Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CC(C[AlH]CC(C)C)C.C(O)(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.O.CCOCC>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([OH:10])[N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CCC(=O)N1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C1CCC(O)N1C(=O)OC(C)(C)C
Yield: 85 %

Procedure:
To a solution of 5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, 1, (7.95 g, 32.7 mmol) in THF (65 mL) at −78° C., neat DIBAL-H (12.8 mL, 8.97 g, 63.1 mmol) dissolved in THF (25 mL) is added dropwise. After the consumption of the starting material, the reaction is cautiously quenched with isopropanol (5 mL), potassium sodium tartrate (26 g, 124 mmol) in H2O (160 mL). The resultant slurry is taken up in ether (200 mL) and then extracted with ether (5×250 mL). The ether layers are combined, washed with brine (1×250 mL), dried with MgSO4, and concentrated in vacuo to afford 6.8 g (85% yield) of the desired product as a clear oil which is used without further purification. MS (ESI): m/e=268.03 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:30])[CH:28]=2)[N:23]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:22]=1.N1C=CC=CC=1>C(Cl)Cl>[NH:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]=[C:13]1[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH:30][C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[O:11])[CH:28]=2)[N:23]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[N:22]=1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)Nc1ccc(F)cc1F
Reaction time: 24 h
Yield: 52 %

Procedure:
2,4-Difluorophenyl isocyanate (10 mg, 0.064 mmol) was added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.059 mmol) and pyridine (0.02 mL, 0.177 mmol) in CH2Cl2 (5 mL), and the mixture was stirred for 24 h. The reaction mixture was filtered through Celite, and the solvent was removed in vacuo. Purification by flash chromatography (2% CH3OH/CH2Cl2) afforded the title compound (15 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.39 (s, 1H), 8.04 (m, 1H), 7.86 (m, 1H), 7.72 (m, 3H), 7.27 (m, 2H), 7.00 (m, 1H), 6.92 (m, 1H), 5.92 (dd, 1H, J=3.2 and 9.2 Hz), 4.02 (m, 1H), 3.85 (m, 1H), 2.67 (m, 1H), 2.14 (m, 1H), 1.71 (m, 1H), 1.28 (m, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:17][C:11]1[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:6]1[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=[C:2]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCc1cccc(Cl)c1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)nc1NCc1cccc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A mixture of 6-chloro-N-(2,3-dichlorobenzyl)-3-nitropyridin-2-amine (3.37 g, 10.1 mmol), morpholine (2.64 g, 30.3 mmol) and K2CO3 (2.09 g, 15.15 mmol) in DMF (50 mL) was stirred at 80° C. for 1 h. The reaction was cooled to room temperature and poured into water (300 mL). It was extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine (300 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with EtOAc/Pet Ether=1/1 to afford the desired product as a yellow solid (3.7 g, 96%); LC/MS: MS (ES+) m/e 383 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.54 (s, 4H), 3.56 (s, 4H), 4.81 (d, J=5.7 Hz, 2H), 6.33 (d, J=9.6 Hz, 1H), 7.27-7.34 (m, 2H), 7.53 (dd, J=2.1, 6.9 Hz, 1H), 8.12 (d, J=9.6 Hz, 1H), 9.33 (t, J=6.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=3)[C:9]([CH3:18])=[C:8]2[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:18])=[C:8]2[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(C)c(CCC(=O)O)n2Cc1ccc(Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1c(CCC(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(O)cc12
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Beginning with 3-[1-p-chlorobenzyl-5-methoxy-3-methylindol-2-yl]propionic acid which is described in J. Med. Chem., 1252 (1968), (2.7 g) was dissolved in 20 ml CH2Cl2 at 0° C. 7.6 ml BBr3 (1M in CH2Cl2) was added dropwise and the reaction stirred for 60 minutes. After 180 minutes at 23° C., another 4 ml BBr3 solution was added. The reaction was stirred for a further 180 minutes. The reaction was cooled to -20° C. and 15 ml MeOH added. The organic phase was washed with NaHCO3 (aqueous), dried with Na2SO4 and chromatographed on silica gel. Hydrolysis of the methyl ester was carried out as described in Example 2 to yield 2.2 g of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K].CN(C)C=O>>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 120.9 %

