Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[O:13]([CH2:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C>CCCCCC.O1CCCC1>[O:22]=[C:21]([CH2:20][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: O=C(Cl)COc1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COP(=O)(CC(=O)COc1ccccc1)OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyl lithium (69 ml. of a 1.2 M solution in hexane) was added to a solution of dimethyl methylphosphonate (10.3 g.) in dry tetrahydrofuran at -78° C. in an atmosphere of nitrogen. After 10 minutes, a solution of phenoxyacetylchloride (4.1 g.) in dry tetrahydrofuran (20 ml.) was added dropwise, and the mixture was stirred for 4 hours at -78° C. The reaction mixture was neutralised with acetic acid and the solvents were removed under reduced pressure. The residue was shaken with a mixture of ether (100 ml.) and water (20 ml.), and the organic phase was separated and washed with brine. The solution was dried, the solvents were evaporated and the residue was distilled in a bulb distillation apparatus at an oven temperature of 160° C. and 0.1 mm. pressure, to give dimethyl 2-oxo-3-phenoxypropylphosphonate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])O)=[O:5])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:24])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])[NH:29][C:28]1[CH:30]=[CH:31][CH:32]=[C:26]([Cl:25])[CH:27]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1C
Reactant: Nc1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cccc(Cl)c1)c1ccc(Cl)cc1C

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 with the intermediate C and the 3-chloroaniline. The reaction mixture was diluted in DCM/water and the phases were separated. The organic phase was dried (Na2SO4) and concentrated. The product was purified by flash chromatography (heptane/EtOAc, 9:1) to give the title compound. tR: 1.47 min (LC-MS 2); ESI-MS: 524.0/526.0/528.2 [M+H]+ (LC-MS 2).
Reaction SMILES: C(OO)(=[O:3])C.[Cl:6][C:7]1[C:17]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[CH:16][C:10]2[N:11]=[C:12]([S:14][CH3:15])[NH:13][C:9]=2[CH:8]=1.[OH2:27]>C(O)(=O)C>[Cl:6][C:7]1[C:17]([O:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[CH:16][C:10]2[N:11]=[C:12]([S:14]([CH3:15])(=[O:3])=[O:27])[NH:13][C:9]=2[CH:8]=1
Reactant: CSc1nc2cc(Oc3ccc(Cl)cc3Cl)c(Cl)cc2[nH]1
Reactant: CC(=O)OO
Reactant: O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1nc2cc(Oc3ccc(Cl)cc3Cl)c(Cl)cc2[nH]1
Yield: 89 %

Procedure:
122 5 ml of 40% strength peracetic acid are added dropwise in the course of 30 minutes to a solution, which is kept at room temperature by cooling, of 100 g of 5-chloro-6-(2',4'-dichlorophenoxy)-2-methylthiobenzimidazole in 800 ml of glacial acetic acid, with stirring. The resulting dark red solution is stirred for a further 15 hours at room temperature. A viscous suspension forms and 4 l of demineralised water are added to this. The precipitate formed is then filtered off with suction, washed with water and dried in vacuo at 50° C. This gives 96 g of 5-chloro-6-(2',4'-dichlorophenoxy)-2-methylsulphonylbenzimidazole with a melting point of 215°-218° C., which corresponds to a yield of 89%.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH:13]3[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:10][C:9]([C:21]([F:24])([F:23])[F:22])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:30][O+](C)C>>[CH3:30][O:20][C:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([C:21]([F:22])([F:23])[F:24])[N:10]=2)[N:19]=1
Reactant: O=C1CCCCC(Cc2nc(C(F)(F)F)nn2-c2ccccc2)N1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Product: COC1=NC(Cc2nc(C(F)(F)F)nn2-c2ccccc2)CCCC1

