Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@H:20]([C:21]2[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:39]=[N:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[NH:44][C:43]([C@@H:45]7[CH2:50][C@@H:49]8[C@@H:47]([CH2:48]8)[N:46]7C(OC(C)(C)C)=O)=[N:42][CH:41]=6)[CH:36]=5)[N:31]=4)[CH:28]=[CH:29][C:23]=3[N:22]=2)[CH2:19][C@@H:18]2[C@H:16]1[CH2:17]2)=O)(C)(C)C>C(Cl)Cl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C@@H:16]12[CH2:17][C@@H:18]1[CH2:19][C@@H:20]([C:21]1[NH:25][C:24]3[CH:26]=[C:27]([C:30]4[CH:39]=[N:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[NH:44][C:43]([C@@H:45]7[CH2:50][C@@H:49]8[C@@H:47]([CH2:48]8)[NH:46]7)=[N:42][CH:41]=6)[CH:36]=5)[N:31]=4)[CH:28]=[CH:29][C:23]=3[N:22]=1)[NH:15]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3nc(-c4ccc5nc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]c5c4)cnc3c2)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2nc([C@@H]3C[C@H]4C[C@H]4N3)[nH]c2cc1-c1cnc2cc(-c3cnc([C@@H]4C[C@H]5C[C@H]5N4)[nH]3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 156.6 %

Procedure:
TFA (0.25 mL, 3.24 mmol) was added to a solution of (1R,3S,5R)-tert-butyl 3-(5-(2-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)quinoxalin-6-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (30 mg, 0.044 mmol) in DCM (0.5 mL) and the mixture was stirred at rt for 16 h. The volatiles were removed under vacuum and the residue was triturated with Et2O to yield a TFA salt of 2-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-6-yl)-6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)quinoxaline (32.7 mg) as yellow solid. LC-MS retention time 1.33 min; m/z 475 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10% methanol:0.1% TFA. Solvent B=10% water:90% methanol:0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220). 1H NMR (400 MHz, MeOD) δ ppm 9.47 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 8.31 (dd, J=8.8, 1.8 Hz, 1H), 8.26 (dd, J=8.5, 1.3 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 7.83 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 4.85-4.97 (m, 1H), 4.67 (dd, J=10.8, 7.5 Hz, 1H), 3.45-3.57 (m, 2H), 2.77-2.86 (m, 1H), 2.65-2.74 (m, 1H), 2.52-2.65 (m, 2H), 2.02-2.15 (m, 2H), 1.18-1.30 (m, 2H), 0.95-1.09 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([NH:9][C@H](C2C=CC=CC=2)C)[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:9][C@H:8]1[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:4][C@H:3]1[CH2:2][OH:1]
Reactant: C[C@H](N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1CO)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](CO)C1
Reaction time: 8 h

Procedure:
A mixture of (3R,4S)-tert-butyl 3-(hydroxymethyl)-4-((S)-1-phenylethylamino)piperidine-1-carboxylate (38 g, 113.6 mMol) and Pd(OH)2 (5 g) were stirred in methanol (250 mL) at rt under 50 psi hydrogen. After overnight stirring, the reaction mixture was filtered through Celite. The solution was concentrated to get the desired product, (3R,4S)-tert-butyl 4-amino-3-(hydroxymethyl)piperidine-1-carboxylate as a pale oil (quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[CH2:26]([S:33](Cl)(=[O:35])=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:24][CH:23]([CH3:25])[C@H:18]([N:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:33]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:35])=[O:34])=[CH:3][CH:4]=3)[CH:9]=2)[C:13]1=[O:17])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NS(=O)(=O)Cc4ccccc4)cc3)ccc2C1=O

Procedure:
The compound of example 300 was prepared analogous to compound of example 284 by reaction of compound of example 223 with benzyl sulfonyl chloride. The compound of example 300 was used directly without isolation, for the preparation of compound of example 301.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N+:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]>>[N+:28]([C:31]1[CH:36]=[C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=4)[N:9]=3)[CH:3]=2)[CH:34]=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: O=[N+]([O-])c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1