Procedure:
To a solution of 1-(bromomethyl)-4-nitrobenzene (1.1 g, 4.69 mmol) in dimethylformamide potassium phthalimide (1.9 g, 10.314 mmol) was added. The mixture was reacted for overnight, extracted with ethyl acetate and washed with brine (3×20 mL). Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave 2-(4-nitrobenzyl)isoindoline-1,3-dione (1.6 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:25][CH:24]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: NC(=O)[C@@H]1CCCC[C@H]1N(Cc1ccc(OC(F)(F)F)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 20 %

Procedure:
The titled compound was prepared in 20% yield from trans-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide and 1-bromomethyl-4-trifluoromethoxy-benzene according to the procedure described in Example 11: 1H NMR (DMSO-d6) δ 7.63 (d, 2 H, J=8.0 Hz), 7.43 (m, 4 H), 7.37 (s br, 1 H), 7.18 (d, 2 H, J=8.0 Hz), 6.81 (s br, 1 H), 4.36 (AB2, 2 H,Δv=12,Jab=72 Hz), 4.01 (s br, 1 H), 1.83 (m, 1 H), 1.30 (m, 8 H); MS m/e 490.97 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:24][CH2:25][C@@H:26]([O:29][C@@H:30]([N:33]2[C:39](=[O:40])[NH:38][C:36](=[O:37])[CH:35]=[CH:34]2)[CH2:31][OH:32])[CH2:27][OH:28])([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.N1C(=O)CC[C@H]1C(O)=O.[C:57](Cl)(=[O:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CCO.C(Cl)Cl>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:9]([O:24][CH2:25][C@@H:26]([O:29][C@@H:30]([N:33]2[C:39](=[O:40])[NH:38][C:36](=[O:37])[CH:35]=[CH:34]2)[CH2:31][O:32][C:57]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[O:64])[CH2:27][OH:28])([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C(OC[C@H](CO)O[C@H](CO)n2ccc(=O)[nH]c2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(C(OC[C@H](CO)O[C@H](COC(=O)c2ccccc2)n2ccc(=O)[nH]c2=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Nucleoside 102-U (3.01 g, 5.50 mmol) was coevaporated with an. toluene (15 mL). The resulting residue was dissolved in an. DCM (150 mL) along with an. Pyr. (4.4 mL) and the mixture was cooled to −70° C. Benzoyl chloride (700 μL, 6 mmol) was slowly added to the reaction mixture and stirred for 1 h at −70° C. EtOH (5 mL) was added to the solution and subsequently allowed to reach rt. The reaction mixture was washed with sat. aq. NaHCO3 (3×100 mL) and brine (100 mL). The combined aqueous phase was back extracted with CH2Cl2 (100 mL). The organic phases were combined and evaporated. The resulting residue was purified by column chromatography (3.5% MeOH in DCM) affording the product 103-U as a white foam after evaporation of the solvents.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=3)=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.I[CH3:24]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=3)=[C:7]([CH3:11])[N:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1ccc(CC(=O)O)cc1
Product: Cc1c(Sc2ccc(CC(=O)O)cc2)c2ccc(Cl)cc2n1C

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: [4-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and iodomethane.
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1.[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:13]([NH:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[C:7]([OH:8])[CH:6]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: O=C(O)c1cccnc1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: O=C(NCCc1ccc(O)c(O)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
To a pyridine solution containing 11.7 g (0.05 mol) dopamine hydrobromide and 6.15 g (0.05 mol) nicotinic acid at 0° C. were added 10.3 g (0.05 mol) dicyclohexylcarbodiimide (DCC). The reaction mixture was stirred at room temperature for 24 hours and the formed dicyclohexylurea was removed by filtration. The pyridine was removed in vacuo and the residue was crystallized from water at 0° C. The product was isolated by filtration and dried over phosphorous pentoxide. Recrystallization from isopropanol gave 9.0 g (0.035 mol), 70% N-nicotinoyldopamine, m.p. 159°-162° C.; aqueous solution of the compound gave a green color with Fe+3 and reduced AgNO3 ; ir (KBr) 3300, 2960, 1725, 1630, 1590, 1520, 1430, 1290, 1190, 1115, 720 and 710 cm-1 ; NMR (d6 -DMSO) β 9.25-6.25 (m, 7H), 3.3 (m, 2H) and 2.65 (m, 2H) ppm. Anal. (C14H14N2O3) C, H, N.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>C(Cl)Cl>[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:39])=[CH:33][CH:32]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (62.8 μL, 0.36 mmol) in DCM (2 mL) was added 4-fluorophenyl isocyanate (40.5 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 to give the title compound as a white solid. MS (ESI, positive ion) m/z: 415 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>CN(C)C=O.C(O)C>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH:26][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:14][CH:13]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: NCc1ccccc1Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](CNCc1ccccc1Cl)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-chlorobenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=98%, [M+H]+=427.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH2:12][C:13]([O:15]CC)=O)=[CH:4][CH:3]=1>CC(O)=O.CCOC(C)=O.[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:12][C:13](=[O:15])[NH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1COc2ccc(Br)nc2N1
Temperature: 90 °C

