Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([I:23])=[CH:4][N:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([I:23])=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1ccc2[nH]c(-c3cc(I)cnc3N)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncc(I)cc1-c1nc2cc(CC(=O)O)ccc2[nH]1

Procedure:
9.2 51 mg (0.121 mmol) of ethyl [2-(2-amino-5-iodopyridin-3-yl)-1H-benzimidazol-5-yl]acetate are dissolved in 5 ml of methanol, and 242 μl of 1N NaOH (0.242 mmol) are added. The reaction mixture is irradiated for 10 min at 100° C. in a microwave unit. After cooling, it is evaporated to dryness and adjusted to pH 4-5 by means of 1N HCl. The precipitate formed is filtered off with suction and dried, giving [2-(2-amino-5-iodopyridin-3-yl)-1H-benzimidazol-5-yl]acetic acid; HPLC-MS [M+H]+ 395.0.
Reaction SMILES: C(#N)C.C(N(CC)CC)C.[CH3:11][N:12]([CH3:17])[C:13](=[O:16])[CH:14]=[CH2:15].Br[C:19]1[CH:28]=[CH:27][C:26]2[N:25]=[CH:24][C:23]3[N:29]=[C:30]([CH2:41][CH2:42][O:43][CH3:44])[N:31]([CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH2:37][C:36]4=[O:40])[C:22]=3[C:21]=2[CH:20]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(Cl)(Cl)Cl.CO>[CH3:44][O:43][CH2:42][CH2:41][C:30]1[N:31]([CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][C:36]2=[O:40])[C:22]2[C:21]3[CH:20]=[C:19]([CH:15]=[CH:14][C:13]([N:12]([CH3:17])[CH3:11])=[O:16])[CH:28]=[CH:27][C:26]=3[N:25]=[CH:24][C:23]=2[N:29]=1
Reactant: COCCc1nc2cnc3ccc(Br)cc3c2n1CCCN1CCCC1=O
Reactant: C=CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: COCCc1nc2cnc3ccc(C=CC(=O)N(C)C)cc3c2n1CCCN1CCCC1=O
Temperature: 120 °C
Yield: 86.4 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (8 mg, 0.04 mmol), acetonitrile (50 mL), triethylamine (0.9 mL, 5.22 mmol), tri-o-tolylphosphine (30 mg, 0.10 mmol), N,N-dimethylacrylamide (189 mg, 1.91 mmol) and 1-{3-[8-bromo-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}pyrrolidin-2-one (0.75 g, 1.7 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath. The reaction was maintained at 120° C. for 18 hours and then cooled to ambient temperature. Upon cooling a precipitate formed that was dissolved by the addition of methanol and chloroform. The remaining insoluble material was removed by filtration through a 0.2 micron PTFE membrane filter. The filtrate was concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-7% gradient of methanol in dichloromethane) to provide 660 mg of 3-{2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}-N,N-dimethylprop-2-enamide as an off-white solid.
Reaction SMILES: CN1CCOCC1.[CH:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:9].Cl.[NH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH:8]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:16])=[CH:17][CH:18]=1)=[O:9]
Reactant: COC(=O)CN
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: COC(=O)CNC(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Added N-methylmorpholine (2.93 mL, 26.6 mmol) to a solution of 4-formylbenzoic acid (1 g, 6.66 mmol), methyl 2-aminoacetate, hydrochloride (1.045 g, 8.33 mmol), 1-hydroxy-7-azabenzotriazole (1.813 g, 13.32 mmol), and EDC (2.55 g, 13.32 mmol) in Dimethyl Sulfoxide (DMSO) (30 mL). Let stir at RT for 16 hours. Added water and extracted with DCM. Combined DCM extracts and washed with water, brine and dried over MgSO4, filtered and rotovapped off DCM. The residue was purified via Biotage (0% to 75% gradient; EtOAc:Hex; 25 g-HP-silica gel column). Obtained 570 mg 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.83 (s, 3H), 4.28 (d, J=5.05 Hz, 2H), 7.98 (s, 4H), 10.10 (s, 1H); [M+H]+=222.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([CH3:29])=[C:10]([CH:26]=[CH:27][CH:28]=2)[CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@@H:13]2[CH3:25])[CH:5]=[CH:4][N:3]=1.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[CH3:29][C:9]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[CH3:25])=[CH:26][CH:27]=[CH:28][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)[N:7]=1
Reactant: NCCc1ccc(O)cc1
Reactant: Cc1c(CN2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cccc1-c1ccnc(Cl)n1
Product: Cc1c(CN2CCNC[C@@H]2C)cccc1-c1ccnc(NCCc2ccc(O)cc2)n1

