Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.O.[CH2:7]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])[CH3:8]>CO>[NH2:11][C:10]1[CH:12]=[CH:13][C:14]([CH:2]([C:14]2[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH2:7][CH3:8])[CH:15]=2)[C:1]([OH:5])=[O:4])=[CH:15][C:9]=1[CH2:7][CH3:8]
Reactant: O=CC(=O)O
Reactant: CCc1ccccc1N
Solvent: O
Solvent: CO
Product: CCc1cc(C(C(=O)O)c2ccc(N)c(CC)c2)ccc1N
Temperature: 25 °C

Procedure:
A mixture of glyoxylic acid 50% w/v (3.05 parts), water (20 parts) and methanol (10 parts) was stirred at ambient temperature. 2-ethylaniline (5.0 parts) was added and the mixture was stirred under reflux for 2 hours. After cooling to ambient temperature, the product was isolated by filtration, washed with a little water (50 parts) and dried to yield di(4-amino-3-ethylphenyl)acetic acid (5.5 parts).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[CH3:11][N:12]([CH3:35])[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[C:23]2=[O:34])=[CH:18][CH:17]=1.[OH-].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[CH3:11][N:12]([CH3:35])[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N+:1]([O-:3])=[O:2])=[CH:31][CH:32]=3)[C:23]2=[O:34])=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN(C)CCOc1ccc(-n2ccn(-c3ccc(O)cc3)c2=O)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc(-n2ccn(-c3ccc(Oc4ccccc4[N+](=O)[O-])cc3)c2=O)cc1

Procedure:
2-Nitrofluorobenzene (0.14 g) was added to a mixture of 1-[4-(2-dimethylaminoethoxy)phenyl]-3-(4-hydroxyphenyl)-1,3-dihydroimidazol-2-one (0.34 g), Aliquat® 336 (0.04 g, tricaprylylmethylammonium chloride), potassium hydroxide (0.077 g) and toluene (10 mL). The mixture was heated under reflux for 3 hours. After cooling, the reaction solution was washed with water, dried and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 460.49 (C25H24N4O5); MS (ESI): 461 ([M+H]+), was obtained as hydrotrifluoroacetate in this way.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[Br:25])[NH2:21].C([O-])(O)=O.[Na+]>CCO>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][C:24]=1[Br:25]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: Nc1ccc(Br)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Br)c(Br)c1
Yield: 31.9 %