Procedure:
2-(3′-Nitro-biphenyl-3-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (1.79 g, 4.0 mmol) and commercially available 3-nitro-phenylboronic acid (0.8 g, 4.8 mmol) according to the general procedure VI. Obtained as a light grey solid (1.74 g, 89%). MS (EI) 489.2 [(M)+]; mp 219° C.
Reaction SMILES: CC(C)[O-].[Al+3:5].CC(C)[O-].CC(C)[O-].[Cl:14][CH:15]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([CH3:36])([CH3:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][CH:21]=1)[C:16]([OH:18])=[O:17]>C(O)(C)C>[Cl:14][CH:15]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([CH3:36])([CH3:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][CH:21]=1)[C:16]([O-:18])=[O:17].[Al+3:5].[Cl:14][CH:15]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([CH3:36])[CH3:35])=[CH:22][CH:21]=1)[C:16]([O-:18])=[O:17].[Cl:14][CH:15]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([CH3:36])[CH3:35])=[CH:22][CH:21]=1)[C:16]([O-:18])=[O:17]
Reactant: CC(C)(COc1ccc(CC(Cl)C(=O)O)cc1)c1ccccc1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: CC(C)(COc1ccc(CC(Cl)C(=O)[O-])cc1)c1ccccc1

Procedure:
Isopropanol solution of aluminum isopropoxide is added to an aqueous isopropanol solution of 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)phenyl]propionic acid to give aluminum 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)-phenyl]propionate. Melting point: 220°-230° C
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([OH:43])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:58](Br)[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67]>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:44]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:41]6[CH:42]([O:43][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:53]([CH3:55])[CH3:54])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC24OC5OC(C(O)C5O2)C4O[Si](C)(C)C(C)(C)C)C13C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h

Procedure:
62.8 mg of compound (6) was dissolved in 0.4 ml of dry dimethylformamide under a nitrogen atmosphere and mixed with about 7 mg of sodium hydride under cooling with ice. After 15 minutes, 80 μl of decyl bromide was added, and the reaction solution was allowed to react at room temperature under stirring for another 18 hours. Then, the reaction solution was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×20 cm) and eluted with n-hexane-ethyl acetate (4:1) to give 85.7 mg of compound (48) as a colorless oily substance.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][NH2:4].[CH2:11]1[O:13][CH:12]1[CH2:14][OH:15]>C1(C)C=CC=CC=1>[OH:13][CH:12]([CH2:14][OH:15])[CH2:11][NH:4][CH2:3][CH:2]([OH:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: OCC1CO1
Reactant: CCCCCCC(O)CN
Solvent: Cc1ccccc1
Product: CCCCCCC(O)CNCC(O)CO
Yield: 90.4 %

Procedure:
108.8 grams of 2-hydroxyoctyl amine were dissolved in 500 ml of toluene, heated to reflux, treated within 10 minutes under stirring with 18.5 grams of glycidol and held at reflux for 2 hours. Subsequently, the solvent was drawn off and the excess amine distilled off in a vacuum. There were obtained as a residue 49.5 grams (90.5% of theory) of N-(2,3-dihydroxypropyl)-N-(2-hydroxyoctyl) amine which after recrystallization from ethylacetate gave colorless crystals having a melting point of 85°-90° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH:17]=1)(=O)=O.[Br-:19].[Li+]>CC(C)=O>[Br:19][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH:17]=1
Reactant: CS(=O)(=O)OCCCCCCCC1=CCCC1=O
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: O=C1CCC=C1CCCCCCCBr
Yield: 79 %

