Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]([C:13]1[O:17][C:16]2[CH:18]=[C:19]([O:22]CC3C=CC=CC=3)[CH:20]=[CH:21][C:15]=2[CH:14]=1)[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:3])[CH3:2].Cl.CO.C(=O)([O-])O.[Na+]>[C].[Pd].O.C(Cl)(Cl)Cl>[C:1]([O:4][CH:5]([C:13]1[O:17][C:16]2[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:15]=2[CH:14]=1)[CH2:6][O:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(COCCN(C)C)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC(=O)OC(COCCN(C)C)c1cc2ccc(O)cc2o1
Reaction time: 1.5 h
Yield: 63.4 %

Procedure:
a mixture of 3.2 g of 1-acetoxy-1-(6-benzyloxybenzo[b]furan-2-yl)-2-[2-(N,N-dimethylamino)ethoxy]ethane, 0.6 g of 5% palladium-carbon, 0.67 ml of concentrated hydrochloric acid and 30 ml of methanol was subjected to hydrogenation at room temperature under atmospheric pressure for 1.5 hours. After the completion of the reaction, the palladium-carbon was removed by filtration. The solvent was removed by distillation under reduced pressure. To the residue thus obtained were added 20 ml of chloroform and 20 ml of water. The resulting mixture was adjusted to pH 7 with sodium hydrogencarbonate. The organic layer was separated. The aqueous layer was extracted with 10 ml of chloroform. The extract was combined with the previously separated organic layer. The combined organic layer was washed with 5 ml of water, and dried over anhydrous magnesium sulfate. The solvent was remove by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/methanol=7/1) to obtain 1.57 g of oily 1-acetoxy-1-(6-hydroxybenzo[b]furan-2-yl)-2-[2-(N,N-dimethylamino)ethoxy]ethane (compound No. 407).
Reaction SMILES: ClCCl.[CH3:4][C:5]1([CH3:12])[C:9]([CH3:11])([CH3:10])[O:8][BH:7][O:6]1.[CH3:13][O:14][C:15]([C:17]1[O:18][C:19]([CH3:31])=[C:20]([CH2:22][S:23][C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)[CH:21]=1)=[O:16]>O1CCCC1.O1CCOCC1>[CH3:13][O:14][C:15]([C:17]1[O:18][C:19]([CH3:31])=[C:20]([CH2:22][S:23][C:24]2[CH:29]=[CH:28][C:27]([B:7]3[O:8][C:9]([CH3:11])([CH3:10])[C:5]([CH3:12])([CH3:4])[O:6]3)=[CH:26][CH:25]=2)[CH:21]=1)=[O:16]
Reactant: CC1(C)OBOC1(C)C
Reactant: COC(=O)c1cc(CSc2ccc(Br)cc2)c(C)o1
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cc(CSc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Temperature: 100 °C

