Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][NH:8][C:9](=[O:21])[N:10]2[C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])=[C:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[CH:4]=1.[CH2:29]([O:31][P:32]([O:36]CC)[O:33][CH2:34][CH3:35])[CH3:30].CCOCC.CCCCCC>CN(C=O)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:5]1[CH:4]=[C:3]([CH2:2][P:32](=[O:36])([O:33][CH2:34][CH3:35])[O:31][CH2:29][CH3:30])[CH:12]=[C:11]2[C:6]=1[CH2:7][NH:8][C:9](=[O:21])[N:10]2[C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20]
Reactant: O=C1NCc2c(-c3ccccc3Cl)cc(CBr)cc2N1c1c(Cl)cccc1Cl
Reactant: CCOP(OCC)OCC
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOP(=O)(Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2)OCC
Temperature: 100 °C
Reaction time: 1.75 h

Procedure:
A mixture of 7-(bromomethyl)-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydroquinazolin-2(1H)-one (55 mg, 0.11 mmol) and triethylphosphite (0.8 mL, 4.66 mmol) in DMF (0.5 mL) was stirred at 100° C. for 1.75 h. After it was cooled to rt, the resulting mixture was treated with ether and hexane to form a precipitate. Filtration of the precipitate provided diethyl [5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methylphosphonate as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.20 (m, 6H), 3.01 (s, 1H), 3.06 (s, 1H), 3.97 (m, 4H), 4.34 (abq, 2H, J=14.1 Hz), 5.12 (s, 1H), 6.12 (s, 1H), 6.86 (s, 1H), 7.26-7.60 (m, 7H). MS (API-ES+): 553 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:22]1[O:31][C:30]2[C:24](=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[O:23]1>>[ClH:1].[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[N:5]=[CH:4][N:3]=[C:2]2[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[C:30]2[O:31][CH2:22][O:23][C:24]=12
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: Nc1cccc2c1OCO2
Product: COCCOc1cc2ncnc(Nc3cccc4c3OCO4)c2cc1OCCOC
Product: Cl

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6,7-di-(2-methoxyethoxy)quinazoline (U.S. Pat. No. 5,747,498; 0.1 g) was reacted with 2,3-methylenedioxyaniline (0.048 g) to give the title compound (0.121 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 3.5 (s, 6H), 3.8 (m, 4H), 4.35 (m, 4H), 6.05 (s, 2H), 6.95 (m, 3H), 7.4 (s, 1H), 8.2 (s, 1H), 8.85 (s, 1H); Mass Spectrum: M+H+ 414.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=2[C:24]([NH2:26])=[O:25])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:32][N:33]([CH2:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][C:43]([O:48][CH3:49])=[C:44]([NH2:47])[CH:45]=2)[CH2:40][CH2:39]1)=[O:37])[CH3:34].Cl.O1CCOCC1>FC(F)(F)CO.[NH4+].[OH-].C1COCC1>[CH3:32][N:33]([CH3:34])[CH2:35][C:36]([N:38]1[C:46]2[C:41](=[CH:42][C:43]([O:48][CH3:49])=[C:44]([NH:47][C:2]3[N:3]=[C:4]([NH:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=4[C:24]([NH2:26])=[O:25])[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=3)[CH:45]=2)[CH2:40][CH2:39]1)=[O:37]
Reactant: COc1cc2c(cc1N)N(C(=O)CN(C)C)CC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: OCC(F)(F)F
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
A mixture of 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (11 g, 24 mmol), 1-[(dimethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (5 g, 20 mmol), a 4M HCl solution in dioxane (25 mL, 100 mmol) and 2,2,2-trifluoroethanol (250 mL) was heated at 80° C. for 16 h. The resulting mixture was allowed to cool to rt and diluted with a 27% aqueous NH4OH solution (250 mL) and THF (250 mL). The reaction mixture was stirred at rt overnight. The resulting slurry was filtered and the solids were triturated using H2O (300 mL), Et2O (300 mL) and finally EtOAc (300 mL). The solids were dissolved in THF, concentrated onto Celite and purified by silica gel chromatography using 0-10% MeOH (containing 0.2% NH3)/CH2Cl2. The solids obtained following chromatography were triturated using a mixture of MeOH and CH2Cl2to afford 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide as a beige solid (6.8 g, 51%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[S:16][CH:17]=[C:18]([CH3:20])[N:19]=2)[N:3]=1.[CH2:21](N(CC)CC)[CH3:22].[B-](F)(F)(F)C=C.[K+].ClCCl>CC(O)C.C1COCC1>[CH3:20][C:18]1[N:19]=[C:15]([CH2:14][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([CH:21]=[CH2:22])=[N:3]2)[S:16][CH:17]=1
Reactant: CCN(CC)CC
Reactant: Cc1csc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: ClCCl
Product: C=Cc1nn(Cc2nc(C)cs2)c2cccc([N+](=O)[O-])c12
Temperature: 90 °C
Yield: 80.5 %

