Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]=1[C:7]([O:9]CC1C=CC=CC=1)=[O:8]>CC(N(C)C)=O.[Pd]>[CH3:1][C:2]1[NH:3][CH:4]=[C:5]([NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1[nH]cc(NC(=O)c2ccccc2)c1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: Cc1[nH]cc(NC(=O)c2ccccc2)c1C(=O)O
Reaction time: 1.17 h

Procedure:
25.8 g (0.01 mol) of the compound obtained in Example 28 are dissolved at room temperature, with stirring, in 150 ml of dimethylacetamide. After the addition of 5 g of palladium-containing carbon (5% Pd on activated carbon), hydrogenation is carried out at an excess pressure of 4 bar. After 70 minutes, the absorption of hydrogen is complete. The catalyst is filtered off and the reaction mixture is concentrated to a residue in vacuo. The residue is then dissolved in 300 ml of methanol. After treatment with activated carbon, the solution is stirred into ice-water. The resulting precipitate is filtered off and dried until the weight is constant.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=3)[CH:19]=[CH:18]2)=[CH:6][CH:7]=1.[CH2:10]([N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][C:27]([OH:29])=[O:28])[CH:24]=2)[CH:19]=[CH:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(Cc3ccc(Cl)nc3)c2c1

Procedure:
The titled compound (26 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2-chloro-5-(chloromethyl)pyridine according to the method of the process (7) of Example 4.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH3:22])[C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH3:22])[C:14]3[CH:15]=[C:16]([NH:21][C:13](=[O:12])[CH2:14][C:10]([CH3:22])([CH3:11])[CH3:7])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(N)cc2c(c1C)OCC2(C)c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OCC2(C)c1ccc(C(C)C)cc1
Yield: 59 %

Procedure:
Using 3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 35, the title compound was synthesized in the same manner as in Example 1. Yield: 59%. Melting point: 132-133° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([O:9][C@H](CC1C=C(C)C2C(=CN(COCC[Si](C)(C)C)N=2)C=1)C(OC)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.CO.O>[C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)OC(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-1-methoxy-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxopropan-2-yl benzoate (14.2 g, 30.3 mmol) in tetrahydrofuran (80 mL) and methanol (80 mL) at 0° C. was added a solution of lithium hydroxide monohydrate (5.09 g, 121 mmol) in water (80 mL). The reaction was stirred at 0° C. for 1 h. The ice bath was removed and stirring continued at room temperature for 2 h. The reaction was concentrated, dissolved in water (5 mL), cooled to 0° C., and treated with 1M hydrochloric acid until mildly acidic. A non-solid ppt formed. The suspension was extracted with ethyl acetate (3×), which were washed with brine, dried over magnesium sulfate, and concentrated to give the crude hydroxy acid as an oil with white solid forming in it (probably residual benzoic acid) which was used without purification. Mass spec.: 349.34 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH2:11][CH:12](C)C=C)(=[O:10])=[O:9])[CH:3]=1.C([Li])CCC.CI.B.[O:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.OO>O1CCCC1.O>[CH3:25][CH:26]([CH:11]([S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)(=[O:9])=[O:10])[CH3:12])[CH2:27][CH2:28][OH:24]
Reactant: C=CC(C)CS(=O)(=O)c1cccc(C)c1
Reactant: C1CCOC1
Agent: B
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: CI
Product: Cc1cccc(S(=O)(=O)C(C)C(C)CCO)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1-Methyl-3-(2-methylbut-3-ene-1-sulphonyl)benzene (444 mg, 1.96 mmol) was dissolved in tetrahydrofuran (5 ml) and cooled to −78° C. n-Butyllithium (1.6M in hexanes, 1.96 mmol) was added. The reaction was treated with methyl iodide (130 μL, 2.16 mmol) and allowed to warm to room temperature. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo to give a 1:1 mixture of dimethyl diastereoisomers containing approximately 28% monomethyl starting material. This crude mixture (265 mg, 1.12 mmol) was dissolved in tetrahydrofuran (3 ml) at 0° C. and treated with borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 4.5 ml, 4.5 mmol) then allowed to warm to room temperature and stirred for 6 hours. The reaction was treated cautiously with pre-mixed hydrogen peroxide 35% w/w (5 ml) and water (5 ml) and stirred for 18 hours. The reaction mixture was extracted with ethyl acetate and the combined organic layers were concentrated in vacuo to give a clear oil which was purified by preparative thin layer chromatography, eluting with 25% ethyl acetate/i-hexane to give a 1:1 mixture of diastereoisomers that was used in the next step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN(c2ccc(Cl)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cs1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.8 %