Procedure:
[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (30 mg) and 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.34 ml of a 1M solution in tetrahydrofuran) were added to a degassed solution of 4-(4-bromo-phenylsulphanylmethyl)-5-methyl-furan-2-carboxylic acid methyl ester (150) (400 mg, 1.17 mmoles) in 1,4-dioxan (120 ml). The mixture was heated at 100° C., under an argon atmosphere, for 20 hours, cooled and evaporated. The residue was partitioned between ethyl acetate and water, and the organic phase washed with brine and dried (MgSO4). After evaporation of the solvent the residue was purified by flash chromatography, using heptane/ethyl acetate 9:1 v/v as eluent, to afford compound 151 (212 mg) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:3]=1.[Se](=O)=[O:31]>C(O)(=O)C>[CH:1]([C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:3]=1)=[O:31]
Reactant: CCCc1c2nc(C(=O)OCC)cc(C)c2cc2c(=O)cc(C(=O)OCC)oc12
Reactant: O=[Se]=O
Solvent: CC(=O)O
Product: CCCc1c2nc(C(=O)OCC)cc(C=O)c2cc2c(=O)cc(C(=O)OCC)oc12
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A mixture of diethyl 6-methyl-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate (19 g), selenium dioxide (20.99 g), and glacial acetic acid (950 ml) was heated on a steam bath with stirring for 2 hours. The resulting suspension was cooled, filtered and poured into brine (8 l). The resulting precipitate was filtered off and the crude product dissolved in CH2Cl2, filtered and evaporated to dryness to give 20.5 g of the crude product (20.5 g). This product was chromatographed using 25:1 CH2Cl2 : ethyl acetate as the solvent, yielding 13.95 g of required product (71%).
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C.O>C1COCC1>[CH:5]1([C:3](=[O:4])[CH2:2][S:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccc(S)cc1
Reactant: O=C(CCl)C1CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(SCC(=O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The intermediate 2-Chloro-1-cyclopentyl-ethanone from Step 1 (1 g, 6.81 mmol), was combined with 4-methoxy-benzenethiol (1.05 g, 7.50 mmol), in THF (20 mL) and treated with Triethylamine (1.05 mL, 7.50 mmol). The mixture was stirred for 1 hour at room temperature then poured into water (50 mL) and extracted with EtOAc (2×50 mL). The organics were then washed with 0.5N HCl (2×50 mL), 2N NaOH (2×50 mL), water (2×50 mL) and brine (1×50 mL) the organics were dried over Na2SO4, filtered and concentrated. The residue was used without further purification (1.65 g, 97%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>CCCCCC>[CH2:10]1[CH2:9][CH:8]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: O=C1CCCCC1
Solvent: CCCCCC
Product: C1=C(N2CCOCC2)CCCC1

Procedure:
A mixture of morpholine (697 ml.), cyclohexanone (820 ml.) and hexane (800 ml.) is heated to reflux under nitrogen with a Dean-Stark trap for 18 hours. The aqueous phase (206 ml.) is collected in the distillate trap. The mixture is distilled under vacuum increasing the vacuum to 29 inches and 90°-100° to give the title compound as an oily residue.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:12]([O:16][C:17](=O)[O:18]C(C)(C)C)([CH3:15])([CH3:14])[CH3:13]>>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][C:17](=[O:18])[O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CNc1ccc(CCN)cc1
Product: CNc1ccc(CCNC(=O)OC(C)(C)C)cc1
Yield: 94.6 %

Procedure:
2.03 g of 2-(4-methylaminophenyl)ethylamine and 3.20 g of di-t-butylcarbonate were subjected to an acylation reaction to obtain 3.20 g of t-butyl 2-(4-methylaminophenyl)ethylcarbamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[C:17](O)[N:18]=[N:19][C:20]=2[CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O=P(Cl)(Cl)[Cl:28]>>[Br:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[C:17]([Cl:28])[N:18]=[N:19][C:20]=2[CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=[CH:6][C:7]=1[O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCCCc1nnc(O)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A suspension of 5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-ol (4.18 mmol, 1.7 g) in POCl3 (20 mL) was kept stirring at 70° C. for 2 h. The reaction mixture was concentrated, to the residue water was added, extracted with ethyl acetate washed with sat NaHCO3 solution, water, brine, dried and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography using a mixture of hexanes in ethyl acetate (9:1) to provide 4-(3-bromo-4-cyclohexyloxy-phenyl)-3-butyl-6-chloro-pyridazine (1.5 g).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.Cl.[CH3:21][NH:22][C:23](=[O:31])[C@H:24]([C:27](=[O:30])[O:28][CH3:29])[NH:25][CH3:26].C(N(CC)CC)C>O>[CH3:29][O:28][C:27](=[O:30])[CH:24]([N:25]([CH3:26])[C:11]([C:10]1[CH:14]=[CH:15][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=1)=[O:12])[C:23]([NH:22][CH3:21])=[O:31]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CNC(=O)[C@@H](NC)C(=O)OC
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
4-Phenylbenzoyl chloride (2.23 g) was added little by little to a chloroform (20 mL) solution of N,N2,O-trimethyl-3-oxoserinamide hydrochloride (Intermediate 5-2, 2.02 g) and triethylamine (2.18 g) under ice cooling, and the mixture was stirred for 30 minutes at the same temperature and for 1 hour, with the temperature raised to room temperature. Water was added to the reaction mixture, and the system was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and the desiccant was filtered out, whereafter the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/methanol=98/2→90/10) to obtain 4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (yellow solid) (3.0 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:25])[CH2:12][C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].B.O.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:25])[CH2:12][CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(CC(=O)O)N2Cc3ccccc3C2=O)cc1OC
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(CCO)N2Cc3ccccc3C2=O)cc1OC
Temperature: 25 °C

