Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.[Br:60][C:61]1[C:65]2[N:66]=[CH:67][N:68]=[C:69](Cl)[C:64]=2[S:63][CH:62]=1.CC1(C)C(C)(C)OB([C:79]2[CH:84]=[CH:83][C:82]([OH:85])=[CH:81][CH:80]=2)O1>>[Br:60][C:61]1[C:65]2[N:66]=[CH:67][N:68]=[C:69]([C:79]3[CH:84]=[CH:83][C:82]([OH:85])=[CH:81][CH:80]=3)[C:64]=2[S:63][CH:62]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Clc1ncnc2c(Br)csc12
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: Oc1ccc(-c2ncnc3c(Br)csc23)cc1

Procedure:
The title compound was prepared using similar conditions as described for the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with compound 65A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.27 (s, 1H), 8.73 (s, 1H), 8.08-8.10 (m, 2H), 7.01-7.03 (m, 2H); ESI (−)/MS: 308 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]1([C:33]2([CH2:38][CH2:39][CH2:40][NH2:41])[O:37][CH2:36][CH2:35][O:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.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([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:41][CH2:40][CH2:39][CH2:38][C:33]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:34][CH2:35][CH2:36][O:37]1
Reactant: NCCCC1(c2ccccc2)OCCO1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N1CCc2ccc(Cl)c(NCCCC3(c4ccccc4)OCCO3)c2CC1)C(F)(F)F
Temperature: 95 °C

Procedure:
Place 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (5 g, 11.7 mmol) in toluene (100 mL) with 3-(2-phenyl-[1,3]dioxolan-2-yl)-propylamine (4.85 g, 23.4 mmol), tris(dibenzylideneacetone)dipalladium (0) (1.1 g, 1.17 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binapthyl (5.1 g, 8.19 mmol), palladium acetate (525 mg, 2.34 mmol) and cesium carbonate (5.34 g, 16.38 mmol). Heat for 16 h at 95° C. in a sealed tube. Cool the reaction to RT, dilute with EtOAc (600 mL) and filter. Concentrate the filtrate and chromatograph on silica gel, eluting with 10:90 to 25:75 EtOAc:hexanes to give the title compound contaminated with some colored impurities. Dissolve the residue in 20:80 EtOAc:hexanes (100 mL) and filter to remove solids. Chromatograph the filtrate on silica gel, eluting with 10:90 EtOAc:hexanes to give the title compound as an orange oil (4.32 g, 76%).
Reaction SMILES: C=O.[C:3]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])([CH3:6])([CH3:5])[CH3:4].[CH:12](O)=O.[OH-].[K+]>>[C:3]([N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:12])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)CNC(C)(C)C
Reactant: O=CO
Agent: C=O
Agent: [K+]
Agent: [OH-]
Product: CC(C)CN(C)C(C)(C)C
Temperature: 52.5 °C

Procedure:
A 37% solution of formaldehyde (6.89 g, 85 mmol) was added dropwise to a mixture of tert-butylisobutylamine (10.00 g, 77 mmol) and 88% formic acid (7.85 g, 0.15 mol) at room temperature. The mixture was heated at 50-55° C. for 5 h. Aqueous 8 M potassium hydroxide (12.5 ml, 0.1 mol) was added, the organic layer was separated and the aqueous layer was extracted with n-pentane (50 ml). The extract was combined with the organic layer and dried over anhydrous magnesium sulfate. The product was isolated by distillation to yield 9.25 g, (84%), bp 44-45° C./18 mm Hg; 1H NMR (CDCl3) δ0.85 (d, J=6.7 Hz, 6H, CH3), 1.01 (s, 9H, CH3), 1.64 (nonet, J=6.7 Hz, 1H, CH), 2.02 (d, J=6.7 Hz, 2H, CH2), 2.15 (s, 3H, CH3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Ca+2].[Cl-].[NH4+]>CN(C=O)C>[CH2:9]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(O)cn1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
To a solution of 5-hydroxy-2-methylpyridine (2.18 g, 20 mmol) in DMF (15 ml) were added under ice-cooling benzylbromide (4.00 g, 24 mmol) and calcium carbonate (3.30 g, 24 mmol). The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added an aqueous solution of ammonium chloride. The mixture was extracted with diethyl ether, washed with water, dried and concentrated. The obtained residue was chromatographed on silica gel (n-hexane-ethyl acetate) to give 5-benzyloxy-2-methylpyridine (2.04 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11](/[CH:12]=[C:13]2\[CH2:14][N:15]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:17][CH:18]\2O)=[CH:10][N:9]=[CH:8]1)=[O:5])[CH3:2].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[C:55]([OH:58])(=[S:57])[CH3:56].C(SC1CCN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C/C/1=C\C1N(CC(OCC)=O)C=NC=1)(=O)C>CN(C)C=O>[C:55]([S:57][CH:12]([C:11]1[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:8]=[N:9][CH:10]=1)[C:13]1[CH2:14][N:15]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:16][CH2:17][CH:18]=1)(=[O:58])[CH3:56]
Reactant: CC(O)=S
Reactant: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Agent: CCOC(=O)Cn1cncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cncc1C(SC(C)=O)C1=CCCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 1.5 h
Yield: 29 %