Procedure:
Intermediate 164 from above was coupled with tyramine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.3 (d, 1H) 8.0 (d, 1H) 7.7 (d, 1H) 7.5 (d, 1H), 7.3 (t, 1H), 7.0 (d, 2H) 6.6 (d, 2H), 3.9 (t, 2H) 3.8-3.7 (m, 3H) 3.6-3.4 (m, 6H) 2.8 (t, 2H), 2.5 (s, 3H), 1.7 (d, 3H).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:21]2[C:30]([N+:31]([O-:33])=[O:32])=[C:29]3[C:24]([CH:25]=[CH:26][CH:27]=[N:28]3)=[CH:23][CH:22]=2)[OH:20])=[C:15]([CH3:34])[CH:14]=1>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[C:30]([N+:31]([O-:33])=[O:32])=[C:29]3[C:24]([CH:25]=[CH:26][CH:27]=[N:28]3)=[CH:23][CH:22]=2)=[O:20])=[C:15]([CH3:34])[CH:14]=1
Reactant: Cc1cc(F)ccc1C(O)c1ccc2cccnc2c1[N+](=O)[O-]
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(F)ccc1C(=O)c1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
PCC (667 mg, 3.1 mmol) was added to a solution of (4-fluoro-2-methyl-phenyl)-(8-nitro-quinolin-7-yl)-methanol (Intermediate 350) (690 mg, 2.21 mmol) in DCM (700 ml) and the mixture was stirred at room temperature for 2 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/DCM (30:70) as the eluent to give the title compound (600 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:16]([CH3:18])[CH3:17])[NH:5][C:6]=1[CH2:7][O:8]CC1C=CC=CC=1.CS(O)(=O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.O1CCOCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:3]=[C:4]([CH:16]([CH3:18])[CH3:17])[NH:5][C:6]=1[CH:7]=[O:8]
Reactant: CC(C)c1nc(Cl)c(COCc2ccccc2)[nH]1
Agent: [Mn+4]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1nc(Cl)c(C=O)[nH]1
Temperature: 25 °C
Yield: 35.4 %

