Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:22][OH:23])[CH:18]=[CH:19][C:20]=1[F:21]>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:22][O:23][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CC1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(F)c(F)c1
Product: CC1Cn2c(cc(OCc3ccc(F)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3,4-dif-luorophenyl)methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1SCl)([O-:11])=[O:10]>C(#N)C.[Ag]>[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[C:7]1[CH:6]=[C:5]([S:8][S:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([C:13]3[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=3[N+:9]([O-:11])=[O:10])[CH:6]=2)[CH:4]=[CH:3][C:2]=1[CH3:1])([O-:11])=[O:10]
Reactant: Cc1ccc(S)cc1
Reactant: O=[N+]([O-])c1ccc(SCl)c([N+](=O)[O-])c1
Agent: [Ag]
Solvent: CC#N
Product: Cc1ccc(SSc2ccc(C)c(-c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])c2)cc1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 31.8 %

Procedure:
In a nitrogen atmosphere, 3.70 g (16.0 mmol) of the silver salt of p-thiocresol and 3.75 g (16.0 mmol) of 2,4-dinitrophenylsulfenyl chloride were stirred for 3 hours in 150 ml of acetonitrile serving as a solvent, while cooling with ice water. The reaction mixture was filtered and the residue obtained after the concentration of the filtrate under reduced pressure was subjected to chromatography on a silica gel column (eluting solvent: hexane/ethyl acetate=5/1), whereby 1.64 g (5.08 mmol, yield: 31.8%) of 2,4-dinitrophenyl p-tolyldisulfide were obtained as yellow crystals.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:15][C:16]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:17]=1[CH:18]=[O:19]>CN(C=O)C.O>[CH2:1]([O:15][C:16]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:17]=1[CH:18]=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1
Temperature: 80 °C
Yield: 92.2 %

Procedure:
Benzyl bromide (18 mL, 14.9 mmol) and cesium carbonate (8.1 g, 24.9 mmol) were added to a solution of 2-hydroxy-5-bromo benzaldehyde 2 g, 9.95 mmol) in anhydrous DMF (25 mL) at room temperature. The reaction was heated to 80° C. for two hours, cooled and diluted with water (50 mL). The mixture was extracted with ethyl acetate (3×40 mL) and the combined organic layers were washed with water (1×50 mL) and brine (1×50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/hexane) to afford 2.67 g of the title compound as a colorless oil (92%). MS: 291 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H); 7.6 (dd, 1H, J=8.9, 2.7 Hz); 7.39 (m, 6H); 6.92 (d, 1H, J=8.9 Hz); 5.18 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=C)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O:14]=[O+][O-].CSC>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[O+][O-]
Reactant: C=Cc1cccc(Cl)c1C(=O)OC
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)c1c(Cl)cccc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Into a solution of methyl 2-chloro-6-vinylbenzoate (6.7 g, 34 mmol) in dry DCM (100 mL) was bubbled O3 at −78° C. over a 30 minute period. Next, nitrogen gas was bubbled into the solution until the solution was colorless. Dimethylsulfane (4.3 g, 68 mmol) was added dropwise and the resulting mixture was warmed to RT and stirred for 2 hours. The reaction mixture was subsequently washed with water (30 mL) and extracted with DCM (3×100 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography eluting with a gradient of EtOAc (0-90%) and PE to give the title compound (3.8 g, 56%). 1H NMR (400 MHz, CDCl3) δ ppm 9.89 (s, 1H), 7.728 (d, J=7.2 Hz, 1H), 7.606 (d, J=8.0 Hz, 1H), 7.489 (t, J=8.0 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[C:12](OC(=O)C)(=[O:14])[CH3:13].Cl.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.O.CCOCC>[C:12]([O:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2)(=[O:14])[CH3:13]
Reactant: OCc1cccc2[nH]ccc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCc1cccc2[nH]ccc12