Procedure:
A suspension of 2-((3-iodo-4-nitro-1H-indazol-1-yl)methyl)-4-methylthiazole (0.414 g, 1.03 mmol) in IPA/THF (4:1; 15 mL) was degassed with argon, treated with triethylamine (0.433 mL, 3.10 mmol), potassium trifluoro(vinyl)borate (0.416 g, 3.10 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (0.0845 g, 0.103 mmol). The mixture was heated at 90° C. for 14 hours under argon. The mixture was filtered through glass fiber filter paper, concentrated under reduced pressure and purified by silica gel chromatography (10-75% EtOAc in hexanes) to provide 4-methyl-2-((4-nitro-3-vinyl-1H-indazol-1-yl)methyl)thiazole (0.249 g, 80% yield) as an amber gum.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC(N(C)C)=C(C)C.[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9]([NH:11][CH3:12])=[CH:10][C:2]=2[F:1])=[CH:27][CH:26]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CNc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-4-methylamino-5-nitro-benzoic acid (0.500 g, 2.34 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (0.371 mL, 2.80 mmol) and DCM (50 mL) is stirred for 30 min, then 4-bromoaniline (0.402 mg, 2.34 mmol) and DIPEA (0.549 mL, 3.15 mmol) are added and it is stirred for 2 h. The mixture is concentrated, water is added and the precipitate is filtered, washed with water and dried to give the subtitle compound.
Reaction SMILES: C(OC1N=CC([NH:15][C:16]2[CH:21]=[C:20]([C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3[CH:24]=[CH:25][N:26]4[Si](C(C)C)(C(C)C)C(C)C)C=C(OCC3C=CC(OC)=CC=3)[CH:17]=2)=CC=1)C1C=CC=CC=1.C([O:58][C:59]1[N:64]=[CH:63][C:62](NC2C=C(OCC3C=CC(OC)=CC=3)C=C(Br)C=2)=[CH:61][CH:60]=1)C1C=CC=CC=1.[CH3:83][C:84]1(C)C(C)(C)OB(C2C=CC=C3C=2C=CN3[Si](C(C)C)(C(C)C)C(C)C)[O:85]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)C1C=CC=CC=1C1C=CC=CC=1N(C)C>[OH:85][C:84]1[CH:17]=[C:16]([NH:15][C:60]2[C:59]([OH:58])=[N:64][CH:63]=[CH:62][CH:61]=2)[CH:21]=[C:20]([C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH:83]=1
Reactant: COc1ccc(COc2cc(Nc3ccc(OCc4ccccc4)nc3)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Reactant: COc1ccc(COc2cc(Br)cc(Nc3ccc(OCc4ccccc4)nc3)c2)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Agent: CN(C)c1ccccc1-c1ccccc1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Oc1cc(Nc2cccnc2O)cc(-c2cccc3[nH]ccc23)c1
Temperature: 120 °C
Yield: 57.1 %

