Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]=[CH:5][CH:6]1[CH:13]2[CH:9]([O:10][CH:11]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12]2)[CH:8]([N:22]2[CH:30]=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[O:7]1.[BH4-].[Na+]>CO.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][C:3](=[O:37])[CH2:4][CH2:5][CH:6]1[CH:13]2[CH:9]([O:10][CH:11]([CH:14]=[CH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12]2)[CH:8]([N:22]2[CH:30]=[N:29][C:28]3[C:23]2=[N:24][CH:25]=[N:26][C:27]=3[NH:31][C:32]([NH:34][CH2:35][CH3:36])=[O:33])[O:7]1
Reactant: CCNC(=O)Nc1ncnc2c1ncn2C1OC(C=CC(=O)OC)C2OC(C=Cc3ccccc3)OC21
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: CCNC(=O)Nc1ncnc2c1ncn2C1OC(CCC(=O)OC)C2OC(C=Cc3ccccc3)OC21
Reaction time: 48 h
Yield: 49.2 %

Procedure:
3-{6-[6-(3-Ethyl-ureido)-purin-9-yl]-2-styryl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl}-acrylic acid methyl ester (250 mg, 0.5 mmol) was dissolved in dry methanol (3 mL). Copper (II) sulfate (90 mg, 0.5 mmol) was added followed by sodium tetrahydroborate (90 mg, 2.5 mmol) and the reaction was stirred 48 h. The reaction was diluted with water, filtered, and concentrated in vacuo. The residue was dissolved in ethyl acetate and precipitated with heptane. The precipitate was dissolved in dichloromethane and was chromatographed on silica gel with dichloromethane-methanol (95:5) as eluent, affording the title compound (125 mg, 50%). 1H-NMR (300 MHz, d6 DMSO) δ 1.15 (t, 3H, J=7 Hz), 1.90 (m, 2H), 2.19 (m, 2H), 3.21 (q, 2H, J=7 Hz), 3.55 (s, 3H), 4.20 (m, 1H), 4.98 (dd, 1H, J=4 Hz, 6 Hz), 5.45 (dd, 1H, J=3 Hz, 7 Hz), 5.85 (d, 1H, J=6 Hz), 6.25 (d, 1H, J=3 Hz), 6.27 (dd, 1H, J=6 Hz, 16 Hz), 6.90 (d, 1H, J 16 Hz), 7.35 (m, 3H), 7.50 (d, 2H, J=7 Hz), 8.56 (s, 1H), 8.57 (s, 1H), 9.30 (t, 1H, J=5 Hz), 9.60 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=O.C1(C)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=C(O)[CH:27]=[CH:28][CH:29]=1.S(=O)(=O)(O)O>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[C:27]3[C:11](=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)[O:10][C:8](=[O:9])[CH:7]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(O)c1
Reactant: COC(=O)CC(=O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc2c(-c3cccc(O)c3)cc(=O)oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
The solution of methyl 3-hydroxybenzoylacetate (about 4.0 kg) and toluene (total weight of solution 5.6 kg) from the step above was charged to a reaction vessel along with 3-methoxyphenol (2.55 kg). The mixture was stirred vigorously at 0° C. while 27 M sulfuric acid (5.55 L) was added over 5 minutes. The resulting dark solution was warmed to 25° C. When the reaction began to thicken (40 minutes), methanol (21.8 L) was added. The addition was exothermic. Continued stirring (15 minutes) yielded a smooth, brown slurry which was cooled to 5° C. over 25 minutes, stirred for one hour, then filtered. The filter cake was washed with methanol (5.50 L) and dried under vacuum at 45-50° C. to give 3.70 kg (13.8 mol, 70% yield for two steps) of 4-[3′-(hydroxy)phenyl]-7-methoxycoumarin (a compound of Formula (b)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[C:21]=3[NH2:26])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)([CH3:7])[CH3:6])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:30]=1>>[CH2:1]([O:3][C:4](=[O:27])[C:5]([CH3:7])([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[C:21]=3[NH:26][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:30]=3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3N)cc2)cc1