Procedure:
A mixture of 6.20 g (26.6 mmol) of 4-chloro-6-nitroquinoline-3-carbonitrile and 8.00 g (31.9 mmol) of 3,4-dibromoaniline in 160 mL of EtOH was refluxed under N2 for 5 hr. Satd NaHCO3 was added and volatile material was removed. The residue was slurried with hexane, collected, washed with hexane and H2O and dried. The insoluble material was repeatedly extracted with boiling EtOAc and the solution was then filtered through silica gel. The solvent was removed to give 3.80 g of 4-(3,4-dibromophenylamino)-6-nitroquinoline-3-carbonitrile as a green solid: mass spectrum (electrospray, m/e): M+H 448.9.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:39][C:40]3[CH:45]=[C:44]([CH3:46])[C:43]([OH:47])=[C:42]([CH3:48])[CH:41]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36]CC)=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[N:7]=[C:6]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:39][C:40]3[CH:41]=[C:42]([CH3:48])[C:43]([OH:47])=[C:44]([CH3:46])[CH:45]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[N:7]=[C:6]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[NH:5]1
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(n4nc(-c5ccccc5)[nH]c4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.2 mg (0.05 mmol) LiOH in 2 mL water was added to a solution of 21 mg (0.03 mmol) (R)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate in 3 mL THF and the reaction mixture was stirred for 1 h at RT. The THF was evaporated down i.vac., the residue was acidified with 1 M HCl and again evaporated down i.vac. The residue was purified by HPLC, the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[C:9](Br)[CH:10]=1)=[O:4].[C:18]1(B2OC(C)(C)C(C)(C)O2)[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>CN(C=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].C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:7][CH:6]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cnc(OCC(F)(F)F)c(C2=CCCCC2)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
5-Bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid methyl ester (CAN 1211589-51-3), 200 mg, 637 μmol), 2-cyclohexenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAN 141091-37-4, 119 mg, 123 μA, 574 μmol), K3PO4 (409 mg, 1.91 mmol) and PdCl2(dppf)-CH2Cl2 adduct (26.0 mg, 31.8 μmol) were combined in degassed DMF (4.38 mL)/THF (1.46 mL) to give a yellow suspension. The mixture was heated to 70° C. and shaken overnight. After cooling the mixture was poured into 100 mL saturated NaHCO3/ice water and extracted with i-propyl acetate (2×100 mL). The organic layers were washed with ice/brine (1×150 mL), combined, dried with Na2SO4 and concentrated in vacuo to give 283 mg of a brown oil. The crude material was purified by preparative TLC (silica gel, 2×2.0 mm, n-heptane/iPrOAc 9:1) to give the title compound (129 mg, 64%) as colorless solid; MS (ESI) 316.2 (M+H)+.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].C(N(CC)CC)C.Br[C:15]1[C:16]([F:23])=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.CCOC(C)=O>[F:23][C:16]1[C:15]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:21][OH:22]
Reactant: OCc1cccc(Br)c1F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cccc(CO)c1F
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere, ethynyl(trimethyl)silane (9.0 ml) was mixed with triethylamine (50 ml), and (3-bromo-2-fluorophenyl)methanol, bis(triphenylphosphine)palladium chloride (II) (1.54 g), and copper iodide (420 mg) were added thereto, followed by stirring at 90° C. overnight. The reaction mixture was cooled to room temperature, and EtOAc was added thereto, followed by filtering using Celite as a filtration adjuvant. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain {2-fluoro-3-[(trimethylsilyl)ethynyl]phenyl}methanol (4.88 g).
Reaction SMILES: [S:1]1[C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[CH3:13][O:14][C:15](=[O:22])[C@H:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH2:17].C(N(C(C)C)CC)(C)C.O>C(Cl)Cl>[CH3:13][O:14][C:15](=[O:22])[C@H:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[NH:17][C:6]([C:5]1[S:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[CH:4]=1)=[O:7]
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: COC(=O)[C@@H](N)CC(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Benzo[b]thiophene-2-carbonyl chloride (4.9 g, 25 mmol) was added to a stirred solution of L-leucine methyl ester (4.5 g, 25 mmol) and diisopropylethylamine (9 ml, 51 mmol) in DCM (200 ml). After stirring for 2 hours at room temperature, the mixture was poured into water and washed with brine and dried (MgSO4). Evaporation under reduced pressure afforded the title compound as a white solid, 7.6 g, 100% yield.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:16]2[CH:15]=[CH:14][C:13]3[C:17](=[O:20])[CH2:18][CH2:19][C:12]=3[C:11]=2[C:10]2[C:9]3[CH2:21][CH2:22][C:23](=[O:24])[C:8]=3[CH:7]=[CH:6][C:5]1=2.[CH3:25][C:26]([CH3:28])=O.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.CO.O1CCOCC1.C(Cl)(Cl)Cl.CO>[CH:26]([NH:1][CH2:2][CH2:3][N:4]1[C:16]2[CH:15]=[CH:14][C:13]3[C:17](=[O:20])[CH2:18][CH2:19][C:12]=3[C:11]=2[C:10]2[C:9]3[CH2:21][CH2:22][C:23](=[O:24])[C:8]=3[CH:7]=[CH:6][C:5]1=2)([CH3:28])[CH3:25]
Reactant: CC(C)=O
Reactant: NCCn1c2ccc3c(c2c2c4c(ccc21)C(=O)CC4)CCC3=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)NCCn1c2ccc3c(c2c2c4c(ccc21)C(=O)CC4)CCC3=O