Procedure:
To a stirred suspension of 3-(3',4'-dimethoxyphenyl)-3-(1'-oxoisoindolinyl)propionic acid (3.74 grams, 10.96 mmol) in THF (60 mL) at -10°-15° C. (ice-salt bath), was added borane in THF (11 mL, 1M, 11 mmol). The suspension was allowed to warm to room temperature slowly overnight. To the resulting clear solution was added water (20 mL), followed by potassium carbonate (6 g). The organic layer was separated. The aqueous layer was extracted with methylene chloride (2×50 mL). The combined organic layers were washed with sodium carbonate (20 mL, sat), brine (20 mL), and dried over magnesium sulfate. Removal of solvent and chromatography (silica gel, 100 grams, 1:2, 1:1 EtOAc/CH2Cl2) gave 3-(3',4'-dimethoxyphenyl)-3-(1'-oxoisoindolinyl)-1-propanol as an oil, (2.52 grams, 70%). Ether (6 mL) and 2 drops of methanol were added to the oil. Hexane was added until the solution was turned cloudy. The mixture was stirred for 30 minutes to give a white solid and the solid was filtered: mp, 101.5°-103.0° C.; 1H NMR (CDCl3)δ1.99-2.36 (m, 3H, CH2, OH), 3.49-3.80 (m, 2H, OCH2), 3.85 (s, 3H, CH3), 3.89 (s, 3H, CH3), 3.91 (d, J=17.2 Hz, 1H, CHH), 4.19 (d, J=17.2 Hz, 1H, CHH), 5.75 (dd, J=4, 11.5 Hz, 1H, NCH), 6.86-7.00(m, 3H, Ar), 7.27-7.56 (m, 3H, Ar), 7.86-7.89 (m, 1H, Ar); 13C NMR (CDCl3)δ33.87, 46.22, 50.61, 55.91, 56.01, 58.55, 111.04, 111.73, 119.66, 122.81, 123.89, 128.64, 131.33, 131.56, 132.09, 141.35, 148.81, 148.24, 169.45; Anal Calcd for C19H21 NO4 : C, 69.71; H, 6.47; N, 4.28. Found: C, 69.5I; H, 6.27; N, 4.12.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:11][CH:10]=2)O1.[CH2:24]([O:26][C:27]([C:29]1[N:30]([CH3:39])[C:31]([CH2:37][CH3:38])=[C:32]([C:35]#[N:36])[C:33]=1I)=[O:28])[CH3:25].C(OC(C)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>O.[Pd].CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2].C(O)C>[C:35]([C:32]1[C:33]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:13][CH:14]=2)=[C:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])[N:30]([CH3:39])[C:31]=1[CH2:37][CH3:38])#[N:36]
Reactant: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Reactant: CC1(C)OB(c2ccc(-c3ccccc3C#N)cc2)OC1(C)C
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CC(=O)OC(C)C
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(-c3ccccc3C#N)cc2)c(C#N)c(CC)n1C
Temperature: 75 °C
Yield: 62.7 %