Procedure:
A solution of 4-chloro-2-(1-methylethyl)-5-{[(phenylmethyl)oxy]methyl}-1H-imidazole (0.710 g, 2.7 mmol) and methanesulfonic acid (6.8 mL, 105 mmol) in chloroform (14 mL) was stirred at RT for 1 h. The reaction mixture was poured into ice (˜50 g) and the solution was neutralized by addition of 5N NaOH until the pH was 10. The solution was extracted with methyl tert-butyl ether (2×40 mL) followed by n-butanol (3×20 mL). The combined n-butanol extracts were concentrated, azeotroped with toluene, and dried in vacuo to provide crude [4-chloro-2-(1-methylethyl)-1H-imidazol-5-yl]nethanol as a brown solid. A solution of this solid and manganese dioxide (1.5 g, 17.0 mmol) in CH2Cl2 (8 mL) and 1,4-dioxane (4 mL) was heated under reflux for 6 h. The reaction mixture was cooled to RT and filtered through celite, and washed thoroughly with CH2Cl2. The filtrate was concentrated and dried to provide the title compound (0.165 g, 37%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 11.82 (br. s., 1H), 9.60 (s, 1H), 3.12 (sept, 1H), 1.34 (d, 6H). ES-LCMS: m/z 173.0 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][O:12][C:13](=[O:18])[C:14]([NH2:17])([CH3:16])[CH3:15].F[C:20]1[C:21]([CH3:40])=[N:22][C:23]2[C:28]([N:29]=1)=[C:27]([C:30]1[NH:38][C:37]3[CH2:36][CH2:35][NH:34][C:33](=[O:39])[C:32]=3[CH:31]=1)[CH:26]=[CH:25][CH:24]=2>CS(C)=O>[CH3:15][C:14]([NH:17][C:20]1[C:21]([CH3:40])=[N:22][C:23]2[C:28](=[C:27]([C:30]3[NH:38][C:37]4[CH2:36][CH2:35][NH:34][C:33](=[O:39])[C:32]=4[CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[N:29]=1)([CH3:16])[C:13]([O:12][CH3:11])=[O:18]
Reactant: COC(=O)C(C)(C)N
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 95 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
Prepared according to Example 131, using DIPEA (1761 μl, 10.12 mmol), aminoisobutyric acid methyl ester hydrochloride (778 mg, 5.06 mmol, Sigma Aldrich), and 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 500 mg, 1.687 mmol) in DMSO (8437 μl) stirring at 95° C. for 2 h. Purification by column chromatography (silica gel: 0 to 10% MeOH/DCM) provided methyl 2-methyl-2-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)propanoate (557 mg, 81%). 1H NMR (CDCl3) δ: 11.16-11.25 (m, 1H), 7.96-8.01 (m, 1H), 7.69-7.74 (m, 1H), 7.40-7.46 (m, 1H), 7.08-7.12 (m, 1H), 5.56-5.71 (m, 1H), 5.15-5.20 (m, 1H), 3.66-3.73 (m, 2H), 3.56 (s, 3H), 3.25 (s, 2H), 2.65 (s, 3H), 1.79 (s, 6H). m/z (ESI, +ve) 394.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:6][C@H:5]2[CH3:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])[C@H:5]2[CH3:16]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H]1Nc2ccccc2-c2ccc(F)cc21
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3[C@@H]2C)cc1
Yield: 39.3 %

Procedure:
The title compound was prepared according to the procedure of Example 19, starting from the (S)-8-Fluoro-6-methyl-5,6-dihydrophenanthridine of Example 20 (38.4 g) and 4-methoxyphenylsulfonyl chloride (37.2 g). The crude product (65.6 g) was purified by filtration over a flash silica gel plug (1 Kg) eluting with 20-25% hexane-ethyl acetate to provide 54.1 (78.4% yield) of product. The material (54.1 g) was recrystallized twice from hot 30% toluene in ethanol. The solution was seeded hot and allowed to cool to room temperature. After about 3 hours the crystalline solid was collected, rinsed with 30% toluene in ethanol (1×15 mL) and with hexane (2×15 mL), and dried to provide 27.1 g (39.3% yield based on (S)-8-fluoro-6-methyl-5,6-dihydrophenanthridine) of title compound. The compound was analyzed by chiral stationary phase HPLC (Chiralpak AD-25×0.46 cm column) on a HP1100 using 90:10 hexane-isopropanol as the mobile phase with a 1 mL/min flow rate. The analysis showed the material to be a 98.7:1.3 mixture of enantiomers,
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl[CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH2:21][CH2:22][N:23]2[C:27](=[O:28])[CH2:26][CH2:25][C:24]2=[O:29])[CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:19][C:18]1[C:13]([CH2:12][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)=[N:14][CH:15]=[CH:16][C:17]=1[O:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[CH2:26][CH2:25][C:24]1=[O:29]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(OCCN2C(=O)CCC2=O)ccnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1c(OCCN2C(=O)CCC2=O)ccnc1CSc1nc2ccccc2[nH]1
Yield: 112.1 %