Procedure:
(6-benzyloxy-pyridin-3-yl)-[3-(4-methoxy-benzyloxy)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-amine. To a tube purged with nitrogen containing (6-benzyloxy-pyridin-3-yl)-[3-bromo-5-(4-methoxy-benzyloxy)-phenyl]-amine (78 mg, 0.158 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-indole (63 mg, 0.158 mmol) and chloro(di-2-norbornylphosphino)(2′dimethylamino-1,1′-biphenyl-2-yl)palladium (II) (9.0 mg, 0.0158 mmol) in dioxane (2 mL) was added 2M aqueous K3PO4 (0.16 mL, 0.32 mmol). The tube was sealed and heated in a microwave reactor at 120° C. for an hour. The crude mixture was loaded directly to Celite®, and purified by chromatography to afford the -[3-hydroxy-5-(1H-indol-4-yl)-phenylamino]-pyridin-2-ol as a white solid (62 mg, 57.1%).
Reaction SMILES: N#N.[CH3:3][C:4]([Si:7]([CH3:21])([CH3:20])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][O:18][CH3:19])[CH:11]=1)([CH3:6])[CH3:5].C([Li])CCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCCCCC.O1CCCC1>[Si:7]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][O:18][CH3:19])[C:11]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])([C:4]([CH3:3])([CH3:5])[CH3:6])([CH3:20])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: COCOc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
Under nitrogen flush, in a 2-necked 100 ml round-bottomed flask equipped with a reflux condenser (flammed for 5 minutes under vacuum and then 3 cycles of N2/vacuum), (1,1-dimethylethyl)(dimethyl){[(3-{[(methyloxy)methyl]oxy}phenyl)methyl]oxy}silane (Intermediate 103, 1.5 g, 5.31 mmol) was dissolved in hexane (20 ml) to give a colourless solution. Butyllithium 1.6N in hexane (4.31 ml, 6.9 mmol) was added dropwise and the reaction mixture was stirred at room temperature. After 2 hours stirring in those conditions, the pale yellow reaction mixture was added to a solution of ethyl chloroformate (1.015 ml, 10.62 mmol) in tetrahydrofuran at −78° C. After 30 min, the reaction was quenched with a 2M aqueous solution of hydrochloric acid while the pH was allowed to reach ˜2 and diluted with 10 ml of ethyl acetate. Two phases were separated and the organic layer was dried over Na2SO4 and evaporated under vacuum affording the crude product as a yellowish oil that was purified by flash chromatography (Biotage system) on silica gel using cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title compound (1.396 g) as a yellow pale oil.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][CH2:10][CH:11]([CH3:21])[O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16].CCN(C(C)C)C(C)C.N1C=CN=C1>O1CCOCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:9][CH2:10][CH:11]([CH3:21])[O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(CO)Oc1ccccc1C=O
Agent: c1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(CO[Si](C)(C)C(C)(C)C)Oc1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.9 %