Procedure:
The product of Example 152 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[O:15])[N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1>CC#N.CCOC(C)=O>[CH:25]1([CH2:24][N:4]2[C:3](=[O:16])[C:2]([CH3:1])=[CH:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[C:5]2=[O:15])[CH2:27][CH2:26]1
Reactant: BrCC1CC1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cn(C(=O)OC(C)(C)C)c(=O)n(CC2CC2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
Tert-butyl 5-methyl-2,4-dioxo-pyrimidine-1-carboxylate (0.10 g, 0.44 mmol) was dissolved in dry MeCN (2.2 mL) and cesium carbonate was added (0.22 g, 0.66 mmol), followed by (bromomethyl)cyclopropane (0.13 mL, 1.33 mmol). The reaction mixture was stirred under nitrogen atmosphere at room temperature for 18 hrs. The reaction was then diluted with EtOAc and saturated aqueous NH4CI solution was added. The aqueous layer was extracted with EtOAc (3×15 mL), the combined organic phases were washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The crude was purified by column chromatography using a Teledyne ISCO apparatus (petroleum ether:EtOAc 80:20) to afford the title compound (0.09 g, 72%) as white solid. 1H NMR (400 MHz, CDCl3) δ 0.38-0.43 (m, 2H), 0.43-0.50 (m, 2H), 1.21-1.32 (m, 1H), 1.61 (s, 9H), 1.97 (s, 3H), 3.84 (d, J=7.2 Hz, 2H), 7.64 (s, 1H). MS (ESI) m/z: 303 [M-Na]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[CH:31]1([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([CH:31]4[CH2:33][CH2:32]4)=[CH:35][CH:36]=3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Nc1ccc(C2CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C4CC4)cc3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 23 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.150 g, 0.399 mmol), thionyl chloride (2.0 mL), 4-cyclopropylaniline (Intermediate-50, 0.079 g, 0.598 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.045 g of the desired product. 1HNMR (DMSO-d6): δ 0.62-0.63 (m, 2H), 0.90-0.92 (m, 2H), 1.56 (s, 6H), 1.89 (m, 1H), 3.09 (s, 2H), 7.05 (d, J=8.4 Hz, 2H), 7.29-7.47 (m, 4H), 7.54 (d, J=8.4 Hz, 2H), 9.67 (s, 1H), 11.00 (s, 2H); MS [M+H]+: 491.28.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12](OCC)=O.[CH3:17]I.[CH3:19][N:20](C=O)C>>[CH3:17][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH2:12][NH:20][CH3:19]
Reactant: CI
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CNCc1cc2ccccc2n1C
Reaction time: 0.25 h

Procedure:
NaH (60% dispersion in mineral oil, 8.02 g, 200.49 mmole) was washed with hexanes, then was suspended in dry DMF (530 mL). Solid ethyl indole-2-carboxylate (25.29 g, 133.66 mmole) was added portionwise over 5–10 min, allowing gas evolution to subside between additions. When the addition was complete, the yellow mixture was stirred for 15 min, then methyl iodide (42 mL, 668.3 mmole) was added all at once. The reaction was exothermic, and the internal temperature rose to 40–45° C. After 1 hr, the reaction was quenched with 10% NH4Cl (100 mL) and concentrated on the rotavap (high vacuum). The residue was partitioned between Et2O(500 mL) and H2O (100 mL), and the layers were separated. The Et2O layer was washed with H2O (100 mL), dried (MgSO4), and concentrated to leave the title compound (27.10 g, quantitative) as a light yellow solid. This was used without further purification: TLC (10% EtOAc/hexanes) Rf=0.39.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:10][C:11](=[O:33])[N:12]([CH2:22][C:23]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)([CH3:25])[CH3:24])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20]O)=[CH:15][N:14]=1)([CH3:9])([CH3:8])[CH3:7].C[N:35](CCN(C)C)C.[N-]=[N+]=[N-].[Na+]>C(OCC)(=O)C.O>[NH2:35][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]([CH2:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)([CH3:24])[CH3:25])[C:11](=[O:33])[O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[N:14][CH:15]=1
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)OC(=O)N(CC(C)(C)c1ccc(F)cc1)c1ccc(CCO)cn1
Agent: CS(=O)(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CC(C)(C)c1ccc(F)cc1)c1ccc(CCN)cn1
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (87 μL, 1.1 mmol, 1.1 equiv) dissolved in 2 mL ethyl acetate was added to a 20 dram vial. To this stirring mixture was added a mixture of tert-butyl-2-(4-fluorophenyl)-2-methylpropyl(5-(2-hydroxyethyl)pyridin-2-yl)-carbamate (414 mg, 1.1 mmol, 1.0 equiv), TMEDA (167 μL, 1.1 mmol, 1.1 equiv), and ethyl acetate (3 mL) in a dropwise manner. The reaction was stirred for 1 h. The reaction mixture was then filtered and washed with saturated sodium bicarbonate and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The resultant solid was dissolved in DMF (4 mL), followed by the addition of sodium azide (139 mg, 2.1 mmol, 2.0 equiv). The reaction was stirred for 24 h, then diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude solid was dissolved in methanol, followed by the addition of 10% palladium on carbon (80 mg), potassium carbonate (100 mg). The reaction was stirred under 45 psi of hydrogen for 24 h, filtered, and concentrated to give tert-butyl 5-(2-aminoethyl)pyridin-2-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])/[C:5]/2=[CH:16]/OC.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[NH:7][C:6](=[O:15])[C:5]2=[CH:16][NH:32][C:29]1[CH:28]=[CH:27][C:26]([N:23]2[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]2)=[CH:31][CH:30]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CO/C=C1/C(=O)NC(=O)c2cc(OC)c(Br)cc21
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)C(=CNc1ccc(N3CCN(C)CC3)cc1)C(=O)NC2=O
Temperature: 110 °C
Yield: 46.7 %