Procedure:
A mixture comprising 0.03 g (0.18 mmol) of 2-mercapto-1H-benzimidazole, 0.06 g (0.21 mmol) of 2-chloromethyl-3-methyl-4-(2-succinimidoethoxy)pyridine, 0.03 g (0.21 mmol) of potassium carbonate and 10 ml of methyl ethyl ketone was heated under reflux in a nitrogen atmosphere for 3 hours, cooled and filtered. The filtrate was concentrated and dried in a vacuum, followed by the addition of water. The obtained mixture was extracted with 50 ml of chloroform thrice. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography to obtain 0.08 g of 2-[{3-methyl-4-(2-succinimidoethoxy)pyridine-2-yl}methylthio]-1H-benzimidazole as a white crystal.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1F
Product: CN1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-fluoronitrobenzene (6.0 mL, 56.9 mmol) and N-methylpiperazine (8.11 mL, 56.9 mmol) was stirred at 0° C. for 20 minutes, then at room temperature for 3 days. The crude mixture was partitioned between methylene chloride and saturated aqueous sodium bicarbonate and the organic layer was then washed with saturated sodium chloride (NaCl), dried and concentrated in vacuo to provide 2-(4-methylpiperazin-1-yl)-1-nitrobenzene as an orange oil, 12.4 g.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.N([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+]>CC(O)=O.O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N:11]=[N+:16]=[N-:17])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2cc(N=[N+]=[N-])ccc2[nH]1
Yield: 65.7 %

Procedure:
In an oven dried, 250 mL round bottom flask flushed with argon, compound 33 (400 mg, 2.74 mmol, 146.19 MW) was dissolved in 90% AcOH (20 mL). After complete solvation, the reaction was placed at 0° C. and protected from light with foil. NaNO2 (1.1×, 3.01 mmol, 208 mg, 69.00 MW) dissolved in cold H2O (2 mL) was added dropwise and stirred for ten minutes. NaN3 (1.1×, 3.01 mmol, 196 mg, 65.01 MW) dissolved in cold H2O (2 mL) was added dropwise. After one hour the reaction was poured into water (40 mL), which was extracted 3 times with CH2Cl2 (40 mL each). The extracts were washed with sodium bicarbonate and brine (100 mL each), dried with sodium sulfate, filtered and concentrated. Purification by silica flash chromatography (100% CH2Cl2) yielded the azide as a light brown solid (310 mg, 66%). 1H NMR (600 MHz, d6-DMSO): δ 11.025 (s, 1H, N—H), 7.295-7.281 (d, J=8.4, 1H, indole-7H), 7.131-7.127 (d, J=2.4, 1H, indole-4H), 6.737-6.719 (dd, J1=8.4, J2=2.4, 1H, indole-6H), 6.108-6.106 (d, J=1.2, 1H, indole-3H), 2.369 (s, 1H, methyl). 13C NMR (150 MHz, d6-DMSO): δ 137.5, 133.9, 130.0, 129.5, 111.7, 111.6, 108.5, 99.0, 13.4. Melting point: 57-60° C. TLC (in 1:1 ethyl acetate:hexanes) Rf=0.56. IR (film): 3409 cm−1, 2111 (aryl-azide). Elemental analysis calculated for C9H8N4: C, 62.78; H, 4.68; N, 32.54. found: C, 62.95; H, 4.68; N, 32.53.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[NH:35][C:29]5=[N:30][C:31](Cl)=[CH:32][CH:33]=[C:28]5[N:27]=4)=[CH:21][CH:20]=3)[C:9]([C:11]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.B(O)(O)[C:37]1[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[NH:35][C:29]5=[N:30][C:31]([C:37]6[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=6)=[CH:32][CH:33]=[C:28]5[N:27]=4)=[CH:21][CH:20]=3)[C:9]([C:11]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2cc(C(=O)NCC(F)(F)F)c(-c3ccc(Nc4nc5ccc(Cl)nc5[nH]4)cc3)c12
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3nc(Nc4ccc(-c5c(C(=O)NCC(F)(F)F)cn6ncnc(N)c56)cc4)[nH]c3n2)cc1
Temperature: 150 °C
Yield: 10.6 %