Reactant: Brc1cccc(-c2ccccc2)n1
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3Nc3cccc(-c4ccccc4)n3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 2-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-2-methyl-propionic acid ethyl ester and 2-bromo-6-phenyl-pyridine.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([CH2:28][CH2:29][O:30]C(=O)C)[C:8]1[CH:27]=[CH:26][C:11]([CH2:12][S:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][CH2:6][N:7]([CH2:28][CH2:29][OH:30])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][S:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([S:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:26][CH:27]=1
Reactant: CSc1ccc2c(SCc3ccc(N(CCOC(C)=O)CCOC(C)=O)cc3)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CSc1ccc2c(SCc3ccc(N(CCO)CCO)cc3)ccnc2c1
Reaction time: 2 h
Yield: 83.2 %

Procedure:
4-[4-[Bis(2-acetoxyethyl)amino]benzylthio]-7-methylthioquinoline (Compound 47; 30 mg, 0.06 mmol) was dissolved in methanol (5 ml) and added with potassium carbonate (34 mg, 0.247 mmol) and stirred at room temperatue for two hours. Methanol was removed under reduced pressure. The reaction mixture was added with water and extracted twice with chloroform. The combined chloroform layers were washed with saturated saline solution. The solvent was removed under reduced pressure and the residue was washed with ethyl acetate to obtain 20 mg of the titled compound (81%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10]/[CH:11]=[C:12](\[CH2:18][CH2:19][CH2:20][F:21])/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@H](C(OC(C)(C)C)=O)C/C=C(/CCCF)\C(OCC)=O)=O)(C)(C)C>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH2:11][CH:12]([CH2:18][CH2:19][CH2:20][F:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C(=C/C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCF
Agent: [Pd]
Agent: CCOC(=O)/C(=C\C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CCCF
Solvent: CCO
Product: CCOC(=O)C(CCCF)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-tert-Butyl 1-ethyl (E)-(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoropropyl)hex-2-enedioate and 6-tert-Butyl 1-ethyl (Z)—(S)-5-[(tert-butoxycarbonyl)amino]-2-(3-fluoro-propyl)hex-2-enedioate (100 mg, 0.25 mmol) and palladium (20.0 mg, 10% on charcoal, 0.02 mmol) in ethanol (10 mL) were stirred for 2 h at r.t. under a hydrogen atmosphere. Then the mixture was filtered through Celite® and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, hexanes/ethyl acetate gradient).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.[F:9][C:10]([F:29])([F:28])[C:11]1[CH:12]=[C:13]([C:17]2[N:18]=[C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[NH:20][CH:21]=2)[CH:14]=[CH:15][CH:16]=1.C(N(CC)C(C)C)(C)C.O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:25]1[CH2:26][CH2:27][CH:22]([C:19]2[NH:20][CH:21]=[C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:29])([F:28])[F:9])[CH:12]=3)[N:18]=2)[CH2:23][CH2:24]1
Reactant: FC(F)(F)c1cccc(-c2c[nH]c(C3CCNCC3)n2)c1
Reactant: Clc1ccncc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1cccc(-c2c[nH]c(C3CCN(c4ccncc4Br)CC3)n2)c1
Temperature: 160 °C
Yield: 64 %

Procedure:
A mixture of 3-bromo-4-chloropyridine (100.0 mg; 0.52 mmol; 1.0 eq.), 4-[4-(3-trifluoromethyl-phenyl)-1h-imidazol-2-yl]-piperidine (153.4 mg; 0.52 mmol; 1.0 eq.), N,N-diisopropylethylamine (0.26 ml; 1.56 mmol; 3.0 eq.) in NMP (2.0 ml) in a microwave vial was heated at 160° C. for 4 h. The reaction mixture was poured into water. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound in 64% yield. LC-MS: (M+1=451, obsd.=451).