Procedure:
Crude compound 59 (1.69 g) was suspended in CH2Cl2 (200 mL). Then acetone (4 mL) and STAB (3.4 g) were added. The mixture was stirred for 24 h (TLC monitoring, eluent: CHCl3-MeOH, 9:1), then poured into an aqueous NaHCO3 solution. Then, another portion of CH2Cl2 and MeOH was added. The organic layer was separated, evaporated, washed with MeCN and ether. Yield of Example 8: 0.759 g. For the preparation of hydrochloride, the isolated product was suspended in a mixture of CH2Cl2 and MeOH, then a solution of HCl in dioxane was added. The resulting mixture was evaporated to dryness, and ethanol was added to the residue. The ethanolic solution was refluxed and cooled, and the precipitate was filtered. Yield of compound Example 8 hydrochloride: 0.684 g. 1H-NMR (DMSO-D6) spectrum: δ 1.24 (6H, d, J=6.6 Hz); 2.77-2.79 (4H, m); 3.34-3.43 (3H, m); 3.81-3.84 (4H, m); 4.91 (2H, t, J=7.3 Hz); 7.83 (2H, d, J=8.6 Hz); 7.91 (2H, d, J=8.6 Hz); 9.11 (2H, br. s). ELSD: 100%, ESI-MS: m/z 360 [M+H].+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:10]1[CH:11]=[C:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:13]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH:39](=O)[CH2:40][CH:41]([CH3:43])[CH3:42].CC(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:10]1[CH:11]=[C:12]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=2)[CH:13]=[C:14]([N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:20][CH:19]=2)[CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH:15]=1)[CH2:6][CH:7]([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(NCc2ccc(C(C)(C)C)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CC(C)CC=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N(CCC(C)C)Cc2ccc(C(C)(C)C)cc2)c1
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of 2-[5-(4-tert-Butyl-benzylamino)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid ethyl ester, compound 37a, (0.06 g, 0.11 mmol), isovaleraldehyde (0.36 mL, 3.3 mmol), AcOH (0.01 mL) in DCM (10 mL) was stirred at room temperature overnight. NaCNBH4 (0.01 g, 0.16 mmol) added and resulting solution was stirred 30 min. The crude product was purified by TLC plate to give the title compound at 50% yield. Calcd MW 595.8. Found MH+ 596.4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C[O-].[Na+]>CO>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[N:3][CH:4]=1
Reactant: Clc1ncnc2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: c1ccc2ncncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 298.8 %