Procedure:
A mixture of (4E)-6-bromo-7-methoxy-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (156 mg, 0.50 mmole), N,N-dimethylformamide (1 mL) and 4-(4-Methyl-piperazin-1-yl)-phenylamine (96 mg, 0.50 mmole) is stirred and heated at 110° C. for one hour, cooled in the refrigerator. The reaction mixture is evaporated to dryness, taken up in 5% methanol in chlororform and passed through a short pad of Florisil eluting with 5% methanol in chloroform. The eluate is evaporated in vacuo and treated with acetonitrile, filtered and dried to give a brown solid 110 mg (47%), mp 274-276° C.; MS (ESI): m/z 471.1, 473.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>C(O)C>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:23]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:35][C:33](=[O:34])[NH:32]2)[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH3:18]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccccc1)c1ccccc1F
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3F)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 39.3 %

Procedure:
To a solution of 1-(2-fluorophenyl)-2-phenylethanone (Intermediate 24) (100 mg, 0.47 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (92.0 mg, 0.47 mmol), and urea (85.4 mg, 1.40 mmol) in 5 mL of ethanol was added 0.2 mL of concentrated HCl solution, and the mixture was refluxed for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 55 (83 mg, yield 39.7%). 1H NMR (DMSO-d6 400 MHz) δ 10.25 (s, 1H), 8.77 (s, 1H), 7.48 (s, 1H), 7.43 (s, 1H), 7.29 (d, J=5.2 Hz, 1H), 7.21-7.6.80 (m, 7H), 6.79 (d, J=6.8 Hz, 2H), 5.18 (s, 1H), 4.01 (m, 2H), 1.30 (t, J=6.8 Hz, 3H); MS (ESI): m/z 450.0 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([CH3:8])=[N:6][CH:7]=1.[Cl-].[NH4+]>[Fe].C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ncc(Br)cc1N
Temperature: 80 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitropyridine (8.0 g, 37 mmol) in 4:1 ethanol/water (250 mL) was added iron (16.5 g, 295 mmol) and ammonium chloride (15.8 g, 295 mmol). The mixture was stirred at 80° C. for 3 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give 5-bromo-2-methylpyridin-3-amine (6.8 g, 99% crude yield), which was without further purification.
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=1.[O:17]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)[CH2:19][CH2:18]1.C(N1CCCC1=O)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH3:16][O:15][C:4]1[CH:3]=[C:2]([N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:20]2[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: c1c[nH]c(C2CCOCC2)n1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(-n2ccnc2C2CCOCC2)cc1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a mixture of 3 g of methyl 4-fluoro-2-methoxy-5-nitrobenzoate, 1.99 g of 2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole, and 15 mL of N-ethylpyrrolidone was added 3.6 g of potassium carbonate, followed by stirring at 100° C. for 3 hours. To the reaction mixture were added water and ethyl acetate, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 4.12 g of methyl 2-methoxy-5-nitro-4-[2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]-benzoate.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([N+:21]([O-])=O)=[C:15]([F:20])[CH:16]=3)[C:11]2=[O:24])[CH2:3][CH2:2]1.C(O)(=O)C>C1COCC1.[Fe]>[NH2:21][C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH2:19][N:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[CH:1]3[CH2:2][CH2:3]3)[C:11]2=[O:24])=[CH:16][C:15]=1[F:20]
Reactant: O=C1c2cc([N+](=O)[O-])c(F)cc2CCN1c1cnccc1C1CC1
Agent: [Fe]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1cc2c(cc1F)CCN(c1cnccc1C1CC1)C2=O
Yield: 96.6 %

