Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([CH3:22])[CH:3]=1.[CH3:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[C:26]([CH3:33])[N:25]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[C:4]([CH3:22])[CH:3]=2)[CH:27]=[C:26]([CH3:33])[N:25]=1
Reactant: Cc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(B(O)O)cc(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)cc(C)n1
Temperature: 75 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A 25 mL round-bottom flask maintained with an inert atmosphere of nitrogen was charged with tert-butyl 4[(4-bromo-2-methylphenyl)methyl]piperazine-1-carboxylate (368 mg, 1.00 mmol, 1.00 equiv), (2,6-dimethylpyridin-4-yl)boronic acid (300 mg, 1.99 mmol, 1.99 equiv), Pd(PPh3)4 (116 mg, 0.100 mmol, 0.10 equiv), potassium carbonate (414 mg, 3.00 mmol, 3.01 equiv), dioxane (6 mL) and water (1 mL). The resulting solution was stirred overnight at 75° C. The reaction progress was monitored by LCMS. The reaction was then quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (3×10 mL) and the organic layers were combined, washed with brine (2×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to yield 350 mg (89% yield) of tert-butyl 4-[[4-(2,6-dimethylpyridin-4-yl)-2-methylphenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 396 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([N+:19]([O-])=O)[CH:13]=1.[H][H]>C(O)C.O1CCCC1.[C].[Pd]>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]2=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([NH2:19])[CH:13]=1
Reactant: [H][H]
Reactant: Cc1ccn2c(C)c(-c3ccc(O)c([N+](=O)[O-])c3)nc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccn2c(C)c(-c3ccc(O)c(N)c3)nc2c1
Yield: 53.8 %

Procedure:
A solution of 3,7-dimethyl-2-(4-hydroxy-3-nitrophenyl)imidazo[1,2-a]pyridine (2.6 g) in a mixture of ethanol (200 ml) and tetrahydrofuran (100 ml) was hydrogenated over 10% palladium-carbon (wet. 2.0 g) under an atomospheric pressure of hydrogen at ambient temperature for 3 hours. The catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 3,7-dimethyl-2-(3-amino-4-hydro-xyphenyl)imidazo[1,2-a]pyridine (1.25 g). mp. 251°-253° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH:18]1([N:24]=[C:25]=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C=NC1CCCCC1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)NC4CCCCC4)cc23)CC1
Yield: 86.6 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 16.37 mg (0.131 mMol) cyclohexyl isocyanate, 20.1 mg (87%) of the title compound were recovered.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)(=O)=O.[C:22]([O:26][C:27](=[O:46])[NH:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][C:30]=1[O:44][CH3:45])([CH3:25])([CH3:24])[CH3:23].C([O-])(O)=O.[Na+].C(OCC)(=O)C>COCCOC.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>[C:22]([O:26][C:27]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=2)=[CH:31][C:30]=1[O:44][CH3:45])=[O:46])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1NC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To a solution of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (I16) (474 mg, 1.43 mmol), tert-butyl(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (I17) (500 mg, 1.43 mmol) and Pd(PPh3)4 (165 mg, 0.143 mmol) in DME (15 mL) was added a solution of 3.5 M aqueous NaHCO3 (2.00 mL, 5.0 eq) and the resulting suspension was heated at 80° C. for 16 hours. On cooling to room temperature ethyl acetate (70 mL) was added and the resulting solution was washed with water (50 mL). The organic layer was dried (MgSO4) and evaporated to dryness. The residue was chromatographal (SiO2, 0-20% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I18) (520 mg, 90%) as a pale yellow liquid; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.1 Hz, 1H), 7.09 (s, 1H), 6.96 (dd, J=8.4, 1.3 Hz, 1H), 6.88 (d, J=1.7 Hz, 1H), 5.98 (s, 1H), 4.08 (d, J=1.9 Hz, 2H), 3.89 (s, 3H), 3.64 (t, J=5.6 Hz, 2H), 2.52 (s, 2H), 1.54 (s, 9H), 1.51 (s, 9H). LCMS Method C: rt 6.87 min; m/z 349.1 [M-t-Bu+2]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7]C)=[O:6].[CH:12]([C:15]1[NH:16][CH:17]=[CH:18][N:19]=1)([CH3:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cu]I>[CH:12]([C:15]1[N:16]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([OH:7])=[O:6])[CH:17]=[CH:18][N:19]=1)([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccnc(Br)c1
Reactant: CC(C)c1ncc[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)c1nccn1-c1cc(C(=O)O)ccn1
Temperature: 120 °C
Yield: 54.9 %