Procedure:
Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) was dissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole) was added. The mixture was mechanically stirred and heated at 90° C. for 5 hr, then was cooled to room temperature and diluted with EtOAc (300 mL). The mixture was filtered through a pad of silica gel and the filtrate was concentrated in vacuo and the residue recrystallized from MeOH (15 g, 52%): MS (ES) m/z 229.0 (M+H)+.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([C:7]2(C)[CH2:10][O:9][CH2:8]2)=[N:4][C:3]=1[CH3:12].CC1N=C(C2COC2)NC=1.CC1N=C(C2(C)COC2)NC=1>>[I:1][C:2]1[NH:6][C:5]([CH:7]2[CH2:10][O:9][CH2:8]2)=[N:4][C:3]=1[CH3:12]
Reactant: Cc1nc(C2(C)COC2)[nH]c1I
Agent: Cc1c[nH]c(C2(C)COC2)n1
Agent: Cc1c[nH]c(C2COC2)n1
Product: Cc1nc(C2COC2)[nH]c1I

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 175.2, except 4-methyl-2-(oxetan-3-yl)-1H-imidazole (compound 180.1) was used in place of 4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound 175.1). m/z (ES+) 265 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][NH:35][C:36]([S:37]([CH3:40])(=[O:39])=[O:38])=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:40][S:37]([C:36]1[NH:35][N:34]=[C:24]2[C:23]=1[CH2:22][CH2:21][C:20]1[N:19]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:13][CH:14]=3)[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][C:25]2=1)(=[O:38])=[O:39]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-c3n[nH]c(S(C)(=O)=O)c3CC4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1[nH]nc2c1CCc1nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc1-2
Reaction time: 0.01 h
Yield: 54.6 %