Procedure:
4-Hydroxymethylindole (17 g) is heated in pyridine (12 ml) with acetic anhydride (11.9 ml) for three hours on the steam bath. After dilution with ether, the reaction mixture is first shaken out with 1N hydrochloric acid, then with saturated sodium bicarbonate solution and finally with water. The ether solution is evaporated. 20 g of 4-acetoxymethylindole remains.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].[Na+].[Br-].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC(C)=O.CC1(C)N([O])C(C)(C)CCC1.CC(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]2([C@@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)[CH2:9][CH2:10][CH2:11][C:12](=[O:13])[O:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCCO)c2cccc(Cl)c2)C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@]2(c3cccc(Cl)c3)CCCC(=O)O2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To a stirred solution of (R)-tert-butyl 3-((S)-1-(3-chlorophenyl)-1,5-dihydroxypentyl)piperidine-1-carboxylate (200 mg, 0.5 mmol) in acetone (3 mL) maintained at 0° C. was added an 15% aq NaHCO3 (2 mL), followed by solid NaBr (10.3 mg, 0.1 mmol) and TEMPO (1.56 mg, 0.01 mmol). Trichloroisocyanuric acid (231 mg, 1 mmol) was then slowly added at 0° C. The mixture was warmed to rt, stirred for 3 h and treated with 2-propanol (0.5 mL). The mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was partitioned between water and EtOAc and the aqueous phase was extracted with EtOAc (3×20 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to provide (R)-tert-butyl 3-((S)-2-(3-chlorophenyl)-6-oxotetrahydro-2H-pyran-2-yl)piperidine-1-carboxylate (160 mg, 81%). 1H NMR (400 MHz, CDCl3): 1.12-1.45 (m, 3H), 1.46 (s, 9H), 1.58-1.81 (m, 6H), 2.22 (m, 2H), 2.42 (m, 2H), 2.56 (m, 2H), 4.05 (m, 1H), 4.36 (m, 1H), 7.16 (m, 1H), 7.27-7.32 (s, 1H). MS (E/Z): 394 (M+H+).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[O:4][CH2:3][CH2:2]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C([O-])(O)=O.[Na+]>C(Cl)Cl>[S:1]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH2:11][O:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH:9]=2)[O:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc2c(cn1)OCCS2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc2c(cn1)OCCS2
Temperature: 0 °C
Yield: 100.5 %

Procedure:
To a suspension of (2,3-dihydro-4-oxa1-thia-6-aza-naphthalen-7-yl)-methanol (0.150 g, 0.8 mmol; prepared as described in WO 2004/058144) in DCM (4 mL), cooled to 0° C., were added TEA (0.228 mL, 1.6 mmol, 2 eq.) and MsCl (0.076 mL, 0.98 mmol, 1.2 eq.). The reaction was stirred at the same temperature. MsCl (0.013 mL, 0.16 mmol) was added after 30 min. A sat. NaHCO3 solution (25 mL) and DCM (20 mL) were added. The two layers were decanted and the org. layer was dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (DCM-MeOH 97-3) to afford the tittle compound as a yellowish oil (0.210 g, 98% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[O:43]1[CH2:48][CH:47]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH2:45][CH2:44]1>>[O:43]1[CH2:44][CH:45]=[C:46]([C:2]2[CH:3]=[C:4]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)[C:5]([NH:8][C:9]3[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)=[N:6][CH:7]=2)[CH2:47][CH2:48]1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: COc1ccc(Nc2ncc(C3=CCOCC3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 247 using 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Frontier Scientific), and was isolated as a yellow amorphous solid (35%). m/z (ESI, +ve ion) 392.0 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.76 (1H, s); 8.83 (1H, d, J=2.5 Hz); 8.54 (1H, d, J=2.7 Hz); 8.44 (1H, d, J=2.5 Hz); 8.17 (1H, dd, J=8.8, 2.7 Hz); 7.87 (1H, br. s.); 7.73 (1H, br. s.); 6.83 (1H, d, J=8.8 Hz); 6.22 (1H, br. s.); 4.24 (2H, d, J=2.5 Hz); 3.82-3.87 (5H, m); 2.47 (2H, m); 2.44 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=[CH:3]1.[F:26]C1C=CC(C2N=CN(C)C=2C2SC3N=CN=C(SC)C=3C=2)=CC=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:6]=2[C:7]2[S:19][C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])[C:9]=3[CH:8]=2)=[CH:21][CH:22]=1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: CSc1ncnc2sc(-c3c(-c4ccc(F)cc4)ncn3C)cc12
Product: Cn1cnc(-c2ccc(F)cc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 17 but using 6-[4-(4-fluorophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 49) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7). Yellow solid (80 mg, 73%);
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:12]([O:14][CH3:15])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C@:21]12([CH3:31])[C:28]([CH3:30])([CH3:29])[CH:25]([CH2:26][CH2:27]1)[CH2:24][C:22]2=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.[Cl-].[Cl-].[Cl-].[Ti+3]>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][O:14][CH:15]=[C:22]2[CH2:24][CH:25]3[C:28]([CH3:30])([CH3:29])[C:21]2([CH3:31])[CH2:27][CH2:26]3)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)C2
Reactant: COC(=O)c1ccc(OC)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Ti+3]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(COC=C2CC3CCC2(C)C3(C)C)cc1O[Si](C)(C)C(C)(C)C