Procedure:
A solution of 988 mg of the crude material prepared in Example XV in 7.5 ml dry acetone was stirred at 25° under argon with 1.80 gm lithium bromide for 18.25 hours at 25°. The acetone was removed in vacuo and water added to the residue. The mixture was extracted with 95:5 hexaneether. The extracts were washed with 10% aqueous sodium thiosulfate and brine, dried over MgSO4, filtered and evaporated in vacuo to afford 737 mg of a yellow oil having the following structure: ##STR39##
Reaction SMILES: [CH2:1]1[C@@H:5]2[C@H:6]3[C:11](=[O:12])[N:10]([OH:13])[C:8](=[O:9])[C@H:7]3[C@H:2]1[CH:3]=[CH:4]2.[O-]CC.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(O)C.CCOCC>[OH:13][N:10]1[C:11](=[O:12])[CH:6]2[CH:7]([CH:2]3[CH2:1][CH:5]2[CH:4]=[CH:3]3)[C:8]1=[O:9]
Reactant: O=C1[C@@H]2[C@H](C(=O)N1O)[C@@H]1C=C[C@H]2C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC[O-]
Solvent: CCOCC
Solvent: CCO
Product: O=C1C2C3C=CC(C3)C2C(=O)N1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
endo-N-Hydroxy-5-norbornene-2,3-dicarboximide (NBD) (3.59 g, 20 mmol) is dissolved in absolute ethanol (100 mL), and is then evaporated to dryness in vacuo to remove the residual moisture from the reagent. The residue is redissolved in freshly prepared absolute ethanol (60 mL), and thallous ethoxide (1.42 mL, 20 mmol) is added dropwise with vigorous stirring. The solution is stirred for 3 h at room temperature and then overnight at 4° C. The white precipitate which forms in the course of the reaction is collected by filtration, washed with cold ethanol, and dried under high vacuum. The solid material is suspended in methylene chloride (100 mL), and di-tert-butyl dicarbonate (4.37 g, 20 mmol) is added dropwise. The solution is stirred overnight at room temperature and is then washed with water (2×10 mL). The organic layer is dried over anhydrous MgSO4, filtered, and evaporated to dryness to give the crude product as a white solid. The solid is suspended, with vigorous stirring, in anhydrous ether (60 mL) for 2 h, followed by filtration, to give 3.0 g of the pure product. Upon storage of the filtrate at −20° C. overnight, additional pure product precipitates giving a total of 3.63 g of the title compound in two crops in an overall yield of 65%.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[N:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CS(C)=O>[N:10]1([C:2]2[S:6][C:5]([C:7](=[O:9])[CH3:8])=[N:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: CC(=O)c1ncc(Br)s1
Solvent: CS(C)=O
Product: CC(=O)c1ncc(N2CCCCC2)s1
Temperature: 50 °C
Yield: 68 %

Procedure:
To a solution of 1-(5-Bromo-thiazol-2-yl)-ethanone (prepared as described above) (250 mg) in dimethylsulfoxide (3 ml) was added piperidine (0.3 ml). The mixture was heated to 50° C. overnight, concentrated to an oil and the residue was purified by flash chromatography (30% ethylacetate/petroleum ether) to afford the sub-titled compound as an yellow solid (170 mg, 68%); 1H NMR (400 Mhz, CDCl3) δ 1.6-1.8 (6H, m), 2.6 (3H, s), 3.25-3.35 (4H, m), 7.05 (1H, s); MS (ES+) 211.1 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[C:21]2[C:28]([CH3:29])=[CH:27][NH:26][C:22]=2[N:23]=[CH:24][N:25]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[CH3:29][C:28]1[C:21]2[C:20]([NH:18][C@H:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH3:17])=[N:25][CH:24]=[N:23][C:22]=2[NH:26][CH:27]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N[C@@H](C)c3nc4ccccc4n3-c3ccccc3)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
Into a 10-mL sealed tube was placed (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (300 mg, 1.26 mmol, 1.00 equiv), 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (250 mg, 1.49 mmol, 1.18 equiv), N-ethyl-N-isopropylpropan-2-amine (322 mg, 2.50 mmol, 1.97 equiv) and BuOH (5 mL). The resulting solution was stirred for overnight at 120° C. and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/hexane (0:100-80:20) to afford 270 mg (58%) of 144 as a white solid. LC-MS (ES, m/z): 369 [M+H]+. H-NMR (300 MHz, CD3OD, ppm): δ 7.98 (s, 1H), 7.70-7.53 (m, 6H), 7.33-7.23 (m, 2H), 7.14-7.11 (m, 1H), 6.83 (d, 1H), 5.68-5.61 (m, 1H), 2.49 (d, 3H), 1.67 (d, 3H)
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=3[F:29])=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CCO.O>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=3)[N:16]=[CH:15][CH:14]=2)=[C:21]([F:29])[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(OCc4ccccc4)ccc23)c(F)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(O)ccc23)c(F)c1
Temperature: 30 °C
Reaction time: 24 h
Yield: 96.9 %

