Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][C:25]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:27]=2)[CH2:22][NH:21][C:20]1=[O:36]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][C:25]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:27]=3)[CH2:22][NH:21][C:20]2=[O:36])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NCc2cc(Cc3ccccc3)ccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2cc(Cc3ccccc3)ccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 159-166° C. C27H25N3O3F2 (MW=477); mass spectroscopy: 477.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([O:21]CC=C)=O)=[N:7][C:6]=2[CH:25]=1.NC[C@@H]1[C@H](C)CCCN1C([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[N:44]1[N:48]=[C:47]([CH3:49])[CH:46]=[N:45]1)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([NH:10][CH2:11][C@@H:12]3[C@H:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]3[C:19]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=3[N:44]3[N:48]=[C:47]([CH3:49])[CH:46]=[N:45]3)=[O:21])=[N:7][C:6]=2[CH:25]=1
Reactant: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanone. ESI-MS (m/z): 479 [M+1]+.
Reaction SMILES: C(O[C:10]1[C:18]2[CH:17]=[C:16]([C:19](=[O:21])[CH3:20])[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-:23].[K+].[K+].[OH-].[Na+]>O1CCCC1>[OH:23][C:11]1[CH:12]=[CH:13][C:14]2[S:15][C:16]([C:19](=[O:21])[CH3:20])=[CH:17][C:18]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc2c(OC(=O)c3ccccc3)cccc2s1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)c1cc2cc(O)ccc2s1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 2-acetylbenzo[b]thiophen-4-yl benzoate (0.13 g), potassium carbonate (0.18 g), tetrahydrofuran (25 ml) and 5M aqueous sodium hydroxide solution (10 ml) was heated under reflux for 1 hour, then cooled to ambient temperature and concentrated in vacuo. The aqueous residue was acidified by the addition of 5M hydrochloric acid (20 ml), then the product was extracted into dichloromethane (2×25 ml). The combined extracts were washed with water (20 ml), 10% aqueous sodium hydrogencarbonate solution (3×20 ml) and water (2×20 ml), then dried (MgSO4) and the solvent was removed in vacuo to give 1-(5-hydroxybenzo[b]thiophen-2-yl]ethan-1-one (0.07 g) as a yellow solid which was used without further purification.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(=[O:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NNc1ccc(N)cc1
Yield: 74.7 %

Procedure:
Then, 16.6 g of 1-acetyl-2-(4-nitrophenyl)hydrazine was catalytically reduced in 800 ml of ethanol at room temperature using palladium-carbon as a catalyst. The reaction mixture was filtered and cooled to provide 10.5 g of 1-acetyl-2-(4-aminophenyl)hydrazine. The yield was 75% and the melting point was 130°-140° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]1)=[O:8])[CH3:5]>C(O)C>[CH3:5][N:4]([CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)=[O:8])[CH3:3]
Reactant: CCOC(=O)C1CCN(C(=O)CN(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CC(=O)N1CCC(C(=O)O)CC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 105.6 %

Procedure:
25 cm3 of a 1 N aqueous sodium hydroxide solution are added, at 20° C., to 4.5 g of ethyl 1-(dimethylaminoacetyl)piperidine-4-carboxylate in solution in 50 cm3 of ethanol. After stirring for 16 hours at 50° C., the ethanol is removed under reduced pressure (2.7 kPa) and the residual aqueous phase is extracted with 50 cm3 of ethyl acetate. The aqueous phase is then brought to pH 6 by addition of 1 N hydrochloric acid, and is then concentrated to dyrness under reduced pressure (2.7 kPa). Twice, the residue is covered with 50 cm3 of toluene and dried under reduced pressure (2.7 kPa). The residue is taken up in 50 cm3 of ethanol at 50° C. and the insoluble matter is removed by filtration. The filtrate is concentrated under reduceed pressure (2.7 kPa) to give 4.2 g of 1-(dimethylaminoacetyl)piperidine-4-carboxylic acid in the form of a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]2[CH2:11][O:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:12].CO>>[NH2:12][CH2:11][CH:9]([OH:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: c1ccc(CCC2CO2)cc1