Procedure:
To a solution of (E)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (560 mg) in N,N-dimethylformamide (5 ml) were added N,N-dimethylformamide dineopentyl acetal (2.5 ml) and thioacetic acid (0.6 ml) at room temperature. After being stirred at the same temperature for 1.5 hour, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Solvents were removed under reduced pressure, and residue was purified by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (1:2:2) as an eluent. In a separate run, further starting material (E)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (1.0 g) was subjected to the similar reaction/purification procedure. Both products were combined to afford an approximately 5:2 mixture of (E)-4-(acetylsulfanyl)-3-{[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine and 5-{(acetylsulfanyl)[1-(ethoxycarbonylmethyl)-1H-imidazol-5-yl]methyl}-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine (500 mg, gross yield: 29%), as a yellow amorphous solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Br:9][CH2:10][CH2:11]Br.[OH-].[K+]>CO>[Br:9][CH2:10][CH2:11][O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1cccc(O)c1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1cccc(OCCBr)c1

Procedure:
A mixture of resorcinol (88 g), 1,2-dibromoethane (180 g) and potassium hydroxide (44.8 g) was stirred under reflux in methanol (600 ml) for 24 hours. The reaction mixture was cooled. The residual solid was removed by filtration and the filtrate was evaporated to give 3-(2-bromoethoxy)phenol as an oil which was essentially pure as indicated by TLC [using silica plates and 10% v/v methanol in dichloromethane as eluant] and was used without purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]([CH3:31])=[C:6]([C:23]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH3:30])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].ClS([N:36]=[C:37]=[O:38])(=O)=O.O.C(OC(C)C)(C)C.CCCCCC>C1C=CC=CC=1>[NH2:36][C:37]([O:1][CH2:2][C:3]1[NH:4][C:5]([CH3:31])=[C:6]([C:23]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH3:30])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:38]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOCCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCOCCOC(=O)C1=C(C)NC(COC(N)=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
2-Hydroxymethyl-6-methyl-4-(3-nitrophenyl)-3-ethoxycarbonyl-5-(β-ethoxyethoxy)carbonyl-1,4-dihydropyridine (420 mg) was dissolved in benzene (20 ml), chlorosulfonyl isocyanate (0.2 ml) was added thereto, and the mixture was reacted under stirring at room temperature for 30 minutes. Water (10 ml) was added to the reaction mixture under cooling, and the mixture was stirred at room temperature for 30 minutes for hydrolysis. The reaction mixture thus obtained was extracted with ethyl acetate, and the extracted solution was washed with water, dried and then concentrated under reduced pressure. The residue was recrystallized from diisopropyl ether/hexane, whereupon crystals (290 mg, yield: 62.6%) were obtained.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH2:7][CH2:8][CH3:9])[NH:5][CH:6]=1.[N:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH2:7]([C:4]1[NH:5][CH:6]=[C:2]([C:13]2[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=2)[N:3]=1)[CH2:8][CH3:9]
Reactant: CCCc1nc(I)c[nH]1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1nc(-c2ccncc2)c[nH]1
Yield: 37 %