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[O:4][CH2:5][CH2:6][C:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH:12]=1.C([SnH](CCCC)CCCC)CCC>C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C>[CH3:13][N:10]1[CH2:9][CH2:8][C:7]2([C:2]3[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=3[O:4][CH2:5][CH2:6]2)[CH2:12][CH2:11]1
Reactant: CN1CC=C(CCOc2ccccc2I)CC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CN1CCC2(CCOc3ccccc32)CC1
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A stirred solution of 4-(2-(2-iodophenoxy)ethyl)-1-methyl-1,2,3,6-tetrahydropyridine (D100, 6.3 g, 0.018 mole) and AIBN (50 mg) in benzene (700 ml) was heated to reflux under argon, then treated dropwise over 1 h with a solution of tributyltin hydride (9.7 ml, 0.036 mole) in benzene (100 ml). The reaction mixture was heated under reflux for a further 3 h after completing the addition, then more tributyltin hydride (3.8 ml, 0.014 mole) and AIBN (30 mg) were added and heating under reflux was continued for 4 h. The reaction mixture was allowed to cool, then concentrated in vacuo and the residue treated with 2M HCl acid (150 ml), washed with ethyl acetate (100 ml), basified with potassium carbonate and extracted with ethyl acetate (2×100 ml). The combined extract was dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was chromatographed on silica gel eluting with 0 to 2% methanol/chloroform to afford the title compound (2.3 g of approx. 86% purity, 51%).
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14]C(=O)C)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OCCCCS(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=S(=O)(CCCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of acetic acid 4-benzenesulfonylbutylester (6.5 g, 25.3 mmol) in MeOH (30 mL) at RT is added NaOH (1.5 g, 37.5 mmol) in water (5 mL). The mixture is stirred at RT for 1 h then the solvent is removed under reduced pressure. To the residue is added 1N HCl (40 mL) then the mixture is extracted with EtOAc. The organic phase is dried over MgSO4 and the solvent is removed under reduced pressure to afford the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]3[CH2:18][O:17][CH2:16][C@H:15]([CH3:19])[N:14]3[C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:20])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:29][C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1.O>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[CH3:19][C@@H:15]1[N:14]2[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([O:20][CH2:29][C:30]5[N:31]=[C:32]([CH3:35])[S:33][CH:34]=5)[CH:8]=4)[N:3]=[C:2]([NH2:1])[C:11]=3[N:12]=[C:13]2[CH2:18][O:17][CH2:16]1
Reactant: Cc1nc(CCl)cs1
Reactant: C[C@H]1COCc2nc3c(N)nc4ccc(O)cc4c3n21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc(COc2ccc3nc(N)c4nc5n(c4c3c2)[C@@H](C)COC5)cs1
Temperature: 50 °C
Reaction time: 8 h
Yield: 33.6 %

Procedure:
A solution of (11S)-6-amino-11-methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-2-ol (500 mg, 1.85 mmol) dissolved in 15 mL of DMF was treated with cesium carbonate (1.80 g, 5.55 mmol), 4-chloromethyl-2-methylthiazole hydrochloride (375 mg, 2.03 mmol) and tetrabutylammonium bromide (715 mg, 2.22 mmol). After stirring overnight at 50° C., the dark brown mixture was poured into 150 mL of H2O and stirred for 30 minutes. The reaction mixture was extracted with CHCl3 (3×75 mL) and the combined extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give a brown solid. Chromatography (SiO2, 0-20% CMA/CHCl3) gave an off-white solid which was crystallized from acetonitrile to give 237 mg of the title compound as an off-white solid, mp 105-107° C. 1H NMR (500 MHz, DMSO-d6) δ 7.59 (s, 1H), 7.57 (s, 1H), 7.51 (d, J=2.7 Hz, 1H), 7.19 (dd, J=2.7, 9.1 Hz, 1H), 6.35 (br s, 2H), 5.25 (m, 2H), 5.14 (m, 1H), 5.09 (d, J=15.5 Hz, 1H), 4.95 (d, J=15.5 Hz, 1H), 4.14 (m, 2H), 2.67 (s, 3H), 1.54 (d, J=6.5 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 165.6, 152.7, 151.5, 150.3, 145.0, 139.6, 130.9, 127.4, 126.7, 117.6, 116.9, 114.3, 102.8, 68.2, 65.6, 64.6, 49.8, 19.0, 18.6; MS (APCI) m/z 382 (M+H)+. Anal. calcd for C19H19N5O2.0.75C4H8O2.0.33H2O: C, 58.88; H, 5.28; N, 19.26. Found: C, 58.62; H, 4.96; N, 19.10.