Procedure:
To a solution of the quinazoline 3 (0.14 g, 0.36 mmol) in MeOH (3 mL) was added NaOMe (1.44 mL, 0.72 mmol) at RT. The reaction was stirred overnight at RT. The reaction mixture was concentrated using rotavap (25° C.), then the residue was taken up with water (75 mL) and washed with EtOAc (3×50 mL). The aqueous phase was dried with lyophilizer to give final product 4 (0.14 g, 98% yield) as solid. LC/MS(10-99%) M/Z 406.0 retention time 3.32 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[C@H:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]1=[O:15].O.O.O.O.O.O.O.[Cl-].[Ce+2].[Cl-].[BH4-].[Na+]>CO.C(OCC)(=O)C>[OH:15][C@H:3]1[C:2]([CH3:16])([CH3:1])[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[C@@H:4]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C=C(C)[C@@H]1CCC(C)(C)C(=O)[C@H]1C(=O)OC
Agent: [BH4-]
Agent: [Ce+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C=C(C)[C@@H]1CCC(C)(C)[C@H](O)[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a mixture of methyl (1S,6R)-3,3-dimethyl-6-(1-methylvinyl)-2-oxocyclohexane-1-carboxylate (1.38 g) and cerium (II) chloride heptahydrate (2.14 g) in methanol (10 ml) was added sodium borohydride (217 mg) at 0° C. The mixture was stirred at room temperature for 1 hr, and the reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with ether. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by flash column chromatography (using n-hexane:ethyl acetate=20:1 as an eluent) gave methyl (1S,2R,6R)-2-hydroxy-3,3-dimethyl-6-(1-methylvinyl)cyclohexane-1-carboxylate (1.15 g, 83% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:30]=[CH:29][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH2:31]([NH:33][CH2:34][CH3:35])[CH3:32]>CO>[CH2:31]([N:33]([CH2:34][CH3:35])[CH2:3][CH:2]([OH:4])[CH2:1][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:19]3=[O:20])[CH2:14][CH2:13]2)=[O:11])=[CH:29][CH:30]=1)[CH3:32]
Reactant: O=C(c1ccc(OCC2CO2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reactant: CCNCC
Solvent: CO
Product: CCN(CC)CC(O)COc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[1-(4-Glycidoxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (200 mg) is dissolved in methanol (4 ml) and thereto is added diethylamine (0.26 ml) and the mixture is stirred at room temperature overnight, and then refluxed with heating for 3 hours. The solvent is concentrated and the residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1→dichloromethane: methanol=10:1) to give 1-{1-[4-(3-diethylamino-2-hydroxypropoxy)benzoyl]-4-piperidinyl]-3,4-dihydrocarbostyril (0.18 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:27])[C@H:13]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:14])([CH3:4])([CH3:3])[CH3:2].Br[CH:30]1[CH2:35][CH:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:33][C:31]1=[O:32].C(N(CC)CC)C.O>C(#N)C>[C:1]([O:5][C:6](=[O:28])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:27])[C@H:13]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:14][CH:30]1[CH2:35][CH:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:33][C:31]1=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCC1CC(Br)C(=O)O1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCC1CC(N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)C(=O)O1
Temperature: 70 °C
Reaction time: 40 h
Yield: 72.2 %

Procedure:
Dissolved in 50 ml of acetonitrile were 2.00 g of Nε -t-butoxycarbonyl-L-lysyl-L-proline t-butyl ester and 3.53 g of 2-bromo-4-pentyl-γ-butyrolactone. After a dropwise addition of 0.76 g of triethylamine, the resultant mixture was heated and stirred at 70° C. for 40 hours. The reaction mixture was poured into chilled water, followed by extraction with ethyl acetate. The extract was washed successively with water, a 2% aqueous solution of sodium hydrogencarbonate, and water. After drying the extract over anhydrous sodium sulfate, it was distilled under reduced pressure. The residue was isolated and purified by chromatography on a silica gel column (chloroform:ethyl acetate=10:1-5:1), thereby obtaining as a colorless syrupy substance 2.00 g of Nα -(2-oxo-5-pentyl-3-tetrahydrofuranyl)-Nε -t-butoxycarbonyl-L-lysyl-L-proline t-butyl ester [in the formula (I), R1 =--(CH2)4CH3, R2 =H, R3 =--(CH2)4NHCOO-t-Bu, R4 and R5 =--(CH2)3 --, R6 = t-Bu (Compound 27)]. Upon analysis of Compound 27 by high-performance liquid chromatography, it was found to be a mixture of 4 types of diastereomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@@H:10]([C:15]([OH:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C@@H:10]([C:15]([OH:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@@H](C(=O)O)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](C(=O)O)C1
Reaction time: 18 h
Yield: 63.1 %