Procedure:
[step 1] 4-Iodo-2-propylimidazole obtained in Reference Example A16 was dissolved in dioxane/water (2 mL/1 mL), 4-pyridineboronic acid (0.108 g, 0.889 mmol), 1,1-bisdiphenylphosphinoferrocene dichloropalladium (0.052 g, 0.064 mmol) and sodium carbonate (0.202 g, 1.91 mmol) were added, and the mixture was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give 2-propyl-4-(4-pyridyl)imidazole (0.044 g, 37%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[H-].[Na+].Br[CH2:28][CH2:29][O:30][CH3:31]>C(OCC)(=O)C.O>[C:1]([O:5][C:6]([N:8]([CH2:28][CH2:29][O:30][CH3:31])[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCBr
Reactant: CCOC(=O)c1cccc(NC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(N(CCOC)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
To a mixture of ethyl 3-[(tert-butoxycarbonyl)amino]benzoate (3.8 g) and DMF (20 ml) were added 60% sodium hydride (1.1 g) and 2-bromoethylmethyl ether (3.9 g) under ice-cooling, followed by stirring at room temperature over one night. To the reaction mixture were added 60% sodium hydride (0.28 g) and 2-bromoethylmethyl ether (0.98 g), followed by stirring at room temperature for 6 hours. Water and ethyl acetate were added thereto, and the organic layer was then separated, washed with 1 M hydrochloric acid and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl 3-[(tert-butoxycarbonyl)(2-methoxyethyl)amino]benzoate (2.7 g).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH:7]=[C:6]([OH:18])[N:5]=1)([CH3:3])[CH3:2].Cl.Cl[CH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2.Cl.ClCC1C(NCCOC)=NC2C(C=1)=CC(OC)=CC=2.[Li+].[OH-]>C1COCC1>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([CH2:21][C:22]2[CH:23]=[N:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:6]([OH:18])[N:5]=1)([CH3:3])[CH3:2]
Reactant: COc1cc2cc(O)nc(C(C)C)c2cc1OC
Reactant: ClCc1cnc2ccccc2c1
Agent: COCCNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(C(C)C)nc(O)c(Cc3cnc4ccccc4c3)c2cc1OC
Temperature: 25 °C

Procedure:
To a solution of 1-isopropyl-6,7-dimethoxyisoquinolin-3-ol SIL 32164 (462 mg, 1.87 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 3-(chloromethyl)quinoline hydrochloride SLA 47064B (400 mg, 1.87 mmol) and a 2 N aq. LiOH solution (1.87 mL, 3.74 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) provided 1-isopropyl-6,7-dimethoxy-4-(quinolin-3-ylmethyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 1-isopropyl-6,7-dimethoxy-4-(quinolin-3-ylmethyl)isoquinolin-3-ol dihydrochloride 79 as a yellow solid (76 mg, 9% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14](Br)[N:13]=1.N#N.CC(C)([O-])C.[Na+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O.O1CCOCC1>[Br:11][C:12]1[N:13]=[C:14]([NH:1][C:2]2[CH:7]=[C:6]([CH:8]3[CH2:10][CH2:9]3)[CH:5]=[CH:4][N:3]=2)[CH:15]=[C:16]([CH3:18])[CH:17]=1
Reactant: Cc1cc(Br)nc(Br)c1
Reactant: Nc1cc(C2CC2)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Br)nc(Nc2cc(C3CC3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A dry round bottomed flask was charged with 2-amino-4-cyclopropylpyridine (5.00 g, 31.7 mmol) and 2,6-dibromo-4-methylpyridine (7.95 g, 31.7 mmol). The reaction vessel was placed under an atmosphere of nitrogen (3× vacuum/N2 cycle), then 1,4-dioxane (100 mL) was added and the mixture was degassed with a steady stream of nitrogen for 30 minutes. Sodium tert-butoxide (3.35 g, 34.8 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.49 g, 0.75 mmol) were added to the reaction flask, then the reaction was stirred at room temperature for 15 minutes then heated to 50° C. for five hours. After cooling to room temperature for 14 hours, the resulting reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were further washed with water and brine (200 mL portions). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield an oil. The crude product was purified by silica gel chromatography (0-30% ethyl acetate/hexanes) to give the title compound as a brown solid. 1H NMR (600 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.06 (d, J=5.3 Hz, 1H), 7.70 (s, 1H), 7.23 (s, 1H), 6.92 (s, 1H), 6.61 (dd, J=1.4, 5.3 Hz, 1H), 2.25 (s, 3H), 1.91-1.78 (m, 1H), 1.09-0.98 (m, 2H), 0.82-0.66 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[C:8]([O:14][CH3:15])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+]>CCOC(C)=O.O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[C:7]([CH:6]=1)[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 29 %