Procedure:
A mixture of methyl 2-bromoisonicotinate (2.00 g, 9.26 mmol), 2-isopropyl-1H-imidazole (1.12 g, 10.2 mmol), cesium carbonate (6.03 g, 18.5 mmol) and copper(1) Iodide (176 mg, 926 umol) in DMSO was heated to 120° C. for eighteen hours, under nitrogen. The crude material was filtered, purified by preparative HPLC (10-90% CH3CN in water). The pure fractions were collected and concentrated to give 2-(2-isopropyl-1H-imidazol-1-yl)isonicotinic acid as a white sticky solid (1.176 g, 55% yield). MS 232 (MH+).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH2:40][CH2:41][CH2:42][NH2:43])[CH:34]=1>O1CCCC1>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:43][CH2:42][CH2:41][CH2:40][O:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:10])=[CH:29][CH:28]=1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Reactant: NCCCOc1cccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCOc2cccnc2)c2ccc(OC)cc2)cc1
Yield: 82.5 %

Procedure:
As described in Example 134, a solution of (E)-5,5-bis (4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.0 g) and 3-(3-pyridinyloxy)proPanamine (0.4 g) in tetrahydrofuran (10 mL) was stirred overnight at room temperature. After the usual work up, the crude product was crystallized from ethyl acetate-hexane to give 0.85 g of (E)-5.5-bis(4-methoxyphenyl)-N-[3-[(3-pyridinyl)oxy]propyl]-2,4-pentadienamide, mp 146°-147° C.
Reaction SMILES: ClC1N=CN=C(C(NC2C=CC(S(NCC(OC)=O)(=O)=O)=CC=2C)=O)C=1.C(NC(C)C)(C)C.C1(CNC2CCCCC2)CC1.[CH:45]1([N:51]([CH2:77][CH:78]2[CH2:80][CH2:79]2)[C:52]2[N:57]=[CH:56][N:55]=[C:54]([C:58]([NH:60][C:61]3[CH:66]=[CH:65][C:64]([S:67]([NH:70][CH2:71][C:72]([O:74]C)=[O:73])(=[O:69])=[O:68])=[CH:63][C:62]=3[CH3:76])=[O:59])[CH:53]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.C1(N(CC2CC2)C2N=CN=C(C(NC3C=CC(S(NCC(OCC)=O)(=O)=O)=CC=3C)=O)C=2)CCCCC1>C(O)C>[CH:45]1([N:51]([CH2:77][CH:78]2[CH2:79][CH2:80]2)[C:52]2[N:57]=[CH:56][N:55]=[C:54]([C:58]([NH:60][C:61]3[CH:66]=[CH:65][C:64]([S:67]([NH:70][CH2:71][C:72]([OH:74])=[O:73])(=[O:69])=[O:68])=[CH:63][C:62]=3[CH3:76])=[O:59])[CH:53]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: COC(=O)CNS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)c(C)c1
Agent: C1CCC(NCC2CC2)CC1
Agent: CCOC(=O)CNS(=O)(=O)c1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)c(C)c1
Agent: COC(=O)CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: Cc1cc(S(=O)(=O)NCC(=O)O)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 160 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
A solution of methyl 2-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)acetate (Intermediate 33, 123 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)cyclohexanamine (56.6 mg; 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give a mixture of methyl 2-(4-(6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)acetate and ethyl 2-(4-(6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)acetate which was used directly without any further purification. The residue was redissolved in methanol (10 ml) and tetrahydrofuran (10 ml) and treated with 5 N NaOH solution (1 ml). After stirring at RT for 5 hours the solvent was removed in vacuo. The residue was redissolved in water (10 ml) and acidified with conc. HCl. The aqueous phase was extracted with EtOAc and the organic extracts passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with petroleum ether to yield the title compound as a white solid (136 mg, 87%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:11]=1[C:12]([N:14]=[C:15]=[O:16])=[O:13]>>[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:11]=1[C:12]([NH:14][C:15]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:16])=[O:13]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)cn1

Procedure:
reacting 2-amino-5-chloropyridine with an equimolar amount of 2,6-dichlorobenzoyl isocyanate in a non-reactive organic solvent to obtain 1-(2,6-dichlorobenzoyl)-3-(5-chloro-2-pyridinyl)urea and,
Reaction SMILES: [C:1](=[O:19])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([OH:18])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH:20]1([CH2:23]O)[CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1](=[O:19])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH2:23][CH:20]2[CH2:22][CH2:21]2)[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(O)c1
Reactant: OCC1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(OCC2CC2)c1
Yield: 79.1 %