Procedure:
To a mixture of 4-amino-5-{4-[(5-chloro-3H-imidazo[4,5-b]pyridin-2-yl)amino]phenyl}-N-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (50 mg, 0.1 mmol), p-tolylboronic acid (27 mg, 0.2 mmol), potassium carbonate (82 mg, 0.6 mmol), in DMF was added 1,1′-bis(diphenylphosphino)ferrocinepalladium (II) chloride (7.3 mg, 0.01 mmol). The mixture was then degassed using nitrogen for 10 min, and then heated (150° C.) in a microwave for 15 min. After cooling to room temperature, the mixture was diluted with methanol and concentrated under reduced pressure. The residue purified by silica gel chromatography using a 1 to 8% methanol/dichloromethane as the eluant to afford the desired product (5.9 mg, 11%). 1H-NMR (300 MHz, CD3OD) 7.86 (s, 1H), 7.81-7.87 (m, 4H), 7.73-7.79 (m, 2H), 7.63-7.69 (m, 1H), 7.53 (s, 1H), 7.40-7.49 (m, 2H), 7.22-7.28 (m, 2H), 3.92-3.99 (m, 2H), 2.38 (s, 3H); ES-MS m/z 558.3 (MH)+; HPLC RT (Method A) 2.64 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH3:19])=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([OH:17])=O)[CH:10]=2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:18][CH3:19])=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[O:17])[CH:10]=2)=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CNc1nc(Nc2cc(C(=O)O)nn2C)ncc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[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: CNc1nc(Nc2cc(C(=O)N3CCOCC3)nn2C)ncc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 100 mL round bottom flask equipped with a stir bar was added 0.116 g of 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylic acid, 0.19 g of o-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate, 0.14 mL of diisopropylethylamine and 2 mL of dimethylformamide. After pre-activating for 10 minutes, 0.05 mL of morpholine was added and the reaction stirred at room temperature for 2 hours. The reaction was concentrated and purified by preparative reverse phase HPLC to yield 53.2 mg of (5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazol-3-yl)(morpholino)methanone. LCMS (Method A): [MH+]=352.0 at 2.80 min. 1H-NMR (DMSO): δ 9.47 (s, 1H), 7.86 (s, 1H), 7.15 (s, 1H), 6.78 (s, 1H), 3.74 (s, 3H), 3.61 (m, 8H), 2.88 (d, 3H). K1=0.16.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:7])[CH:5]=[CH2:6])[CH3:2].[CH:8]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9]1>CO>[CH:8]1([NH:13][CH2:6][CH2:5][C:4]([NH:3][CH2:1][CH3:2])=[O:7])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C=CC(=O)NCC
Reactant: NC1CCCC1
Solvent: CO
Product: CCNC(=O)CCNC1CCCC1
Yield: 80.3 %

Procedure:
N-ethylacrylamide (ABCR: 1.045 g, 10.50 mmol) and cyclopentylamine (Aldrich; 987 uL, 10.00 mmol) in methanol (10 mL) were combined in a microwave reaction vessel, which was sealed and irradiated to 140° C. for 30 minutes. The reaction mixture was allowed to cool and loaded directly onto a 50 g SCX-2 cartridge, washing with methanol (100 mL) and eluting the desired product with 7 N methanolic ammonia (100 mL). Concentration under reduced pressure of combined product containing fractions afforded the title compound as a brown oil (1.48 g, 80%)
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][N:16]([CH3:26])[C:17]1[N:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:26])[C:17]1[CH:18]=[CH:19][C:20]([C:2]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:21][N:22]=1
Reactant: O=[N+]([O-])c1cc(Br)nc2ccccc12
Reactant: CN(C)c1ccc(B(O)O)cn1
Product: CN(C)c1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cn1