Procedure:
2-{[4-(2-{(4-Chlorophenyl)[(2-nitrophenyl)sulfonyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (1.2 g) synthesized in Example 286-1 and thiophenol (0.26 mL) were dissolved in N,N-dimethylformamide (12 mL), potassium carbonate (0.88 g) was added, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 3:1) to give the title compound (0.52 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[OH:11].[H-].[Na+].FC(F)(F)S(O[CH2:20][C:21]([F:24])([F:23])[F:22])(=O)=O.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:11][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:9]=[O:10]
Reactant: COc1cc(C=O)ccc1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCC(F)(F)F
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a solution of 3.96 g of vaniline (e-1) (26.0 mmol) in 26 ml of dry DMF was added 1.04 g of 60% NaH (26.0 mmol) slowly, and the mixture was stirred for 30 min. in a stream of nitrogen. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (6.64 g: 28.6 mmol) was added dropwise to the mixture and stirred overnight at room temperature. The reaction solution was poured into water and extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting with benzene-AcOEt to give 5.98 g of the objective compound 3-methoxy-4-(2,2,2-trifluoroethoxy)benzaldehyde (f-1) (Yield: 98.2%).
Reaction SMILES: Br[C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:18])[N:15]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)#[N:28].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:7]([N:6]1[C:2]([C:32]2[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[CH:30][CH:31]=2)=[C:3]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:18])[N:15]=2)[CH:4]=[N:5]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc(C#N)cc1
Yield: 56.1 %

Procedure:
A solution of 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (102 mg, 0.23 mmol), 4-cyanophenylboronic acid (50.9 mg, 0.35 mmol), tripotassium phosphate (98 mg, 0.46 mmol), S-Phos (7.59 mg, 0.02 mmol) and palladium(II) acetate (2.075 mg, 9.24 μmol) in toluene (1.5 ml) was stirred under an argon atmosphere at 90° C. for 20 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (solvent gradient; 50% ethyl acetate/hexane→5% methanol/ethyl acetate) to give the title compound (60 mg, 0.129 mmol, 56.0%) as a white powder.
Reaction SMILES: O1CCCC1.[CH3:6][N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([C:13]([NH:15][CH2:16][CH:17]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=O)[CH2:8]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>CO>[CH3:6][N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([CH2:13][NH:15][CH2:16][CH:17]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:8]1
Reactant: CN1CCCC(C(=O)NCC2CCCCCCC2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCCC(CNCC2CCCCCCC2)C1
Yield: 85.8 %