Solvent: CO
Product: NCC(O)CCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
2-(2-phenylethyl)oxirane (8.0 g, 54 mmol) was placed in a sealed tube with 7N NH3-MeOH (130 mL) and stirred 2 hours at 70° C. followed by concentration to a clear oil (and was used without further purification in the following step.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[N:10]([C@H:12]([C:14](=[O:24])[NH:15][C:16]1[C:17](=[O:23])[NH:18][C:19]([Br:22])=[CH:20][CH:21]=1)[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Li+].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH2:43]Cl)[CH:42]=2)=[O:36])=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C>O(C(OC)C)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:25])[N:10]([C@H:12]([C:14](=[O:24])[NH:15][C:16]1[C:17](=[O:23])[N:18]([CH2:43][C:41]2[CH:40]=[N:39][CH:38]=[C:37]([C:35](=[O:36])[C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)[CH:42]=2)[C:19]([Br:22])=[CH:20][CH:21]=1)[CH3:13])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1cncc(CCl)c1
Reactant: C[C@@H](C(=O)Nc1ccc(Br)[nH]c1=O)N(C)C(=O)OCc1ccccc1
Agent: COC(C)OC
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](C(=O)Nc1ccc(Br)n(Cc2cncc(C(=O)c3ccc(F)cc3)c2)c1=O)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
To a solution of [(S)-1-(6-bromo-2-oxo-1,2-dihydro-pyridin-3-ylcarbamoyl)-ethyl]-methyl-carbamic acid benzyl ester (1C) (100 mg, 0.25 mmol) in dimethoxylethane (DME) (3 mL) at room temperature, is added lithium iodide (36 mg, 0.27 mmol) in one portion. After being stirred at room temperature for 5 minutes, to the reaction mixture, is added 4-fluoro-phenyl-(5-chloromethyl-pyridin-3-yl)-methanone (IF) (80 mg, 0.32 mmol) in one portion. After being stirred at room temperature for 5 minutes, to the reaction mixture, is added drop wise diisopropylethylamine (DIPEA) (0.09 mL, 0.50 mmol). The reaction mixture is stirred at 60□C for 6 hours. The reaction solution is diluted with ethyl acetate (EtOAc) (30 mL) and washed with 2×8 mL of water. After concentration, the crude product is purified by chromatography (heptanes 60%, EtOAc 40%) to give ((S)-1-{6-bromo-1-[5-(4-fluoro-benzoyl)-pyridin-3-ylmethyl]-2-oxo-1,2-dihydro-pyridin-3-ylcarbamoyl}-ethyl)-methyl-carbamic acid benzyl ester (1D) (95.7 mg, yield 63%) as light yellow solid, MS (ESI) m/e 621.2, 623.3 (M+H+).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:37]5[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Reactant: C1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCCCC1
Temperature: 60 °C
Yield: 17.1 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 79A (225 mg, 0.426 mmol) in DMF (3 mL) was added piperidine (0.126 mL, 1.278 mmol) followed by diisopropyl ethylamine (0.222 mL, 1.278 mmol) and tetrabutyl ammonium iodide (157.35 mg, 0.426 mmol). The reaction mixture was heated at 60° C. for 2 days. Formation of product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea (42 mg, 17%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.20 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.22 (m, 5H), 6.45 (s, 1H), 4.30 (m, 2H), 3.95 (s, 3H), 2.85-2.30 (m, 6H), 1.70-1.30 (m, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:12][CH:13]([N:15]1[C:28]2[CH:27]=[C:26]([C:29]#[N:30])[CH:25]=[CH:24][C:23]=2[S:22][C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])(=O)=O>C1(C)C(C)=CC=CC=1>[N:1]1([CH2:14][CH:13]([N:15]2[C:28]3[CH:27]=[C:26]([C:29]#[N:30])[CH:25]=[CH:24][C:23]=3[S:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: Cc1ccccc1C