Procedure:
Tert-butyl 4-tert-butyl-3-hydroxyphenyl carbonate (1.5 g, 5.6 mmol), cyclopropylmethanol (0.5 mL, 6.2 mmol), triphenylphosphine (1.6 g, 6.2 mmol) and diethyl azodicarboxylate (DEAD) (1.0 mL, 6.2 mmol) were treated in the same procedure described in Example 31(a). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (19/1 to 9/1) to furnish 1.42 g (79% yield) of the title compound as a yellow oil.
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[CH2:11]([S:14][C:15]1([C:18]([CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=O)[CH2:17][CH2:16]1)[CH2:12][CH3:13].[OH-].[K+]>C(O)(C)(C)C>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:21]=[CH:20][C:18]1([C:15]2([S:14][CH2:11][CH2:12][CH3:13])[CH2:16][CH2:17]2)[CH2:10][O:9]1
Reactant: COS(=O)(=O)OC
Reactant: CCCSC1(C(=O)C=Cc2ccc(Cl)cc2Cl)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CSC
Product: CCCSC1(C2(C=Cc3ccc(Cl)cc3Cl)CO2)CC1
Reaction time: 14 h
Yield: 89.2 %

Procedure:
30 ml (0.41 mol) of dimethyl sulphide and 43.5 g (0.35 mol) of dimethyl sulphate are added to 60 ml of tert.-butanol and allowed to stand at room temperature for 14 hours. A solution of 40 g (0.13 mol) of 2,4-dichlorophenylethenyl 1-propylmercaptocyclopropyl ketone in 120 ml of tert.-butanol is first added to the reaction mixture with stirring and 39.1 g of potassium hydroxide powder are then introduced, while keeping the temperature of the reaction mixture at 20° to 30° C. The mixture is stirred at 30 C. for 3 hours more, then the dimethyl sulphide is removed under reduced pressure and the reaction mixture is then poured into 70 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted with ethyl acetate. The organic phase is washed with water and concentrated by removing the solvent under reduced pressure after drying over sodium sulphate. In this manner, 38.2 g (91% of theory) of 2-(2,4-dichlorophenylethenyl)-2-(1-propylmercaptocyclopropyl)-oxirane are obtained in the form of an oily product, which is reacted further without additional purification. ##STR73##
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[N+:26]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]2[C:37]=1[NH:36][CH:35]=[C:34]2[CH:38]=O)([O-:28])=[O:27]>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:38]/[C:34]3[C:33]4[C:37](=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=[CH:31][CH:32]=4)[NH:36][CH:35]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: O=Cc1c[nH]c2c([N+](=O)[O-])cccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4c([N+](=O)[O-])cccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 518.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.077 g, 0.022 mmol) in methanol (2.0 mL) was added with 7-nitro-1H-indole-3-carboxaldehyde (0.038 g, 0.020 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(7-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.054 g, 50%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)=[CH:5][N:4]=1.[CH3:22]I.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:22])=[CH:5][N:4]=1
Reactant: CI
Reactant: Cc1nc(Nc2ccc(N(C)C)nc2)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(N(C)c2ccc(N(C)C)nc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-dimethylamino-pyridine-5-yl)-(2-methyl-quinazolin-4-yl)-amine (45 mg, 0.16 mmol), methyl iodide (0.016 ml, 0.24 mmol), sodium hydride (9.6 mg, 0.24 mmol, 60% oil dispersion) in DMF similar to example 21 to give 22 mg (47%) of paint yellow solids. 1H NMR (CDCl3): 8.07 (d, J=2.4 Hz, 1H), 7.63 (dd, J=0.9 Hz, J=8.4 Hz, 1H), 7.56-7.51 (m, 1H), 7.27-7.18 (m, 2H), 7.05-7.00 (m, 1H), 6.50 (d, J=9.3 Hz, 1H), 3.55 (s, 3H), 3.12 (s, 6H), 2.72 (s, 3H).
Reaction SMILES: Cl.[C:2]1([CH:8]2[N:12]3[C:13](=[O:17])[CH2:14][NH:15][CH2:16][CH:11]3[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28]>ClCCl>[CH:27]([NH:30][C:31]([N:15]1[CH2:14][C:13](=[O:17])[N:12]2[C@@H:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10][C@H:11]2[CH2:16]1)=[O:32])([CH3:29])[CH3:28]
Reactant: CC(C)N=C=O
Reactant: O=C1CNCC2CCC(c3ccccc3)N12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NC(=O)N1CC(=O)N2[C@@H](CC[C@@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the HCl salt of racemic-(6R,8aS)-6-phenylhexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (0.25 g, 0.99 mmol) and DIEA (0.345 mL, 1.99 mmol) in dichloromethane (4 mL) at ambient temperature was added isopropyl isocyanate (0.146 mL, 1.48 mmol). The mixture was stirred at ambient temperature for 18 h. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and brine. The EtOAc layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Concentration of appropriate fractions afforded (6R,8aS)-N-isopropyl-4-oxo-6-phenylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide. HPLC RT=2.68 min (Method A); ES MS (M+H)=302.3.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[I:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(C)nc1
Reactant: CN1CCc2[nH]c3ccc(I)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(CCn2c3c(c4cc(I)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15.2 %