Procedure:
To a suspension of 5-tert-butyl-2-methoxy-1,3-dinitrobenzene (10.2 g, 0.04 mol) in EtOAc (150 mL) was added in a single portion a solution of sodium sulfide nonahydrate (19.2 g, 0.08 mol) in water (200 mL). Aliquat® 336 (0.8 g, 5 mole %) was added in a single portion, and the two-phase mixture was brought to a reflux. All solids dissolved, and the mixture became red/brown. After about 3 h, TLC (3:1 hexanes:EtOAc) revealed almost complete loss of starting material. The mixture was filtered warm through a pad of diatomaceous earth to remove insolubles, and the filter cake was washed with fresh EtOAc. The clarified two-phase mixture was separated, and the organic layer was washed with sodium carbonate solution, followed by water and then saturated sodium chloride solution. After drying over magnesium sulfate, the solution was concentrated under reduced pressure to a thick, dark oil. This oil was extracted three times with refluxing hexanes, leaving behind a dark residue. The orange extract deposited some more dark oil, from which the warm supernatant was decanted. The resulting orange solution was heated back to reflux, and treated with both activated charcoal and diatomaceous earth. The solution was filtered hot, and the filter cake washed with hot hexanes. Re-heating the orange filtrate resulted in a clear solution. Quickly cooling the solution in an ice/acetone bath and scratching the flask with a glass rod resulted in the deposition of an orange/yellow precipitate. The suspension was allowed to cool for 1 h, and then filtered. The filter cake was washed with a small portion of cold hexanes, and then dried on the filter, providing the title compound as a yellow/orange powder (2.6 g, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16](I)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(I)c1OC
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cc(Cc2cnc(N)nc2N)cc(C=Cc2ccccc2)c1OC
Temperature: 0 °C
Yield: 53.7 %

Procedure:
A mixture of 500 mg of 5-(3,4-dimethoxy-5-iodo-benzyl)pyrimidine-2,4-diamine, 1.53 g of styrene, 1.46 g of triethylamine and 31 mg of palladium-(II) acetate in 25 ml of dioxan is held at reflux under argon for 14 hrs. The mixture is poured on to ice-water, adjusted to pH 5 to 7 with 3N aqueous hydrochloric acid and extracted with methylene chloride. The organic phase is dried over magnesium sulphate, concentrated and the residue is chromatographed on silica gel with methylene chloride/methanol 97:3. 252 mg (53%) of 5-(3,4-dimethoxy-5-styryl-benzyl)pyrimidine-2,4-diamine are isolated as an orange solid. M.p.226°.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)C>CS(C)=O>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[CH:25]1[CH2:30][CH2:29][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:27][CH2:26]1
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Solvent: CCO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 5-chloro-3-(piperidin-4-yl)-1H-indole using ethanol as the reaction solvent. Yield 0.380 g (42%) as a yellowish foam. mp 109°-114° C. (dec) FDMS m/e=423 (M+ of free base). α[D]589 =+6.5 (c=1.04, dimethylsulfoxide).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1.C(Cl)(Cl)Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[O:37])[CH:34]([CH3:35])[CH3:36])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1

Procedure:
Example 36 was prepared from 1-(4-fluoro phenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.33 (dd, 2H, J=5.8, 3.6 Hz,), 7.29–7.26 (m, 2H), 7.25–7.20 (m, 1H), 7.02–6.95 (m, 2H), 6.93 (d, 1H, J=7.1 Hz), 6.54–6.49 (m, 1H), 3.26 (q, 2H, J=6.5 Hz), 3.22–3.14 (m, 1H), 2.90 (d, 1H, J=12.0 Hz), 2.55–2.37 (m, 4H), 2.29 (t, 2H, J=6.5 Hz), 2.06 (s, 4H), 2.00–1.90 (m, 3H), 1.82–1.75 (m, 4H), 1.73–1.66 (m, 3H), 1.65–1.57 (m, 4H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 494.3 (M+H)+; Anal. Calc. for C30H40FN3O2.0.10 CHCl3.0.650 DMF: C, 70.92; H, 8.27; N, 8.64. Found: C, 70.83; H, 8.11; N, 8.93.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:27])=[CH:23][CH:24]=3)[C:19](=O)[N:18]2[CH3:29])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].O.[Na]>C1COCC1>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:27])=[CH:23][CH:24]=3)[CH2:19][N:18]2[CH3:29])=[CH:15][CH:16]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1ccc2c(c1)C(=O)N(C)C(c1ccc(C(C)(C)C)cc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)CN(C)C(c1ccc(C(C)(C)C)cc1)C2
Yield: 89.7 %

Procedure:
To 70 ml of a suspension containing 1.28 g of lithium aluminum hydride in THF, 30 ml of a solution containing 4.93 g of 3-(4-tert-butylphenyl)-2,7-dimethyl-1,2,3,4-tetrahydroisoquinoline-1-one in THF was added and the resulting mixture was heated to reflux for 14 hours.After the reaction, 1.28 g of water, 1.28 g of 15% aqueous sodium hydroxidesolution and 3.84 g of water were sequentially added in the order mentionedwhile cooling the mixture in ice and the generated precipitates were removed by filtration. The filtrate was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residuewas purified by column chromatography on silica gel (hexane/ethyl acetate=9/1 v/v) to obtain 4.22 g of 3- (4-tert-butylphenyl ) -2,7-dimethyl-1.2,3,4-tetrahydroisoquinoline.