Procedure:
In a dry flask (3S,4R)-4-aminopiperidine-1,3-dicarboxylic acid 1-tert-butyl ester (1.32 g, 5.40 mmol) was dissolved in dichloromethane (30 mL) and triethylamine (1.0 mL, 7.2 mmol) and benzyl chloroformate (0.94 mL, 5.9 mmol) were added. The mixture was stirred for 18 hours. Water (30 mL) was added and the layers separated. The aqueous layer was extracted with dichloromethane (30 mL). The combined organic layers were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude oil (2.13 g). Purification by flash column chromatography (5-20% methanol/chloroform) provided a colorless oil (1.29 g, 63%). 1H NMR (400 MHz, DMSO-d6, 120° C.), δ: 7.34 (m, 5H), 6.76 (bs, 1H), 5.04 (s, 2H), 4.01, (bs, 1H), 3.78 (dd, J=14, J′=7, 1H), 3.47 (m, 2H), 3.26 (m, 1H), 2.67 (dt, J=7, J′=4, 1H), 2.49 (m, 1H), 1.79 (m, 1H), 1.59 (m, 1H), 1.40 (s, 9H). MS (ESI), m+/z: (M+Na)+=401.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:9]([CH3:11])=[O:10])=[C:4]([CH3:12])[CH:3]=1.[N+:13]([C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](=O)[CH3:23])=[CH:18][CH:17]=1)([O-:15])=[O:14].N1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:23][C:22]1([CH2:21][O:20][C:19]2[CH:25]=[CH:26][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[CH2:11][C:9](=[O:10])[C:5]2[C:6](=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[CH3:12])[O:8]1
Reactant: CC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1c(C)cc(C)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCNC1
Solvent: c1ccccc1
Solvent: O
Product: Cc1cc(C)c2c(c1)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Yield: 30.6 %

Procedure:
A procedure similar to that described in Preparation 1 was repeated, except that 10 g of 2-hydroxy-4,6-dimethylacetophenone, 12 g of 4-nitrophenoxyacetone, 6 ml of pyrrolidine, 3 g of p-toluenesulfonic acid monohydrate and 200 ml of benzene were reacted, to afford 6.36 g of the title compound, colored a pale yellow and melting at 86°-88.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCO>COCCOC.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]>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[N:12]=[CH:13][C:14]([C:30]3[CH:29]=[N:28][C:27]([O:26][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:32][CH:31]=3)=[CH:15][CH:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(OCc2ccccc2)nc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3ccc(OCc4ccccc4)nc3)cn2)CC1
Temperature: 100 °C
Yield: 84.1 %

Procedure:
To a solution of [1-(5-iodo-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (0.25 g, 0.69 mmol) in DME (1 mL) was added PdCl2(dppf).dichloromethane complex (57 mg, 0.07 mmol). This solution was transferred to a microwave vial containing 2-benzyloxypyridine-5-boronic acid (0.17 g, 0.76 mmol) and K3PO4 (1M, 0.90 mL, 0.90 mmol). Water (0.4 mL) and EtOH (0.3 mL) were added and the mixture heated in a microwave at 100° C. for 10 minutes. The mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated to give [1-(6′-benzyloxy-[3,3′]bipyridinyl-6-yl)-cyclopropyl]-carbamic acid tert-butyl ester (0.24 g, 0.58 mmol) as a brown solid, m/z 418.8 [M+H]+.
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH:24]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]1)[CH2:19][CH2:18]2.[Li+].C[Si]([N-:41][Si](C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.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]>[NH2:41][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH:24]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25]1)[CH2:19][CH2:18]2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3cc(Br)ccc32)C1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3cc(N)ccc32)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
A suspension of Pd2(dba)3 (0.124 g, 0.136 mmol) and PtBu3 (1.65 mL, 0.544 mmol, 10% wt in hexane) in anhydrous THF (5 mL) was treated with a solution of compound 3 (1.0 g, 2.722 mmol) in THF (15 mL) followed by LiHMDS (5.44 mL, 5.445 mmol, 1 M solution in THF) at room temperature. The resulting dark brown mixture was heated to 100° C. and stirred for 3 hours in a sealed tube. The reaction mixture was cooled to room temperature and treated with TBAF (5 mL, 1 M solution in THF) and stirred for 20 min. The reaction was diluted with water (25 mL) and product was extracted into ether (3×30 mL) and the combined organic fractions were dried (Na2SO4) and concentrated to give a dark brown residue. The crude product was purified by column chromatography (2 N NH3 in methanol:CH2Cl2, 3:97) to obtain compound 4 (0.68 g, 82%) as a foam. ESI-MS (m/z, %): 304 (MH+, 16), 248 (100), 134 (25).