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:9](=[O:23])[C:8]2=O)(=[O:3])[CH3:2].Cl.[NH2:26][NH:27][C:28]([NH2:30])=[O:29]>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][N:16]([CH:17]([CH3:18])[CH3:19])[CH:20]([CH3:21])[CH3:22])[C:9](=[O:23])/[C:8]/2=[N:26]/[NH:27][C:28]([NH2:30])=[O:29])(=[O:3])[CH3:2]
Reactant: NNC(N)=O
Reactant: CC(=O)Nc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Agent: Cl
Product: CC(=O)Nc1ccc2c(c1)/C(=N\NC(N)=O)C(=O)N2CCN(C(C)C)C(C)C
Yield: 32 %

Procedure:
By using 5-acetamido-1-(2-diisopropylaminoethyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out, and the reaction product was purified with silica gel column chromatography (eluent: chloroform/methanol=50/1) and then recrystallized from chloroform-hexane to obtain (E)-5-acetamido-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 135°-137° C. (yield: 32.0%).