Procedure:
2-(4-Cyclopropylpyridin-3-yl)-6-fluoro-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (I-82a: 400 mg, 1.219 mmol) was reduced with iron powder (340 mg, 6.09 mmol) and acetic acid (10 mL) in THF (10 mL) at 75° C. for 4 hours to afford 350 mg of the product (96.6% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]([F:20])=[C:18]2[C:13]([C:14]([CH3:21])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1C(O)=O.C([N:27]([CH2:30]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:39])C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:11](=[CH:12][C:13]3[C:14]([CH3:21])=[N:15][CH:16]=[N:17][C:18]=3[C:19]=2[F:20])[NH:27][C:30]1=[O:39]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: Cc1ncnc2c(F)c(Nc3ccc(I)cc3F)c(C(=O)O)cc12
Solvent: Cc1ccccc1
Product: Cc1ncnc2c(F)c3c(cc12)[nH]c(=O)n3-c1ccc(I)cc1F
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a suspension of 7-(2-fluoro-4-iodophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid (190 mg, 0.47 mmol) in toluene (10 ml) was added triethylamine (0.19 ml, 1.41 mmol) and diphenylphosphoryl azide (0.20 ml, 0.94 mmol). The reaction was heated at reflux for 4 h. The mixture was cooled to room temperature and concentrated to dryness. Silica gel chromatography (EtOAc:Hexane=75:25) yields 143 mg (75%) of the title compound as a tan solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:18][C:17]([C:21]2[S:22][CH:23]=[C:24]([C:26]3[C:27]([O:41][CH:42]4[CH2:45][CH2:44][CH2:43]4)=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]([C:36]([O:38][CH3:39])=[O:37])[C@@H:31]([CH3:40])[CH2:30][CH2:29]4)[N:25]=2)([O:19][CH3:20])[CH2:16]1)=O)(C)(C)C>ClCCl>[CH:42]1([O:41][C:27]2[C:26]([C:24]3[N:25]=[C:21]([C:17]4([O:19][CH3:20])[CH2:18][NH:15][CH2:16]4)[S:22][CH:23]=3)=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH2:30][C@H:31]([CH3:40])[N:32]3[C:36]([O:38][CH3:39])=[O:37])[CH2:43][CH2:44][CH2:45]1
Reactant: COC(=O)N1c2ccc(-c3csc(C4(OC)CN(C(=O)OC(C)(C)C)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1c2ccc(-c3csc(C4(OC)CNC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-3-methoxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.070 g, 0.13 mmol) in dichloromethane (3 mL), and the resulting solution stirred for 2 h at room temperature. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative-HPLC with the following conditions (Waters I): Column, Xbridge C18, 5 um, 19×150 nm; Mobile phase water (0.05% ammonium bicarbonate) and acetonitrile (25% to 65% acetonitrile in 10 min; flow rate: 20 mL/min); Detector, 220&254 nm. This afforded (S)-methyl 5-cyclobutoxy-6-(2-(3-methoxyazetidin-3-yl)thiazol-4-yl)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.037 g, 65%) as an off-white solid. 1H NMR (400 MHz, CD3OD) 1.20 (d, J=6.80 Hz, 3H), 1.25-65 (m, 3H), 1.95-2.20 (m, 4H), 2.20-2.31 (m, 1H), 2.45-2.55 (m, 1H), 2.90-3.01 (m, 1H), 3.30 (s, 3H), 3.80 (s, 3H), 3.92-3.98 (m, 2H), 4.10-4.22 (m, 3H), 4.55-4.62 (m, 1H), 7.36 (d, J=8.40 Hz, 1H), 7.82 (d, J=8.40 Hz, 1H), 7.95 (s, 1H). MS (ESI, pos. ion) m/z 444 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OCC(=O)c2ccccc2)c([N+](=O)[O-])c1