Procedure:
Tert-butyl-chloro-dimethyl-silane (649 mg; 4.3 mmol; 1.1 eq.) was added to a solution of 2-(2-hydroxy-1-methyl-ethoxy)-benzaldehyde (705 mg; 3.91 mmol; 1 eq.), DIEA (867 μL; 4.69 mmol; 1.2 eq.) and 1H-imidazole (27 mg; 0.39 mmol; 0.1 eq.) in 1,4-dioxane (20 mL) and the resulting mixture was stirred at room temperature for 10 minutes. After dilution with EA, the solution was washed with sat. aq. NH4Cl (3×), dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (20% to 50% EA in cyclohexane) to afford the title compound (690 mg, 60%) as a colourless oil. 1H NMR (300 MHz, DMSO-d6) δ 10.47-10.33 (m, 1H), 7.72-7.55 (m, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 4.71 (d, J=4.2 Hz, 1H), 3.77 (dd, J=4.8, 2.1 Hz, 2H), 1.28 (d, J=6.2 Hz, 3H), 0.84-0.75 (m, 9H), 0.04-0.07 (m, 6H).
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[CH:8]=[CH:7]1)(C)(C)C.[CH3:17][C:18]1([CH3:26])[O:25][C:23](=[O:24])[CH2:22][C:20](=[O:21])[O:19]1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N1CCC[C@H]1C(O)=O>C(#N)C>[CH3:17][C:18]1([CH3:26])[O:25][C:23](=[O:24])[CH:22]([CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:8]2[C:9]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:6][CH:7]=2)[C:20](=[O:21])[O:19]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cccnc21
Reactant: O=Cc1ccccc1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC#N
Product: CC1(C)OC(=O)C(C(c2ccccc2)c2c[nH]c3ncccc23)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a room temperature (RT) solution of 1-(tert-butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine (Synthesis 1999, 615-620) (2.88 g, 9.47 mmol) in acetonitrile (20 ml) was added Meldrum's acid (1.5 g, 10 mmol), benzaldeyde (1.9 ml, 19 mmol) triethylamine (TEA) (1.9 ml, 14 mmol) and proline (catalytic quantity). The mixture was stirred overnight at RT, concentrated, and the residue was partitioned between EtOAc and brine. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc), affording 2,2-dimethyl-5-[phenyl-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-[1,3]dioxane-4,6-dione.
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[CH2:15][CH2:14]2.Cl>C1COCC1>[OH:5][CH:4]=[C:15]1[CH2:14][C:13]2[C:17](=[CH:18][CH:19]=[C:11]([O:10][CH3:9])[CH:12]=2)[C:16]1=[O:20]
Reactant: COc1ccc2c(c1)CCC2=O
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(=CO)C2=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a mixture of sodium methoxide (1.2 g, 22 mmol) in THF (20 mL) was added ethyl formate (1.6 g, 22 mmol) and 5-methoxy-1-indanone (3.24 g, 19.7 mmol) and the mixture stirred for 16 h at 23° C. The reaction mixture was added to aqueous HCl (0.1 N) and extracted with a mixture (1:1) of ethyl acetate and ether (2×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated to a residue, which was purified by chromatography (silica, 40% ethyl acetate in hexanes) to give an oil (2.6 g, 69%): 1H NMR (CDCl3) δ 7.81 (d, J=9.6 Hz, 1H), 7.47 (s, 1H), 7.00 (m, 2H), 3.94 (s, 3H), 3.9 (m, 2H); MS m/z 191 [M+H]+.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[OH:3].C(#N)C.[H-].[Na+].[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1>O>[Cl:13][C:14]1[N:19]=[C:18]([O:3][CH:2]([C:1]([O:6][CH3:7])=[O:5])[CH3:4])[CH:17]=[CH:16][N:15]=1.[Cl:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([O:3][CH:2]([C:1]([O:6][CH3:7])=[O:5])[CH3:4])[N:19]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COC(=O)C(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccnc(Cl)n1
Product: COC(=O)C(C)Oc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.12 g of methyl lactate and 10 ml of acetonitrile was added to a mixture of 1.2 g of sodium hydride and 40 ml of acetonitrile dropwise under ice cooling, and the mixture was stirred for 30 minutes. To this was added a mixture of 4.47 g of 2,4-dichloropyrimidine and 10 ml of acetonitrile dropwise at the same temperature, and the mixture was stirred at 60° C. for 2 hours. This reaction solution was cooled to room temperature, then, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.5 g of 2-chloro-4-[1-(methoxycarbonyl)ethoxy]pyrimidine and 0.25 g of 4-chloro-2-[1-(methoxycarbonyl)ethoxy]pyrimidine. 2-Chloro-4-[1-(methoxycarbonyl)ethoxy]pyrimidine
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[C:24]([CH2:16][C:12]2[S:13][CH:14]=[CH:15][C:11]=2[S:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])=[C:23]1[CH3:32]
Reactant: O=Cc1sccc1S(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)Cn1c(C)cc2cc(Cl)ccc21
Product: COC(=O)Cn1c(C)c(Cc2sccc2S(=O)(=O)c2ccc(F)cc2)c2cc(Cl)ccc21

Procedure:
The title compound was prepared by the method of Preparation 29a using 3-(4-fluorobenzenesulfonyl)thiophene-2-carbaldehyde and (5-chloro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:35][CH2:36][CH2:37][CH:38]([OH:42])[CH2:39][CH2:40][CH3:41].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:24](=[O:26])[O:42][CH:38]([CH2:39][CH2:40][CH3:41])[CH2:37][CH2:36][CH3:35])=[CH:18][CH:17]=1
Reactant: CCCC(O)CCC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(CCC)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 71.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-heptanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (53 mg, yield 61%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([NH:19][NH2:20])(=[O:18])[CH:15]([CH3:17])[CH3:16].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]([NH:20][NH:19][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)NN
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C(=O)NNC(=O)CCNC(=O)OC(C)(C)C