Procedure:
Add 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzenecarbonitrile (0.916 grams, 0.003 moles, prepared in preparation 58), 4-cyano-5-ethyl-3-iodo-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.996 grams, 0.003 moles, prepared in preparation 38), isopropyl acetate (14 mL) and ethanol (6 mL) to a 100 mL 3-neck flask. Stir the mixture under a nitrogen atmosphere and add palladium black (0.0319 grams, 0.0003 moles). Add a solution of potassium carbonate (0.663 grams, 0.0048 moles) in water (6 mL). Heat the mixture to reflux at 75° C. for 135 minutes. Add bis(acetato)bis(triphenylphosphine)palladium (II) (0.045 grams, 0.00006 moles) and continue heating at reflux for an additional 105 minutes. Add a solution of potassium carbonate (0.16 grams, 0.00116 moles) in water and continue heating at reflux for an additional 195 minutes. Cool the mixture to room temperature and stir for about 16 hours. Warm the mixture to 75° C. and filter to remove palladium black. Transfer the filtrate to a separatory funnel and add acetone (20 mL) to redissolve a precipitate and then separate the phases. Discard the aqueous phase. Concentrate the organic phase to a solid under reduced pressure (15-25 mm) and suspend the solid in ethanol (3 mL) and water (7 mL). Filter the suspension to recover the solid, and transfer the solid to a 20 mL vial. Add ethanol (12 mL) and warm to reflux. Slowly cool the resulting solution to about 23° C. and filter the resulting suspension to recover the precipitate. Dry the solid at 45° C. under reduced pressure (15-25 mm) to provide the title compound (0.72 g, 0.00188 moles) in 62.6% yield. 1H NMR (CDCl3, 500 MHz): δ 7.77 (app d, 2H, J=8); 7.66 (app. td, 1H. J=117.5): 7.57 (m, 3H), 7.49-7.43 (m,3H); 4.10 (q, 2H, J=6.5); 3.91 (s, 3H); 2.87 (q, 2H, J=8); 1.32 (t, 3H, J=7.5); 1.04 (t, 3H, J=7).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccc(Cl)cc2)CC1
Reaction time: 16 h
Yield: 102 %

Procedure:
To a mixture of 1-t-butoxycarbonyl-4-carboxypiperidine (2.3 g, 10 mmol), 4-chlorobenzylamine (1.56 g, 11 mmol), and 1-hydroxy-7-azabenzotriazole (1.5 g, 11 mmol) in tetrahydrofuran (20 mL) at room temperature under argon, was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.1 g, 11 mmol), and the resulting mixture was stirred for 16 h. The solvent was evaporated under vacuum, and the residue was dissolved in ethyl acetate (50 mL). The resulting solution was washed sequentially with 0.01 M aqueous hydrochloric acid (50 mL), 1.0 M aqueous sodium hydroxide (25 mL), and brine (25 mL) before drying (anhydrous sodium sulfate) and evaporation under vacuum to obtain 4-(N-(4-chlorobenzyl)aminocarbonyl)-1-t-butoxycarbonylpiperidine (3.6 g, quantitative yield).
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[C:14]1([C:20]2[N:25]=[CH:24][C:23]([C:26]3[N:27]=[C:28]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[NH:29][CH:30]=3)=[CH:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(C)(C)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]1([C:20]2[N:25]=[CH:24][C:23]([C:26]3[N:27]=[C:28]([CH:31]4[CH2:36][CH2:35][N:34]([C:8]5[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=5)[CH2:33][CH2:32]4)[NH:29][CH:30]=3)=[CH:22][N:21]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(-c2ncc(-c3c[nH]c(C4CCNCC4)n3)cn2)cc1
Reactant: Brc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2ncc(-c3c[nH]c(C4CCN(c5cccnc5)CC4)n3)cn2)cc1
Temperature: 120 °C