Procedure:
Methyl 3-tert-butyldimethylsilyloxy-4-methoxybenzoate (170 mg, 0.57 mmol, prepared in Example 1, Step 2 above) and (1R)-(+)-camphor (Aldrich, 120 mg, 0.79 mmol) were mixed and dissolved in anhydrous tetrahydrofuran (THF, 1.98 ml) and coupled as described in the procedure of Example 1, Step 3, above, by using titanium trichloride (1.9 g, 12.32 mmol), LAH (0.22 g, 5.80 mmol) and THF (13.8 ml). The product was purified on a preparative TLC plate (silica gel). Development with hexane/ethyl acetate (10:1)gave the title compound as a mixture of two isomers (58 mg). NMR(δ): 0.18 (s, 6H), 1.00 (s, 15H), 1.29 (s, 3H), 3.23 (s, 1H, minor isomer), 3.30 (s, 2H, major isomer), 3.85 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH3:21])[C:6](=[O:20])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:25]([O:24][C:22]([N:29]1[CH2:34][CH2:33][N:32]([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][N:5]([CH3:21])[C:6](=[O:20])[N:7]3[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[CH2:31][CH2:30]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN1Cc2c(Br)cccc2N(Cc2cccc(F)c2)C1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN1Cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2N(Cc2cccc(F)c2)C1=O
Temperature: 25 °C
Yield: 35.2 %

Procedure:
A solution of 5-bromo-1-(3-fluoro-benzyl)-3-methyl-3,4-dihydro-1H-quinazolin-2-one (156 mg, 0.45 mmol) and 1-Boc-piperazine (100 mg, 0.54 mmol) in 1 ml toluene was added to a mixture of Pd2(dba)3 (8 mg, 0.009 mmol), BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (14 mg, 0.022 mmol), and NaOt-Bu (65 mg, 0.67 mmol). With stirring, the solution was heated at 95° C.-100° C. for 1 hour and was allowed to cool to room temperature. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by prep TLC to give 72 mg 4-[1-(3-fluoro-benzyl)-3-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester as yellow solid (75 mg, 35%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]2[N:11]([CH:12]=[CH:13][CH:14]=2)[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=1)(=O)=O.[SiH](CC)(CC)CC.CN([CH:33]=[O:34])C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:33]([C:7]1[C:15]2[N:11]([CH:12]=[CH:13][CH:14]=2)[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=1)=[O:34]
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c2cccn12
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC[SiH](CC)CC
Product: CCOC(=O)c1ccc(C=O)c2cccn12
Temperature: 60 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of ethyl 8-(((trifluoromethyl)sulfonyl)oxy)indolizine-5-carboxylate (4 g, 11.87 mmol) in DMF (1200 mL) was added TEA (3.6 g, 35.61 mmol), Et3SiH (4.14 g, 35.61 mmol) and Pd(dppf)2Cl2 (0.9 g, 10 mol %) under N2. The reaction mixture was stirred at 60° C. under CO (50 psi) overnight. The mixture was concentrated and to the residue were added EA and water, washed with brine, dried and concentrated and purified by column to give product ethyl 8-formylindolizine-5-carboxylate (1 g, yield 39%). 1H NMR (400 MHz, DMSO-d6): δ 10.15 (s, 1H), 8.61 (s, 1H), 7.76 (m, 1H), 7.63 (m, 1H), 7.37 (m, 1H), 7.10 (m, 1H), 4.46 (q, 2H), 1.39 (t, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:14]([Cl:16])=[CH:13][C:12](=O)[CH2:11][C:10]=3[C:9]3([CH2:21][NH:20][C:19](=[O:22])[NH:18]3)[C:8]2=[O:23])=[C:4]([F:26])[CH:3]=1.Cl.[OH-:28].C[N+](C(C1C=CC=CC=1)C)(C)C>CO>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[Cl:16])[C:9]3([C:21](=[O:28])[NH:20][C:19](=[O:22])[NH:18]3)[C:8]2=[O:23])=[C:4]([F:26])[CH:3]=1
Reactant: [OH-]
Reactant: O=C1C=C(Cl)C2=C(C1)C1(CNC(=O)N1)C(=O)N2Cc1ccc(Br)cc1F
Agent: CC(c1ccccc1)[N+](C)(C)C
Agent: Cl
Solvent: CO
Product: O=C1NC(=O)C2(N1)C(=O)N(Cc1ccc(Br)cc1F)c1c(Cl)cccc12
Temperature: 70 °C
Reaction time: 48 h