Product: CC(CN1CCCCC1)N1c2ccccc2Sc2ccc(C#N)cc21

Procedure:
Piperidine (19.8 cc) is added to a suspension of 2-(2-cyano-10-phenothiazinyl)-1-propyl methane-sulphonate (36.05 g) in xylene (360 cc). The mixture is brought to reflux for 19 hours. After cooling, the mixture is washed with distilled water (6×150 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa). The residue is purified by chromatography on a column (height: 96 cm; diameter: 4.8 cm) of silica gel (0.06-0.2 mm), eluting with 90:10, 85:15, 80:20 and 75:25 (by volume) mixtures (4 liters, 4 liters and 4 liters, respectively) of cyclohexane and ethyl acetate and collecting 500- cc fractions. The first 9 liters are discarded and fractions 8 to 13 are combined and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give 10 -[(2RS)-1-piperidino-2-propyl]-2-phenothiazinecarbonitrile (13.6 g).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[Br-].[CH3:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[Zn+].C1COCC1>CCOC(C)=O.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]>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:21]3[S:22][CH:23]=[CH:24][C:20]=3[CH3:19])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1ccsc1[Zn+]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sccc3C)c(C)nc12
Temperature: 65 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To mixture of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (12.0 g, 34.96 mmol) and PdCl2(dppf) (1.28 g, 1.75 mmol) is added a 0.5 M solution of 3-methyl-2-thienylzinc bromide in THF (100 mL, 50.0 mmol). The mixture is stirred at 65° C. overnight, diluted with EtOAc (500 mL), washed with 10% citric acid (500 mL), water (400 mL), brine (400 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (10%-20% EtOAc/hexane gradient) furnish the title compound (8.83 g, 28.17 mmol, 81%). 1H NMR (CDCl3), δ 0.92 (t, J=7.4 Hz, 6H), 1.78-1.95 (m, 4H), 2.18 (s, 3H), 2.50 (s, 3H), 2.54 (s, 3H), 3.33-3.43 (m, 1H), 6.69 (s, 1H), 7.06 (d, J=4.9 Hz, 1H), 7.46 (d, J=4.9 Hz, 1H). LC/MS (m/z): calcd. for C18H23N3S (M+H)+: 314.6; found: 314.2.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:20])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[O:14]1>COCCOC>[CH3:3][O:4][C:5](=[O:20])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH:17][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])[O:14]1
Reactant: COC(=O)CCCCCCCC1CCC(C=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCC(=O)C=CC1CCC(CCCCCCCC(=O)OC)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 144.4 %

Procedure:
50% sodium hydride in mineral oil (1.11 g, 0.0230 mole) was suspended in 1,2-dimethoxyethane (115 ml). At 15° C and under vigorous stirring (2-oxoheptyl)-phosphoric acid dimethyl ester (5.11 g, 0.0230 mole) in dimethoxyethane (23 ml) was added dropwise over a period of 15 minutes. The reaction mixture containing a white voluminous precipitate was stirred for 1 hour at room temperature. A solution of crude II (7.20 g), prepared from I (7.55 g, 0.0250 mole), in 1,2-dimethoxyethane (46 ml) was added dropwise over a period of 15 minutes to the stirred reaction mixture, maintained below 25° C. The resulting turbid, yellow solution was stirred at room temperature for 2 hours. The solvent was distilled off from a water bath (40° C, 10 mm Hg). The oily residue was dissolved in ether (230 ml), washed with cold 10% aqueous sodium chloride (60 + 60 + 60 ml) and cold water (60 + 60 ml), and dried over sodium sulfate. After filtration, the solvent was removed from a water bath (60° C, 10 mm Hg). The residual light tea-coloured oil (9.60 g) was distilled under nitrogen to give 7.15 g (81%) of III as a light yellowish oil, b0.05 160°-190° C, nD25 1.4712.