Procedure:
To 50 ml of distilled tetrahydrofuran were added 3.2 g of 1-methyl-3-cyclooctylmethylaminocarbonylpiperidine and 1.5 g of lithium aluminum hydride. The mixture was refluxed for 10 hours under a nitrogen current. After cooling, the reaction mixture was mixed with methanol and 2N sodium hydroxide. The resulting mixture was stirred and then the insoluble materials were removed by filtration. The filtrate was concentrated. The residue was distilled in a glass tube over under reduced pressure to obtain 2.6 g of N-(1-methyl-3-piperidinylmethyl)-N-cyclooctylmethylamine.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[C:31]5[CH:35]=[CH:36][C:28]([F:27])=[CH:29][CH:30]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, light yellow solid (72 mg, 64%), MS (ISP) m/z=451.3 [(M+H)+], mp 213° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-fluoro-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:39][CH:40]1[CH2:42][O:41]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH:40]4[CH2:42][O:41]4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCC3CO3)cc2)c2ccccc21
Temperature: 80 °C
Yield: 98.3 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.5 g, 1.14 mmol) was dissolved in DMF at room temperature and K2CO3 (1.26 g, 9.13 mmol) was added. 2-Chloromethyl-oxirane (0.42 g, 4.57 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (50% EtOAc/50% Hexane) to afford (2S,4R)-N-(4-chloro-phenyl)-N-[2-methyl-1-(4-oxiranylmethoxy-benzoyl)-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.55 g, 77%), which was further elaborated to the product following ref. (Tetrahedron Lett 2002, 43(46), 8327).
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7](=[O:28])[C:8]([NH:19][NH:20]C(OC(C)(C)C)=O)([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)(=[O:3])[CH3:2].Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>ClCCl>[C:1]([O:4][CH2:5][O:6][C:7](=[O:28])[C:8]([NH:19][NH2:20])([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:12]([O:17][C:5]([O:4][CH2:1][CH3:2])=[O:6])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)OCOC(=O)C(C)(Cc1ccc(O)c(O)c1)NNC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(CC(C)(NN)C(=O)OCOC(C)=O)cc1OC(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
To an ice cold reaction mixture containing compound 103 (0.358 g, 0.9 mmol) and TEA (0.224 mL, 1.8 mmol) in dichloromethane (5 mL) was added ethyl chloroformate (0.18 mL, 1.8 mmol). The mixture was stirred at 0° C. for 30 min and then at room temperature for 1 h. After removal of solvent, 10% citric acid was added and the organic phase was separated and dried over MgSO4. After removing the solvent under reduced pressure, the resulting residue was treated with 50% trifluoroacetic acid in dichloromethane at room temperature for 30 min. After removing the solvent under reduced pressure, the resulting residue was purified by reverse phase preparative HPLC to afford 208 mg of the title compound. 1H NMR (CD3OD, 400 MHz): 1.35 (t, 6H), 1.45 (s, 3H), 3.08 (dd, 2H), 3.80 (s, 3H), 4.28 (q, 4H), 5.83 (dd, 2H), 7.12–7.24 (m, 3H). MS (ESI) m/z 443.28 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29](B5OC(C)(C)C(C)(C)O5)[CH:30]=4)[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:43]([O:47][C:48]([N:50]1[CH:55]([C:56]2[NH:60][C:59]3[CH:61]=[C:62](Br)[CH:63]=[CH:64][C:58]=3[N:57]=2)[CH:54]2[CH2:66][CH:51]1[CH2:52][CH2:53]2)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)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].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:43]([O:47][C:48]([N:50]1[CH:55]([C:56]2[NH:60][C:59]3[CH:61]=[C:62]([C:29]4[CH:28]=[CH:27][C:26]5[C:31](=[CH:32][CH:33]=[C:24]([C:21]6[CH:22]=[CH:23][C:18]([C:15]7[NH:14][C:13]([CH:9]8[CH2:10][CH2:11][CH2:12][N:8]8[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:17][CH:16]=7)=[CH:19][CH:20]=6)[CH:25]=5)[CH:30]=4)[CH:63]=[CH:64][C:58]=3[N:57]=2)[CH:54]2[CH2:66][CH:51]1[CH2:52][CH2:53]2)=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(Br)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(B5OC(C)(C)C(C)(C)O5)ccc4c3)cc2)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5ccc6nc(C7C8CCC(C8)N7C(=O)OC(C)(C)C)[nH]c6c5)ccc4c3)cc2)[nH]1
Temperature: 90 °C
Yield: 34.9 %

Procedure:
A mixture of 2-(5-{4-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (216 mg, 0.382 mmol), 3-(6-Bromo-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1 eq., 150 mg, 0.382 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(5%, 16 mg), tetrakis(triphenylphosphine)palladium (5%, 22 mg) and potassium carbonate (2 eq., 106 mg) in 4 mL DME and 1 mL water was heated to 90° C. under Argon for 5 hours. The reaction mixture was cooled and diluted in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 3-[6-(6-{4-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-naphthalen-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (100 mg, yield 35%). LCMS-ESI−: calc'd for C46H50N6O4: 750.93; Found: 751.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2c1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CC1CN2c1ccc(N)cc1
Reaction time: 3 h