Procedure:
(±)-1'-(4-Bromo-2-fluorobenzyl)-7'-chloro-spiro[imidazoline-4,3'-indoline]-2,2',5'-trione (64.4 g.) was dissolved in a 0.253 M solution of (-)-N,N,N-trimethyl-(1-phenylethyl)ammonium hydroxide in methanol (581 ml.). The solution was filtered and the filtrate was evaporated. The residue was dissolved in 2-methoxyethanol (132 ml.). The solution was warmed to 70° C. and then diluted with 1,2-dimethoxyethane (440 ml.) previously warmed to 70° C. The clear solution was stored at 0° C. for 48 hours and the crystals of the quaternary ammonium salt were collected by filtration [27 g.; [α]D23 +21.1°, c. 0.93, MeOH)]. This product was recrystallised from 2-methoxyethanol (55.3 ml.) and 1,2-dimethoxyethane (184 ml.) to give crystals [20 g.; [α]D23 +22° (c.1.11, MeOH)]. A third recrystallisation gave crystals [15.8 g.; [α]D23 +21.9° (c.1.12 MeOH)]. The crystalline salt (15.8 g.) thus obtained was dissolved in methanol (50 ml.) and treated with 0.25 M aqueous hydrochloric acid (105 ml.). The solution was chilled at 0° C. overnight and the solid removed by filtration, washed with water and dried over phosphorus pentoxide under vacuum to give the (+)-enantiomer of 1'-[4-bromo-2-fluorobenzyl]-7'-chloro-spiro[imidazolidine-4,3'-indoline]-2,2',5-trione (9.1 g.), m.p. 260°-262° C., [α]D23 +17.9° (c. 0.89, MeOH).
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[Cl:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:15]=1[CH2:16]Br>>[Cl:13][C:14]1[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:15]=1[CH2:16][N:9]1[C:8](=[O:10])[CH2:7][NH:6][C:5]2[N:11]=[CH:12][C:2]([I:1])=[CH:3][C:4]1=2
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: Fc1ccc(F)c(CBr)c1Cl
Product: O=C1CNc2ncc(I)cc2N1Cc1c(F)ccc(F)c1Cl

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (300 mg) was reacted with 2-chloro-3,6-difluorobenzyl bromide as in General Procedure 1. The title compound was obtained as an off white solid (63% yield). M.p. 237° C., LCMS: m/z=436.17 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.01 (s, 2H), 5.24 (s, 2H), 7.05 (d, J=1.5 Hz, 1H), 7.23-7.32 (m, 1H), 7.41-7.48 (m, 1H), 7.79 (d, J=1.5 Hz, 1H).
Reaction SMILES: C(OC(N1CC(=C)CC1C1NC(C2C=CC(C3C=CC4C(=CC=C(C5NC(C6CCCN6C(=O)C(NC(OC)=O)C(C)C)=NC=5)C=4)C=3)=CC=2)=CN=1)=O)(C)(C)C.[C:56]([O:60][C:61]([N:63]1[CH2:67][CH2:66][CH2:65][CH:64]1[C:68]1[NH:69][C:70]([C:73]2[CH:82]=[CH:81][C:80]3[C:75](=[CH:76][CH:77]=[C:78](Br)[CH:79]=3)[CH:74]=2)=[CH:71][N:72]=1)=[O:62])([CH3:59])([CH3:58])[CH3:57].[CH3:84][O:85][C:86](=[O:121])[NH:87][CH:88]([C:92]([N:94]1[CH:99]([C:100]2[NH:101][C:102]([C:105]3[CH:110]=[CH:109][C:108](B4OC(C)(C)C(C)(C)O4)=[CH:107][CH:106]=3)=[CH:103][N:104]=2)[CH:98]2[CH2:120][CH:95]1[CH2:96][CH2:97]2)=[O:93])[CH:89]([CH3:91])[CH3:90]>>[C:56]([O:60][C:61]([N:63]1[CH2:67][CH2:66][CH2:65][CH:64]1[C:68]1[NH:69][C:70]([C:73]2[CH:82]=[CH:81][C:80]3[C:75](=[CH:76][CH:77]=[C:78]([C:108]4[CH:107]=[CH:106][C:105]([C:102]5[NH:101][C:100]([CH:99]6[CH:98]7[CH2:120][CH:95]([CH2:96][CH2:97]7)[N:94]6[C:92](=[O:93])[CH:88]([NH:87][C:86]([O:85][CH3:84])=[O:121])[CH:89]([CH3:91])[CH3:90])=[N:104][CH:103]=5)=[CH:110][CH:109]=4)[CH:79]=3)[CH:74]=2)=[CH:71][N:72]=1)=[O:62])([CH3:59])([CH3:58])[CH3:57]
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Agent: C=C1CC(c2ncc(-c3ccc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)ccc5c4)cc3)[nH]2)N(C(=O)OC(C)(C)C)C1
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Yield: 70.6 %