Procedure:
tert-butyl(1-(4-(3-(methylsulfonyl)-8-phenyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (40 mg, 0.070 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and freeze-dried to give the desired product as an off-white solid (18 mg, 37% yield). 1H-NMR (500 MHz, CD3OD) δ 8.10 (1H, s), 7.50 (2H, d), 7.44 (2H, d), 7.31-7.35 (3H, m), 7.24-7.29 (2H, m), 3.32 (2H, t), 3.28 (3H, s), 3.24 (2H, t), 2.74-2.82 (2H, m), 2.54-2.64 (2H, m), 2.19-2.30 (1H, m), 1.92-2.03 (1H, m). LCMS (Method A) RT=3.81 min, M+H+=471.16.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[S:23][C:22]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)[N:13]=2)[CH2:4][CH2:3]1.C([NH:38][CH2:39][C:40](O)=[O:41])(OC(C)(C)C)=O>>[NH2:38][CH2:39][C:40]([N:28]1[CH2:27][CH2:26][N:25]([CH2:24][C:22]2[S:23][C:9]3[C:8]([N:5]4[CH2:4][CH2:3][O:2][CH2:7][CH2:6]4)=[N:13][C:12]([C:14]4[CH:19]=[N:18][C:17]([NH2:20])=[N:16][CH:15]=4)=[N:11][C:10]=3[CH:21]=2)[CH2:30][CH2:29]1)=[O:41]
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Product: NCC(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
The HCl salt of 5-(4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (100 mg) was reacted with Boc-glycine via General Procedure B followed by Boc removal with TFA to generate 44 mg of 106 after purification. MS (Q1) 470.2 (M)+.
Reaction SMILES: [Br-:1].[CH3:2][N:3](C(=O)OC(C)(C)C)[CH2:4][CH2:5][CH2:6][C:7](=[O:32])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][P+:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(OCC)C.N>C(Cl)Cl.CO>[Br-:1].[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][P+:13]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:32]
Reactant: CN(CCCC(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N
Agent: [Br-]
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CNCCCC(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
11,14,14-trimethyl-7,12-dioxo-1,1,1-triphenyl-13-oxa-6,11-diaza-1-phosphoniapentadecane bromide (910 mg, 1.50 mmol) was dissolved in methylene chloride (4.6 mL) and methanol (0.50 mL). The solution at room temperature was treated with 2.0 M hydrogen chloride in diethyl ether (1.63 mL, 3.26 mmol). The mixture was stirred overnight at room temperature, then cooled with an ice bath and treated with 7N ammonia in methanol (0.61 mL, 4.30 mmol). After 30 minutes, the slurry that resulted was filtered, and the solids were washed with methylene chloride. The filtrate was concentrated to give the title compound (690 mg, 91%, 91% pure) as a white foam. The product of step 2 was used crude in next step.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH:12]1[CH2:16][CH2:15][CH:14]([C:17](OCC)=[O:18])[N:13]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=O)C.ClC1C=CC(N2[C@@H](CO)CC[C@@H]2CO)=CC=1>O1CCCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:13]2[CH:12]([CH2:10][OH:9])[CH2:16][CH2:15][CH:14]2[CH2:17][OH:18])=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1CCC(C(=O)OCC)N1c1ccc(Cl)cc1
Agent: OC[C@H]1CC[C@H](CO)N1c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC1CCC(CO)N1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Lithium aluminum hydride (1.0 M in tetrahydrofuran, 20.7 mL) was added to tetrahydrofuran (68 mL) at 0° C. 1-(4-Chloro-phenyl)-pyrrolidine-2,5-dicarboxylic acid diethyl ester (4.50 g, 13.81 mmol) in tetrahydrofuran (17 mL) was added rapidly dropwise and the mixture was stirred at room temperature for 4 hours. Mix was quenched by careful addition of water (2.5 mL) followed by 10% sodium hydroxide (1.7 mL) and stirred for 15 h then filtered through Celite and the cake was washed with ethyl acetate (2×100 mL). The filtrate was dried with magnesium sulfate and concentrated to yield a mixture of cis and trans [1-(4-Chloro-phenyl)-5-hydroxymethyl-pyrrolidin-2-yl]-methanol (3.34 g, 100%) as a golden oil. Oil was used without further purification.
Reaction SMILES: [C:1]([O-:5])(=O)[CH:2]=[CH2:3].[Na+].Cl[Si:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11]>C1COCC1>[C:1]([Si:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([CH:2]=[CH2:3])=[O:5]
Reactant: CCO[Si](Cl)(OCC)OCC
Reactant: C=CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC(=O)[Si](OCC)(OCC)OCC
Temperature: -70 °C

Procedure:
6.123 g (0.0651 mol) sodium acrylate is dissolved to 25 mL THF and cooled to −70° C. 12.8 mL (0.0651 mol, 12.938 g) chlorotriethoxysilane in THF (15 mL) is added dropwise to reaction solution. The solution is stirred for over night allowing it to warm up to room temperature. NaCl is removed by filtration and solution evaporated to dryness to result clear liquid, acryltriethoxysilane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]2[CH2:32][O:33][CH2:34][CH:28]2[CH2:27]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:19][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH:29]5[CH2:32][O:33][CH2:34][CH:28]5[CH2:27]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: ClCCCN1CCC2COCC2C1
Reactant: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)cc3)c2cc1OCCCN1CCC2COCC2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
A mixture of 4-((4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (140 mg, 0.44 mmol, 1 eq), 5-(3-chloropropyl)octahydrofuro[3,4-c]pyridine (90 mg, 0.44 mmol, 1 eq) and K2CO3 (135 mg, 0.98 mmol, 2 eq) in DMF (10 mL) was heated to 80° C. and stirred overnight, then cooled to room temperature. To the resulted mixture was added 50 mL of CH2Cl2. The mixture was washed with brine (20 mL×3) and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the title compound as a yellow solid (50 mg, 25.00%), HPLC: 96.56%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 453.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.76-1.77 (2H, m), 2.24-2.48 (3H, m), 2.50-2.64 (3H, m), 2.68-2.71 (2H, m), 2.73-2.75 (2H, m), 2.96-3.03 (3H, m), 3.07-3.12 (2H, m), 3.61-3.90 (2H, m), 4.24-4.27 (2H, m), 7.02 (1H, s), 7.06-7.10 (1H, m), 7.16 (1H, s), 7.76-7.82 (1H, m), 7.82 (1H, s), 8.09-8.11 (1H, m), 8.59 (1H, s) ppm.