Procedure:
To a mixture of 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)quinoline (16.38 g, 42 mmol) and HCOONH4 (26.46 g, 420 mmol) in a mixture solution of EtOH/H2O (84 mL, v/v=4:1) was added a catalytic amount of Pd/C (0.50 g, 5% amount, 53%˜55% water content, w/w). The reaction was stirred at 30° C. for 24 hours, and was monitored by LC-MS. After the complete consumption of 7-(benzyloxy)-4-(2-fluoro-4-nitrophenoxy)quinoline, 6 M HCl (80 mL) was added to the reaction mixture until the solid was dissolved. The resulted solution was filtered. Saturated aqueous NaHCO3 solution (210 mL) was added to the filtrate to adjust the final pH to 6.0˜6.5 followed by the addition of a mixture of water (20 mL) and CH2Cl2 (50 mL). The resulted mixture was stirred at room temperature for 4 hours. The solid was collected by filtration, washed with a mixture of MeOH/DCM (50 mL, v/v=1/1), and dried in vacuo at 45° C. to give the title compound as a light yellow solid (11.0 g, 92%).
Reaction SMILES: C(O[C:4](=[O:31])[CH2:5][N:6]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:7][CH2:8][NH:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:24]([O:23][C:21]([N:6]1[CH2:7][CH2:8][N:9]([N:10]2[C:11](=[O:20])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]2=[O:19])[C:4](=[O:31])[CH2:5]1)=[O:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)CN(CCNN1C(=O)c2ccccc2C1=O)C(=O)OCc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=C(OCc1ccccc1)N1CCN(N2C(=O)c3ccccc3C2=O)C(=O)C1
Yield: 63.9 %