Reaction SMILES: C(C(N=C=O)CCC)CC.NC(CCC)CCC.[CH2:19]([C:21]([N:28]=C=O)([CH2:25][CH:26]=[CH2:27])[CH2:22][CH:23]=[CH2:24])[CH3:20].C(#N)CC.C([Mg]Br)C=C.CCOCC.[NH4+].[Cl-]>CCOCC>[CH2:19]([C:21]([NH2:28])([CH2:25][CH:26]=[CH2:27])[CH2:22][CH:23]=[CH2:24])[CH3:20]
Reactant: C=CCC(CC)(CC=C)N=C=O
Agent: C=CC[Mg]Br
Agent: CCCC(CCC)N=C=O
Agent: CCCC(N)CCC
Solvent: CCOCC
Solvent: CCC#N
Product: C=CCC(N)(CC)CC=C
Yield: 34 %

Procedure:
1-Propylbutyl isocyanate: This intermediate was prepared from commercially available 4-aminoheptane by the procedure of V. S. Goldesmidt and M. Wick, Liebigs Ann. Chem., 575, 217 (1952). (b) 1-Ethyl-1-(2-propenyl)-3-butenyl isocyanate: A solution of propionitrile (14.5 g, 264 mmol) in dry Et2O (40 mL) was added dropwise to 1.0M allyl magnesium bromide/Et2O (880 mL). The reaction mixture was mechanically stirred at reflux for 2 h, after which time it was cooled to 0°. A saturated aqueous solution of NH4Cl (320 mL) was added cautiously to the cooled reaction mixture. The organic phase was separated, dried (MgSO4), cooled to 0° and then mixed at the same temperature with 1M HCl/Et2O (200 mL). The resulting solid was collected and dried under reduced pressure (ca 27 g). The latter material dissolved in CH2Cl2 (200 mL). The solution was washed with a 10% aqueous solution of Na2CO3 (2 X) and then brine, dried (MgSO4) and concentrated to dryness to afford a yellow oil. The oil was distilled (82°-85°/20 Torr) to give 1-ethyl-1-(2-propenyl)-3-butenylamine as a colorless liquid (11.6 g, 34%); 1H NMR(CDCl3) δ0.89 (t, J=7Hz, 3H), 1.39 (q, J=7 Hz, 2H), 2.11 (d, J=7 Hz, 2H), 5.06-5.14 (m, 4H), 5.80-5.89 (m, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:7]([C:8]4[CH:9]=[CH:10][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][CH:13]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: CC(C)(C)c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1ccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4ccc(C(C)(C)C)cc4)cc3)cc2)cc1
Yield: 41.6 %

Procedure:
8.1 g (0.036 mol) of N-phenyl-p-tertiarybutylaniline, 7.3 g (0.018 mol) of 4,4'-diiodobiphenyl, 7.5 g (0.054 mol) of anhydrous potassium carbonate, and 0.53 g (0.008 mol) of copper powder were mixed. The mixture was then allowed to undergo reaction at a temperature of 210° to 225° C. for 12 hours. The reaction product was then extracted with 70 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to obtain an oily material. The crude product thus obtained was then purified by column chromatography (carrier: silica gel; elute: 1/4 mixture of toluene and n-hexane) to obtain 4.5 g (yield: 41.7%) of N,N'-bis(p-tertiarybutylphenyl)-N,N'-diphenylbenzidine. The melting point of the product was from 232.2° C. to 232.6° C.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([Cl:17])[N:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1>C1COCC1.[Li+].[OH-].O>[Cl:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:18])=[O:2])=[CH:9][CH:8]=2)[CH:16]=1
Reactant: COC(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Nc2cc(Cl)ncn2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(6-Chloro-pyrimidin-4-yl-amino)-benzoic acid methyl ester, (0.1 g, 0.38 mmol) in THF (3 mL), LiOH×H2O (0.017 g, 0.42 mmol) dissolved in H2O (1 mL) was added and the mixture stirred at room temperature for 18 h. The reaction mixture was then diluted with H2O (5 mL) and extracted with EtOAc (2×). The water layer was acidified (2.5M HCl) and extracted with EtOAc (3×). The combined organic layers were dried (MgSO4) and the solvent evaporated under reduced pressure to afford 4-(6-Chloro-pyrimidin-4-yl-amino)-benzoic acid, as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[CH2:20][CH2:19][CH2:18][C:12]=3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)=[O:4].[Mg]>CO.C1COCC1>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)=[O:4]