Procedure:
Under an inert atmosphere, 4-methoxy-2-nitrophenol (1.5 g; 8.86 mmol) is dissolved in 30 ml of acetone, and then 2-bromoacetophenone (1.5 eq.; 13.29 mmol; 2.79 g) and also potassium carbonate (1.2 eq.; 10.64 mmol; 1.47 g) are added. The mixture is stirred vigorously, at reflux, for 3 hours. After returning to ambient temperature, the potassium carbonate is filtered off, the filtrate is evaporated and the residue is taken up in a water/ethyl acetate mixture. The organic phase is dried over MgSO4 and then concentrated under reduced pressure. The crude reaction product is purified by flash chromatography on silica gel (eluant: PE/AcOEt (8/2)). The title product is obtained in the form of a yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:12](Br)=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[O:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)[CH2:33][CH2:32]1>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:12]([C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:33][CH2:32][O:31][CH2:36][CH2:35]4)=[CH:42][CH:41]=3)=[CH:11][N:10]=2)[CH2:4][CH2:3]1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)CC1

Procedure:
Using the procedure of Example 1 Step 3, tert-butyl 4-((2-(cis-4-methylcyclohexylamino)-5-bromopyrimidin-4-yloxy)methyl)piperidine-1-carboxylate was reacted with 4-morpholinophenylboronic acid to provide the title compound at 70% yield. 1H NMR (CDCl3, 400 MHz) 8.03 (s, 1H), 7.35 (d, 2H), 6.89 (d, 2H), 5.17 (sb, 1H), 4.16-4.03 (m, 6H), 3.83 (m, 4H), 3.15 (m, 4H), 2.66 (m, 2H), 1.91-1.44 (m, 11H), 1.41 (s, 9H), 0.95 (d, 3H); MS (ESI) m/z: Calc: 565.4 (M+). Found. 566.3 (M+1).
Reaction SMILES: ClC(OC(Cl)C)=O.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[CH2:30][CH2:29][N:28](CC4C=CC=CC=4)[CH2:27][C:21]=3[N:22]=[C:23]([S:25][CH3:26])[N:24]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(N(C(C)C)CC)(C)C>ClCCCl>[C:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[CH2:30][CH2:29][NH:28][CH2:27][C:21]=3[N:22]=[C:23]([S:25][CH3:26])[N:24]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCNC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
1-Chloroethyl chloroformate (732 mg, 5.12 mmol) was added dropwise to a mixture of N-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine (1.07 g, 2.56 mmol) and diisopropylethyl amine (660 mg, 5.12 mmol) in 1,2-dichloroethane (10 mL, anhydrous) at 0° C. After addition, the reaction mixture was stirred at room temperature for 1 hr. Solvent was removed in vacuo, residue was dissolved in methanol (10 mL) and was stirred at room temperature overnight. Solvent was removed in vacuo, residue was dissolved in ethyl acetate and was washed with saturated aqueous sodium bicarbonate, brine and dried over sodium sulfate. Solvent was removed in vacuo and residue was triturated by diethyl ether to yield the product as a light brown solid (303 mg, 36%).