Procedure:
A solution of {benzyloxycarbonyl-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylamino)-ethyl]-amino}-acetic acid ethyl ester (0.22 g, 0.52 mmol) in diphenyl ether (3 mL) is heated to reflux for 2 h. Diphenyl ether is removed by vacuum distillation and the residue is purified by flash silica gel chromatography (2:1:1 to 1:1:1 heptane:DCM:EtOAc gradient elution) to afford 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-oxo-piperazine-1-carboxylic acid benzyl ester as a solid (0.126 g, 64%). MS: 380 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.86-7.95 (m, 2H), 7.75-7.86 (m, 2H), 7.24-7.42 (m, 5H), 5.20 (s, 2H), 4.42 (s, 2H), 3.90-4.05 (m, 2H), 3.65-3.87 (m, 2H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][NH:17][CH:18]1[CH:23]2[CH2:24][CH2:25][CH:19]1[CH2:20][N:21]([CH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1)[CH2:22]2.[CH3:38][CH:39]([CH3:44])[CH2:40][C:41](O)=[O:42].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[C:34]([C:33]1[CH:32]=[CH:31][C:30]([NH:29][CH2:28][CH2:27][CH2:26][N:21]2[CH2:22][CH:23]3[CH:18]([N:17]([CH3:16])[C:41](=[O:42])[CH2:40][CH:39]([CH3:44])[CH3:38])[CH:19]([CH2:25][CH2:24]3)[CH2:20]2)=[CH:37][CH:36]=1)#[N:35]
Reactant: CC(C)CC(=O)O
Reactant: CNC1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CC(=O)N(C)C1C2CCC1CN(CCCNc1ccc(C#N)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
1,3-Dicyclohexylcarbodiimide on N-methylpolystyrene (0.67 g of 2.39 mmol/g, 1.74 mmol) was added to a solution of 4-({3-[8-(methylamino)-3-azabicyclo[3.2.1]oct-3-yl]propyl}amino)benzonitrile (Peparation G; 74.6 mg, 0.25 mmol) in DMF (3.0 mL). A solution of 3-methylbutyric acid (105.0 mg, 1.02 mmol) in DCM (1.0 mL) was added, and the mixture was stirred overnight at rt, followed by a further 72 h at 50° C. Polystyrene isocyanate (150 mg) and DCM (1.5 mL) were added, and this mixture was stirred for 1.5 h. K2CO3 (75 mg) was added and the mixture stirred for an additional 5 h. The solvents were evaporated and DCM (3 mL) was added to the resulting residue. This mixture was added to an ion-exchange solid-phase extraction plug (CBA). The plug was washed with DCM:MeCN (4:1; 10 mL). The product was then eluted with DCM:MeOH:TEA (90:5:5; 7.5 mL) to give 75 mg (70.9%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][O:7][CH2:8][C@H:9]1[NH:14][C:13](=[O:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:10]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.I[CH3:39].[H-].[Na+].O>C1COCC1>[F:35][C:32]([F:33])([F:34])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:31]=1)[CH2:6][O:7][CH2:8][C@H:9]1[N:14]([CH3:39])[C:13](=[O:15])[CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:10]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)N[C@H](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)CN(C(=O)OC(C)(C)C)[C@@H](c2ccccc2)[C@H]1COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl (2S,3S)-3-(3,5-bis(trifluoromethyl)benzyloxymethyl)-5-oxo-2-phenylpiperizine-1-carboxylate (6.6 g, 12.4 mmol) and iodomethane (1.0 mL, 16.1 mmol) in THF (50 mL) was added NaH (0.55 g, 13.6 mmol) at 0° C. After stirring overnight, the reaction was stopped with water (50 mL). The product was extracted with ether, and purified by washing with 0.5 mol/L KHSO4 solution, saturated NaHCO3 solution and saturated brine in order. The organic layer was dried over sodium sulfate anhydride. Sodium sulfate was filtered off and the solvent was removed by evaporation from the filtrate under reduced pressure to give tert-Butyl (2S,3S)-3-(3,5-bis(trifluoromethyl)benzyloxymethyl)-4-methyl-5-oxo-2-phenylpiperizine-1-carboxylate 6.5 g (96%) was obtained.
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][CH2:18][C@@H:12]1[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=O)C1C=CC=CC=1>[OH-].[Pd+2].[OH-].CO>[CH3:16][N:15]([CH3:17])[C:13](=[O:14])[C@H:12]1[CH2:18][CH2:19][CH2:20][NH:11]1
Reactant: CN(C)C(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the subtitle compound of step i) (4.45 g) was added palladium hydroxide (0.20 g) and methanol (50 ml). The mixture was stirred under a hydrogen atmosphere (4 bar) at room temperature for 3 h before the catalyst was filtered through celite and the solvent was evaporated to afford the subtitle compound as a solid. Yield: 2.25 g.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([N+:18]([O-])=O)=[CH:15][CH:16]=3)[CH:11]=[N:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=3)[CH:11]=[N:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2CCN2CCOCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(cnn2CCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
A mixture of 1-(2-morpholin-4-yl-ethyl)-5-nitro-1H-indazole (4.3 g, 16 mmol), iron powder (8.8 g, 157 mmol), and ammonium chloride (430 mg, 8 mmol) in a 4:1 ethanol/H2O solution (75 mL) was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 50 mL) for 15 minutes, filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound (3.4 g, 93%). 1H NMR (300 MHz, DMSO-d6) ppm 2.40 (t, J=4.75, 4H), 2.70 (t, J=6.78, 2H), 3.50 (t, J=4.75, 4H), 4.38 (t, J=6.78, 2H), 4.78 (s, 2H), 6.72 (m, 1H), 6.80 (m, 1H), 7.35 (m, 1H), 7.60 (m, 1H); MS (DCI/NH3) m/z 247 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[NH:30][C:29]3[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:28]=3[N:27]=2)[CH:21]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:35]([C:33]1[CH:32]=[CH:31][C:29]2[NH:30][C:26]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[N:27][C:28]=2[CH:34]=1)=[O:36]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc2[nH]c(-c3cccnc3)nc2c1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2[nH]c(-c3cccnc3)nc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-pyridin-3-yl-1H-benzoimidazole-5-carboxylic acid. MS: 481.3 (M+H).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[F:19][C:20]1[CH:21]=[C:22]([NH2:27])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([NH:27][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1cc(F)cc(F)c1
Temperature: 130 °C

Procedure:
Prepared according to Procedure A using diethyl 2-methylmalonate (34.5 mL, 205 mmol), pyridine (15.6 mL, 190 mmol), and 3,5-difluorobenzenamine (12.4 g, 96 mmol). The reaction was heated to 130° C. for 2 days. Purification afforded ethyl 3-(3,5-difluorophenylamino)-2-methyl-3-oxopropanoate. Mass Spectrum (ESI) m/e=258.2 (M+1).