Procedure:
A suspension of 5-(4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (450 mg) and palladium(II) hydroxide (20% on carbon; 0.15 g) in ethanol (30 ml) was vigorously stirred under a hydrogen atmosphere (atmospheric pressure) for 3 hours. The catalyst was then removed by filtration, and the filtrate was concentrated. The product with the molecular weight of 289.38 (C16H23N3O2); MS (ESI): 290 (M+H+) was obtained in this way.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6](=[O:17])[N:7]([C@@H:11]([CH2:15][CH3:16])[C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:18]([O:22][C:23](=[O:41])[CH2:24][CH:25]([NH2:40])[CH:26]([OH:39])[CH2:27][O:28][C:29]1[C:34]([F:35])=[C:33]([F:36])[CH:32]=[C:31]([F:37])[C:30]=1[F:38])([CH3:21])([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:18]([O:22][C:23](=[O:41])[CH2:24][C@H:25]([NH:40][C:12](=[O:14])[CH:11]([N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:6]1=[O:17])[CH2:15][CH3:16])[C@H:26]([OH:39])[CH2:27][O:28][C:29]1[C:30]([F:38])=[C:31]([F:37])[CH:32]=[C:33]([F:36])[C:34]=1[F:35])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)COc1c(F)c(F)cc(F)c1F
Reactant: CC[C@@H](C(=O)O)n1cccc(NC(C)=O)c1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CCC(C(=O)N[C@@H](CC(=O)OC(C)(C)C)[C@H](O)COc1c(F)c(F)cc(F)c1F)n1cccc(NC(C)=O)c1=O
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A stirred mixture of (S)-2-(3-Acetylamino-2-oxo-2H-pyridin-1-yl)-butyric acid (100 mg, 0.42 mmol), 3-amino-5-(2,3,5,6-tetrafluorophenoxy)-4-hydroxy-pentanoic acid tert-butyl ester (163 mg, 0.462 mmol), HOBt (62 mg, 0.462 mmol), DMAP (56 mg, 0.462 mmol) and THF (5 mL) was cooled to 0° C. then EDC (89 mg, 0.462 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (50-50% ethyl acetate/hexane) to afford the title compound as a white foam (221 mg, 92%); 1H NMR (400 MHz, CDCl3) δ 0.88-0.93 (3H, m), 1.37-1.38 (9H, 2 s), 1.86-1.96 (1H, m), 2.15-2.25 (4H, m), 2.55-2.71 (2H, m), 3.70-4.64 (5H, m), 5.30-5.39 (1H, m), 6.30-6.35 (1H, m), 6.75-6.86 (1H, m), 7.17-7.31 (2H, m), 8.31-8.47 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=1)=[O:4]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccccc2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)cc(-c2ccccc2)c1

Procedure:
5-Nitro-biphenyl-3-carboxylic acid methyl ester (1.85 g, 7.19 mmol) and 10% Pd/C (0.185 g) in EtOAc (20 mL) were hydrogenated under balloon for 2 h. The catalyst was filtered and the filtrate was concentrated to dryness. The crude 5-amino-biphenyl-3-carboxylic acid methyl ester was a yellow solid and was taken to the next step.
Reaction SMILES: [CH2:1]([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[OH:23])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31]Cl)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>>[CH2:1]([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[O:23][CH2:31][CH2:30][C:27]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCc1ccccc1
Reactant: Oc1c2c(nc3ccccc13)CCN(Cc1ccccc1)CC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: c1ccc(CCOc2c3c(nc4ccccc24)CCN(Cc2ccccc2)CC3)cc1
Reaction time: 207 h
Yield: 73 %

Procedure:
A mixture of 4.5 gm (15 millimols) of 3-benzyl-11-hydroxy-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline, 4.2 gm (30 millimols) of β-phenethyl chloride, 4.15 gm (30 millimols) of potassium carbonate, 5 gm of sodium iodide and 10 ml of butanone-(2) was boiled for 207 hours. The mixture was then suction-filtered, and the filter cake was purified by column chromatography on silicagel with ethyl acetate as the eluant. Yield: 73% of theory; m.p. <20° C.