Procedure:
N,N-Dimethyl-5-(4-nitroquinolin-2-yl)pyridin-2-amine T480P was prepared using general procedure A from 2-Bromo-4-nitroquinoline (50 mg, 0.2 mmol) and (6-(dimethylamino)pyridin-3-yl)boronic acid (34 mg, 0.2 mmol). The product was obtained as a yellow solid (40 mg, 68%). 1H NMR (400 MHz, CDCl3): δ 8.99 (d, J=2.4 Hz, 1H), 8.36-8.34 (m, 2H), 8.30 (s, 1H), 8.19 (m, 1H), 7.81 (m, 1H), 7.65 (m, 1H), 6.66 (d, J=9.0 Hz, 1H), 3.21 (s, 6H); MS (ESI): 295 (M+H+).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH2:16])[CH2:11][C:12]([F:15])([F:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:19](O)[C:20]([F:23])([F:22])[F:21]>C1C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10](/[N:16]=[CH:19]/[C:20]([F:23])([F:22])[F:21])[CH2:11][C:12]([F:15])([F:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(F)(F)C[C@H](N)CO[Si](C)(C)C(C)(C)C
Reactant: COC(O)C(F)(F)F
Solvent: c1ccccc1
Product: CC(F)(F)C[C@@H](CO[Si](C)(C)C(C)(C)C)/N=C/C(F)(F)F

Procedure:
A solution of (2S)-1-((tert-butyl(dimethyl)silyl)oxy)-4,4-difluoropentan-2-amine, from Step 5, and trifluoroacetaldehyde methyl hemiacetal (80%, 0.9 mL) in benzene (20 mL) was refluxed over night with a Dean-Stark apparatus. The solvent was evaporated under vacuum and the residue purified by silica gel chromatography using ethyl acetate and hexanes to afford (2S)-1-((tert-butyl(dimethyl)silyl)oxy)-4,4-difluoro-N-((1E)-2,2,2-trifluoroethylidene)pentan-2-amine.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:14])=[O:7])(C)(C)C.[CH3:15][N:16]1[CH2:21][CH2:20][C:19]2[N:22]=[C:23](C([O-])=O)[S:24][C:18]=2[CH2:17]1.[Li+].[ClH:29].CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[ClH:29].[CH3:15][N:16]1[CH2:21][CH2:20][C:19]2[N:22]=[C:23]([C:6]([NH:8][C@@H:9]3[CH2:13][CH2:12][CH2:11][C@H:10]3[NH2:14])=[O:7])[S:24][C:18]=2[CH2:17]1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2nc(C(=O)N[C@@H]3CCC[C@H]3N)sc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.3 %

Procedure:
(±)-trans-N-tert-Butoxycarbonyl-1,2-cyclopentane-diamine (175 mg) was dissolved in N,N-dimethylformamide (3 ml), and to the solution lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (purity: 90%, 258 mg), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (252 mg) and 1-hydroxybenzo-triazole monohydrate (60 mg) were added. The mixture was stirred at room temperature for 2 days. The solvent was distilled off under reduced pressure using a pump, and dichloromethane and a saturated solution of sodium hydrogencarbonate were added to the residue to separate an organic layer. The resultant organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by medium-pressure flash column chromatography on silica gel (dichloromethane:methanol=47:3). The resultant pale yellow oil was dissolved in a saturated ethanol solution (5 ml) of hydrochloric acid, and the solution was stirred at room temperature for 1 hour. Ethyl acetate was then added, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue to collect precipitate by filtration, thereby obtaining the title compound (120 mg) as a pale yellow solid.