Reaction SMILES: [OH:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[CH3:21][O:1][C:2]1[C:6](=[O:7])[O:5][CH:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:3]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCC1OC(=O)C(O)=C1c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)CCC1OC(=O)C(OC)=C1c1ccccc1

Procedure:
To a mixture of ethyl 3-(4-hydroxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate (86 g) and potassium carbonate (51.62 g) in N,N-dimethylformamide (855 ml) was added dropwise methyl iodide (23.25 ml) at ambient temperature with stirring and the mixture was stirred for 2.5 hours at the same temperature. The solvent was evaporated in vacuo to give a residue which was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine successively and dried. Evaporation of the solvent gave ethyl 3-(4-methoxy-5-oxo-3-phenyl-2,5-dihydro-2-furyl)propionate which was recrystallized from diisopropyl ether (73.07 g).
Reaction SMILES: O[CH:2]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]2[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:14]=12)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:26][N:23]1[CH2:24][CH2:25][C:14]2=[C:13]([CH2:2][C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)[C:21]3[C:16]([N:15]2[CH2:22]1)=[CH:17][CH:18]=[CH:19][CH:20]=3
Reactant: COC(=O)c1ccc(C(O)c2c3n(c4ccccc24)CN(C)CC3)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2c3n(c4ccccc24)CN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.7 %

Procedure:
To a solution of methyl 4-(hydroxy(2-methyl-1,2,3,4-tetrahydropyrimido[1,6-a]indol-5-yl)methyl)benzoate (80 mg) and Et3SiH (0.5 mL) in 5 mL of CH2Cl2 was added 0.1 mL of TFA. After stirring for 10 min at r.t., the reaction mixture was poured into 15 mL of saturated aqueous solution of NaHCO3 and the mixture was extracted with 2×20 mL of EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with up to 100% EtOAc/hexanes to give 70 mg of the title product as white solid.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>C1COCC1>[CH3:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:40][CH:39]=2)[CH2:36][CH2:37]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)cc2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 25, 100 mg, 0.248 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (52.2 mg, 0.248 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of ice cold THF yielding 33% (48 mg, 0.083 mmol) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH3:13])[N:6]([CH3:14])[C:5]2=[O:15].[C-:16]#[N:17].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:12]([C:7]1[N:6]([CH3:14])[C:5](=[O:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:16]#[N:17])[CH:3]=2)[N:8]=1)[CH3:13]
Reactant: CCc1nc2ccc(Br)cc2c(=O)n1C
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Product: CCc1nc2ccc(C#N)cc2c(=O)n1C
Temperature: 25 °C
Yield: 41.7 %

Procedure:
The substrate of 6-bromo-2-ethyl-3-methyl-3H-quinazolin-4-one (50.0 mg, 0.189 mmol), KCN (23.1 mg, 0.37 mmol), Pd (PPh3)4 (10.0 mg, 0.0094 mmol), and CuI (3.6 mg, 0.019 mmol) was added to a flask, which was flushed with N2. The solvent acetonitrile (2 ml) was added via syringe. The resulting mixture was irradiated at 170° C. for 2 hours in the SmithSynthesizer Microwave Reactor (Personal Chemistry) with vigorous agitation by a magnetic stirrer. The mixture was cooled to room temperature, diluted with ethyl acetate (5 ml), and then filtered through Celite. The filtrate was washed with water and brine, dried over anhydrous MgSO4, and concentrated by rotary evaporation. Purification was accomplished by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give 2-Ethyl-3-methyl-4-oxo-3,4-dihydro-quinazoline-6-carbonitrile (Yield 16.8 mg, 46.2%). 1H NMR (400 MHz, CDCl3): δ 1.35 (t, 3H, J=7.30 Hz), 2.85 (q, 2H, J=14.62, 7.30 Hz), 3.54 (s, 3H), 7.68 (d, 1H, J=8.58 Hz), 7.83 (dd, 1H, J=8.58, 2.02 Hz), 8.51 (d, 1H, J=2.02 Hz). MS/M/Z calc. 213.2, Found (ESI); 214.0 (M+1)+. Retention time 2.13 minutes.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:25]([C:26]3[N:31]=[C:30](S(C)=O)[C:29]([F:35])=[CH:28][N:27]=3)=[CH:24][N:23]([S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:20]2=[N:21][CH:22]=1>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]2[C:25]([C:26]3[N:31]=[C:30]([NH:1][C@H:2]4[CH2:7][CH2:6][CH2:5][C@@H:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3]4)[C:29]([F:35])=[CH:28][N:27]=3)=[CH:24][N:23]([S:36]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)(=[O:38])=[O:37])[C:20]2=[N:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H](N)C1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](NC(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