Procedure:
This compound was synthesized using the procedure used to make 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.200 g, 0.452 mmol) and [2-Methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester (0.283 g, 0.543 mmol) to give 2-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-3-methyl-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.242 g, 71% yield). LCMS-ESI+: calc'd for C44H51N7O5: 757.40 (M+); Found: 758.50 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.Cl.[CH3:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1.C(N(CC)CC)C>>[CH3:17][C:15]1([CH3:18])[CH2:14][O:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[CH3:20])=[CH:7][CH:8]=2)=[N:16]1
Reactant: C[C@@H]1CCCN1
Reactant: CC1(C)COC(c2ccc(OCCCCl)cc2)=N1
Agent: Cl
Solvent: CCN(CC)CC
Product: C[C@@H]1CCCN1CCCOc1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 120 °C
Reaction time: 3.75 h
Yield: 21 %

Procedure:
A mixture of 2-[4-(3-chloropropoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole ax10 (0.25 g, 0.9 mmol, 1 eq), 0.15 g of (2R)-2-methylpyrrolidine hydrochloride (1.2 mmol, 1.4 eq) and triethylamine (0.3 ml, 2.2 mmol, 2.4 eq) is stirred under microwave irradiation (120° C., 3.75 h). The mixture is then filtered. Triethylamine (0.2 ml, 1.44 mmol, 1.6 eq) is added to the organic layer, and the mixture is again stirred under microwave irradiation, at 120° C. for another 1.5 h. The solvent is then removed under vacuum and the residue diluted with ethyl acetate. The organic layer is washed with water, with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated under vacuum. The residue is purified over silicagel (eluent: dichloromethane/ethanol/ammonia, gradient from 98:2:0.2 to 96:4:0.4) to give 4,4-dimethyl-2-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4,5-dihydro-1,3-oxazole 15 (60 mg) as a beige powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2.[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH2:26])[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)=[C:11]1[C:6]([CH2:7][CH2:8][CH2:9][CH2:10]1)=[N:5]2
Reactant: Clc1ccc2c(Cl)c3c(nc2c1)CCCC3
Reactant: CN1CCN(CCN)CC1
Product: CN1CCN(CCNc2c3c(nc4cc(Cl)ccc24)CCCC3)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-1,2,3,4-tetrahydroacridine and 2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained; MS (Found M+1=359). 1H NMR (CDCl3, 300 Hz): 7.97-7.95 (m, 2H, J=9 Hz), 7.95-7.91 (d, 1H, J=9 Hz), 7.28-7.25 (m, 1H), 5.25 (b, 1H), 3.58-3.49 (m, 2H), 3.05 (m, 2H), 3.73 (m, 2H), 2.63-2.59 (m 10H), 2.39 (s, 3H), 1.94-1.90 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:35])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:14]=1)[CH:8]=[CH:7][CH:6]=2.[CH:36](=O)[CH:37]([CH3:39])[CH3:38]>>[NH2:1][C:2]1[C:3](=[O:35])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([N:29]3[CH2:34][CH2:33][N:32]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:31][CH2:30]3)[N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)C=O
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(N4CCNCC4)n3)cccc2[nH]c1=O
Product: CC(C)CN1CCN(c2nc(Oc3cccc4[nH]c(=O)c(N)nc34)cc(-c3ccc(C(F)(F)F)cc3)n2)CC1

Procedure:
The reaction of 3-amino-5-(2-(piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (97 mg, 0.2 mmol, Example 135) with isobutyraldehyde (43 mg, 0.6 mmol, Aldrich) under the conditions of Example 36 provided the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 540 (M+1).