Procedure:
The title compound is prepared in a similar manner as described in Tetrahedron Letters, 2007, 48(14), 2519-2525. In this case, to a degassed solution of sodium tert-butoxide, palladium acetate, and 2-dicyclohexlphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos) in tert-butanol and toluene is added 3-bromopyridine and 2-phenyl-5-(2-(piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine. The reaction is stirred and heated at 120° C. under nitrogen for 18 hours. The reaction mixture is cooled, diluted with water and the organic material is extracted with ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica to give the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[N:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:3]1.[C:41]1([CH:47]2[CH2:49][O:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[C:21]([C:18]1[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:15]([C:13]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@H:6]2[CH2:7][C@@H:2]([NH:1][CH2:49][CH:47]([OH:48])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:3][N:4]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])[CH2:5]2)=[O:14])=[CH:20][N:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N)CN(C(=O)OCc2ccccc2)C1
Reactant: c1ccc(C2CO2)cc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](NCC(O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Benzyl (3R,5S)-3-amino-5-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]piperidine-1-carboxylate (100 mg) and 2-phenyloxirane (55 μl) were dissolved in acetonitrile (5 ml), and lithium perchlorate (55 mg) was added. The mixture was stirred at room temperature for 3 days and thereafter stirred at 80° C. for 7 hr. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane-methanol (10:90:0-100:0:0-85:0:15) and concentrated under reduced pressure to give the object compound (53.2 mg).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=1)[CH:7]=[CH:6]2.Cl.N1C=CC=CC=1>>[C:18]1([C:15]2[N:14]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[C:13]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]4)=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 165 °C
Yield: 78.2 %

Procedure:
In a similar manner as described in step 5 of Example 1, the title compound was prepared from 2-(6-methoxy-2-naphthyl)-5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrole (0.70 g, 1.5 mmol), prepared in the previous step, and pyridine hydrochloride (7 g) heated to 165° C. under nitrogen for 12 hours. Purification on a Biotage Horizon™ system with a KP-Sil Flash 40+M column (100 g Silica Gel, 60 Å) using 50% to 90% methylene chloride in hexane as the eluent gave 6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthol as a reddish-brown amorphous solid (0.52 g, 77%), mp 63–66° C. Elemental Analysis for C28H20F3NO Calc'd: C, 75.84; H, 4.55; N, 3.16. Found: C, 75.18; H, 4.41; N, 3.13.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[C:14]([CH3:29])([CH3:28])[S:13][CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:31][O:32][C:33](=[O:59])[NH:34][CH:35]([C:39]([N:41]1[CH2:45][CH2:44][CH2:43][CH:42]1[C:46]1[NH:47][C:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57]#[CH:58])=[CH:53][CH:52]=2)=[CH:49][N:50]=1)=[O:40])[CH:36]([CH3:38])[CH3:37].C(N(CC)CC)C>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.CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:58]#[C:57][C:54]4[CH:55]=[CH:56][C:51]([C:48]5[NH:47][C:46]([CH:42]6[CH2:43][CH2:44][CH2:45][N:41]6[C:39](=[O:40])[CH:35]([NH:34][C:33]([O:32][CH3:31])=[O:59])[CH:36]([CH3:38])[CH3:37])=[N:50][CH:49]=5)=[CH:52][CH:53]=4)=[CH:23][CH:22]=3)=[CH:19][N:20]=2)[C:14]([CH3:29])([CH3:28])[S:13][CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Reactant: COC(=O)NC(C(=O)N1CSC(C)(C)C1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#Cc3ccc(-c4cnc(C5N(C(=O)C(NC(=O)OC)C(C)C)CSC5(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 20 h
Yield: 23.8 %

Procedure:
(1-{4-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5,5-dimethyl-thiazolidine-3-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (83 mg, 0.167 mmol) was combined with (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (66.0 mg, 0.167 mmol) and PdCl2(PPh3)2 (11.7 mg, 0.017 mmol) under an argon atmosphere. DMF (2.0 mL degassed with Argon) was added followed by triethylamine (168 mg, 1.67 mmol) and copper(I) iodide (3.2 mg, 0.017 mmol). The mixture was heated at 80° C. After 20 hours, volatiles were removed in vacuo and the crude material was semi-purified via chromatography on silica gel (eluent EtOAc w MeOH 10%/hexanes) and further purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product [1-(4-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-5,5-dimethyl-thiazolidine-3-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (32.1 mg) as a TFA salt.