Reactant: COC(=O)CCc1ccc2c3c(c(=O)[nH]c2c1)CCC3
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCc1ccc2c(c1)NC(=O)C1CCCC21
Temperature: 25 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
A solution of 550 mg (2.0 mmol) of 7-(methoxycarbonylethyl)-1,2,3,5-tetrahydrocyclopenta[c]-quinolin-4-one in 130 ml of methanol-THF 3:1 is mixed with 972 mg (40.0 mmol) of magnesium and stirred for 24 hours at room temperature. The reaction mixture is filtered over glass fibers, the filter residue is washed with dichloromethane-methanol, and the combined filtrates are concentrated by evaporation in a vacuum. Purification of the residue on silica gel yields 120 mg of product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:28][CH2:29]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:20][CH:21]3[CH2:22][O:23][CH2:29][CH2:28][O:24]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3=[N:17][CH:18]=[CH:19][N:9]23)=[CH:4][CH:3]=1
Reactant: OCC(O)CC1(c2ccc(Br)cc2)c2ccccc2-c2nccn21
Reactant: ClCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: Brc1ccc(C2(CC3COCCO3)c3ccccc3-c3nccn32)cc1
Temperature: 55 °C

Procedure:
To a mixture of 3-[5-(4-bromophenyl)-5H-imidazo[2,1-a]isoindol-5-yl]propane-1,2-diol (30 mg) and tetrabutylammonium bromide (30 mg) in 1,2-dichloroethane (1.125 mL) was added aqueous NaOH (35%, 1.5 mL) and heated at 55° C. for 17 h. After cooling to room temperature the reaction mixture was diluted with water and extracted with CH2Cl2 (3×). Combined organic layers were dried over Na2SO4 and concentrated. Purification by reversed phase HPLC (21×100 mm Phenomenex Gemini, 15-75% MeCN/water containing 0.05% NH4OH over 20 min at 20 mL/min) to give title compound as a slightly impure solid which was then repurified by flash chromatography using EtOAc as eluent to give desired product as a white solid. HRMS. Found, 411.0681; calcd for (M+H)+, 411.0703. 1H NMR (500 MHz, CDCl3): δ 7.89-7.83 (m, 2 H); 7.45-7.26 (m, 5 H); 7.15 (d, J=7.71 Hz, 0.5 H); 7.02 (s, 0.5 H); 7.00-6.92 (m, 3 H); 3.53-3.40 (m, 3 H); 3.36-2.97 (m, 4 H); 2.76 (dd, J=14.88, 5.92 Hz, 0.5H); 2.68 (dd, J=14.78, 5.44 Hz, 0.5 H); 2.47 (ddd, J=29.48, 14.82, 4.79 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([N:41]1[CH:45]=[C:44]([CH2:46][CH2:47][C:48](O)=[O:49])[N:43]=[CH:42]1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O.CO.CCCCCC>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:48](=[O:49])[CH2:47][CH2:46][C:44]3[N:43]=[CH:42][N:41]([C:22]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:45]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 62 %

Procedure:
Preparation of example 51 from the title compound of Example 7 (hydrochloride) (31 mg, 0.10 mmol), 3-(1-Trityl-1H-imidazol-4-yl)-propionic acid (46 mg, 0.12 mmol), triethylamine (0.021 mL, 0.15 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (46 mg, 0.12 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (3% triethylamine in 5:4:1 hexane:CH2Cl2:methanol), also in an analogous manner, afforded the title compound (40 mg, 0.062 mmol) as a yellow powder in 62% yield.