Procedure:
To a solution of 8-Iodo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g, 0.0016 mol) in N-methyl 2-pyrolidone (5 mL) was added powdered potassium hydroxide (0.9 g, 0.016 mol) and allowed to stir for 10 min at RT. 2-Methyl-5-vinyl-pyridine (0.969 g, 0.0048 mol) was added and stirred for further 24 hours at 100° C., after completion (TLC), reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×150 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was semi-purified through column chromatography (6% Methanol:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), then further purified by preparative HPLC to get the desired compound as brown solid (0.105 g, 15.2% yield). 8-Iodo-2-methyl-5-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.095 g, 0.00022 mol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.0277 g, 0.00022 mol) in THF (2.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.09 g, 79% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)[CH2:9][CH2:8]1
Reactant: OCCOCCN1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(N2CCN(CCOCCO)CC2)cc1
Temperature: 120 °C
Yield: 67.6 %

Procedure:
A mixture of 54.3 grams (0.61 mol) of N-[2'-(2"-hydroxyethoxy)ethyl]piperazine, 50 grams (0.40 mol) of 4-fluorobenzaldehyde, 50 grams of anhydrous potassium carbonate, and 50 mL of DMSO was heated to 120° C. for four days under nitrogen. After cooling to room temperature, the solution was diluted with one liter of water. The aqueous solution was "processed" as follows. It was extracted with dichloromethane; the separated organic layers were combined and dried over anhydrous magnesium sulfate or sodium sulfate. The organic layer was separated, and solvent was removed on a rotary evaporator under reduced pressure (hereafter these steps will be referred to as "processed" and the product was dried under vacuum overnight to afford 75.3 grams (96%) of 4-[4'-(2"-(2'"-hydroxyethoxy)ethyl)piperazino]benzaldehyde (F).
Reaction SMILES: [CH2:1]([C:4]([CH2:9][OH:10])([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1>>[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]23[O:10][CH2:9][C:4]([CH2:1][CH2:2][CH3:3])([CH2:7][O:8]2)[CH2:5][O:6]3)=[CH:14][CH:13]=1
Reactant: CCCC(CO)(CO)CO
Reactant: O=C(Cl)c1ccc(I)cc1
Product: CCCC12COC(c3ccc(I)cc3)(OC1)OC2

Procedure:
1-(4-Iodophenyl)-4-propyl-2,6,7-trioxabicyclo[2,2,2]octane was prepared from 2-n-propyl-2-hydroxymethyl-propan-1,3-diol and 4-iodobenzoyl chloride using the method described in Example 1 stages (i)-(iii)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.Br[CH2:27][CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:27][CH2:28][CH2:29][N:30]1[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]1=[O:40])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([CH3:25])=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
N,N-Dimethylformamide (3 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (100 mg), 2-(3-bromo-propyl)-isoindole-1,3-dione (242 mg), and potassium carbonate (125 mg), and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (108 mg, yield 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccncn2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cccc(-c2ccncn2)c1
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a suspension of (57) (6.3 g, 31 mmol) in a mixture of MeOH (60 ml) and THF (30 ml) was added 5% palladium on activated carbon (300 mg) and the mixture was hydrogenated at ambient pressure for 1 hr. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column-chromatography on silica gel using a mixture of hexane and ethylacetate (3:1) as the eluent to give (58) (5.1 g, 96%).