Procedure:
25.00 g (132 mmol) 3-tert-butoxycarbonylamino-propionic acid, 13.50 g (132 mmol) isobutyric acid hydrazide, 50.91 g (159 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and 50 ml diisopropylethylamine are stirred in 500 ml of tetrahydrofuran/dichloromethane for 24 hours at ambient temperature. Then the mixture is evaporated down, the residue is extracted with ethyl acetate and 10% potassium hydrogen carbonate solution. The organic phase is dried and evaporated to dryness. The residue is crystallised from toluene/isopropylether.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21](OCC)=[O:22])[CH2:14][CH:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:29]=1)[CH3:2].[NH2:30][NH2:31]>C(O)C>[CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21]([NH:30][NH2:31])=[O:22])[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:29]=1)[CH3:2]
Reactant: NN
Reactant: CCNc1ncc2c(n1)N1CCCC1CN(c1cccc(C(=O)OCC)c1)C2=O
Solvent: CCO
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Compound 18 (1.15 g, 2.19 mmol) obtained in Example 18 was dissolved in ethanol (11 mL), and the mixture was stirred overnight at 80° C. after adding hydrazine.monohydrate (1.06 mL, 21.9 mmol). The mixture was concentrated, diluted with chloroform, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (S)-3-(9-ethylamino-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (1.10 g, quantitative).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.Br[CH2:30][C:31]([CH3:33])=[CH2:32]>C1COCC1>[CH3:32][C:31](=[CH2:30])[CH2:33][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:18][CH:17]=1)[C:20]([OH:22])=[O:21]
Reactant: C=C(C)CBr
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a stirring solution of diisopropylamine (0.537 g, 5.31 mmol) in THF (5.2 mL) at 0° C. was added n-butyllithium (2.1 mL, 5.22 mmol, 2.5M in hexane) dropwise. After stirring for 15 min at 0° C., the mixture was cooled to -78° C. and a solution of 4-biphenylacetic acid (0.500 g, 2.36 mmol) in THF (2 mL) was added dropwise. After again warming to 0° C. and coolling to -78° C., 3-bromo-2-methylpropene (0.485 g, 3.54 mmol) was added to the mixture in one portion. After stirring at -78° C. for 1 h, the reaction was quenched with 2 mL of water then concentrated. The residue was redissolved in water and extracted with ether (100 mL). The aqueous layer was acidified (3N HCl) and extracted with ether (3×100 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield a white solid (0.449 g, 72%). MS(ESI): 265.3 (M+H)-.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH3:13].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[CH2:13][Br:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c(F)cc(F)cc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(F)c2cccc(CBr)c2c1

Procedure:
1.35 g of 5,7-Difluoro-1-methylnaphthaline in 10 ml of carbon tetrachloride are refluxed for 41/2 hours with 1.4 g of N-bromosuccinimide and 50 mg of dibenzoylperoxide. The cooled mixture is filtered and the solvent removed under vacuum. The purity of the crystalline crude product is sufficient for further reaction, m.p. 74°-76.5°.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>C1(C)C(C)=CC=CC=1.C(O)C>[CH2:13]([O:12][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1)[CH3:14]
Reactant: CC[O-]
Reactant: Nc1nc(Cl)c2c(n1)CCC2
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: CCOc1nc(N)nc2c1CCC2
Yield: 98 %

Procedure:
5.1 grams of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 200 ml xylene and 30 ml absolute ethanol. Then 6.8 gram for sodium ethoxide was added and the mixture was refluxed for 3 hours. Then the solvent was removed in vacuo and 100 ml water was added to the residue. Filter and wash the cake with water (50 ml). The solid was further vacuumed to dry for several hours. The desired product weighed 5.3 gram (98% yield). Mp: 133.8˜134.9° C.