tert-Butyl N-[(1R,3S)-3-aminocyclohexyl]carbamate, 20a, (0.15 g, 0.70 mmol) and 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (0.49 g, 1.05 mmol) were dissolved in THF (30 mL) and allowed to stir at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by two rounds of silica gel chromatography—first with (0%-10% MeOH/CH2Cl2) second with (10%-50% EtOAc/hexanes) to provide tert-butyl N-[(1R,3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]carbamate (20b) (330 mg, 38%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N-:13]=[N+:14]=[N-:15].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[N:13]([CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[N+:14]=[N-:15]
Reactant: O=C(CCCCl)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
4-Chlorobutyrophenone (300.0 mg, 1.64 mmol) was dissolved in N,N-dimethylformamide (20 ml) at room tempaerature and then added to sodium azide (1.07 g, 16.42 mmol) at the same temperature, and thereafter stirred at 100° C. for 24 hours. The reaction solution was added to a saturated aqueous sodium hydrogencarbonate solution and then extracted by ethyl acetate, to obtain an organic layer. The extracted organic layer was washed with water and brine sequentially, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant saubstance was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/1), whereby the target compound was obtained as a colorless oil (285.5 mg, 91.9%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:19]=[C:9]2[NH:10][C:11](=[O:18])[C:12]3[C:17]([N:8]2[N:7]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[NH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:28]=[C:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][C:6]1[CH:19]=[C:9]2[NH:10][C:11](=[O:18])[C:12]3[C:17]([N:8]2[N:7]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=c1[nH]c2cc(Cc3cccc(Br)c3)nn2c2ccccc12
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: O=C1CCCN1c1cccc(Cc2cc3[nH]c(=O)c4ccccc4n3n2)c1

Procedure:
A mixture of Example 61B (0.1 g, 0.282 mmol), pyrrolidin-2-one (0.048 g, 0.565 mmol) cesium carbonate (0.130 g, 0.395 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.026 g, 0.028 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.025 g, 0.043 mmol) in DME (2 mL) was heated in a microwave (Personal Chemistry SmithSynthesizer) at 200° C. for 60 minutes. The mixture was filtered evaporated. The residue was purified by chromatography on silica gel with 20% to 80% ethyl acetate in hexane to provide the desired product. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.01-2.08 (m, 2 H) 2.47 (t, J=8.09 Hz, 2 H) 3.81 (t, J=7.02 Hz, 2 H) 3.99 (s, 2 H) 5.67 (s, 1 H) 7.08 (d, J=7.63 Hz, 1 H) 7.30 (t, J=7.78 Hz, 1 H) 7.43-7.50 (m, 2 H) 7.66 (s, 1 H) 7.80-7.88 (m, 1 H) 8.04 (d, J=8.24 Hz, 1 H) 8.12 (d, J=7.93 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:28]1[CH2:33][CH2:32][N:31]([C:34]([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[CH:40][CH:41]=2)=[O:35])[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:42][C:39]3[CH:40]=[CH:41][C:36]([C:34]([N:31]4[CH2:32][CH2:33][NH:28][CH2:29][CH2:30]4)=[O:35])=[CH:37][N:38]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)nc2)CC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 4 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (205 mg, 0.7 mmol) and 4-(6-amino-pyridine-3-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (236 mg, 0.8 mmol), followed by deprotection using General Procedure A to give 7-cyclopentyl-2-[5-(piperazine-1-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (13 mg, 41%).