Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:33])[C:15]([C:17]3[C:22]([C:23]#[C:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=4)=[CH:21][N:20]=[C:19]([NH2:32])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:33])[C:15]([C:17]3[C:22]([CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=4)=[CH:21][N:20]=[C:19]([NH2:32])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(-c2nc(N)ncc2C#Cc2cccc(O)c2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cn1c(-c2nc(N)ncc2CCc2cccc(O)c2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O

Procedure:
2-[2-Amino-5-(3-hydroxy-phenylethynyl)-pyrimidin-4-yl]-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (obtained as described in Example 9) (25 mg, 0.054 mmol) was dissolved in a methanol (25 mL) and the solution was submitted to continuous hydrogenation in a H-Cube apparatus equipped with a Pd/C 10% cartridge (1 atm of hydrogen, 40° C., flux: 1 mL/min). The solution was then evaporated to dryness and the crude product was purified by chromatography on silica gel (DCM/EtOH 95:5). 2-{2-Amino-5-[2-(3-hydroxy-phenyl)-ethyl]-pyrimidin-4-yl}-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]-pyridine-5-carboxylic acid tert-butyl ester were obtained as a white solid (19 mg, 76%).
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C1C=CC(COC([NH:34][C@H:35]([C:44](O)=[O:45])[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)=O)=CC=1>>[NH2:34][C@@H:35]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)[C:44]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:45]
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: Cl
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
The title compound was prepared substantially following the procedures as set forth in Step 4, Example 1, Method A, and employing ((R)-3-Amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-L-tyrosine-OH as the starting materials. Subsequent hydrogenation of the resulting product in accordance with the procedures of Step 5, Example 1, Method B, and RP-HPLC purification yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 7.11 (d, 2H), 6.78 (d, 2H), 4.14-3.86 (m, 2H), 3.40 (dd, 1H), 3.22-3.03 (m, 2H), 3.01-2.88 (m, 1H), 1.94 (br.d, 2H), 1.86-1.58 (m, 6H), 1.51 (dd, 2H), 1.40-1.13 (m, 3H), 1.11-0.93 (m, 2H). 31P NMR (CD3OD, 300 MHz): δ 40.19. LCMS m/z: [M+H]+=399.3.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)[C:10]([OH:12])=O)=[O:7])(C)(C)C.CN1CCOCC1.C(OC(Cl)=O)(C)C.[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([CH:45]([NH:51][C@H:52](C(O)=O)[CH2:53][CH:54]([CH3:56])[CH3:55])[C:46]([N:48]([CH3:50])[CH3:49])=[O:47])=[CH:44][C:39]=2[CH:38]=[CH:37]1>O1CCCC1.C1(C)C=CC=CC=1.CN(C)C=O>[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C@@H:45]([N:51]3[C@H:52]([CH2:53][CH:54]([CH3:56])[CH3:55])[C:6](=[O:7])[NH:8][C@H:9]([CH:13]4[CH2:14][C:15]5[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH2:21]4)[C:10]3=[O:12])[C:46]([N:48]([CH3:49])[CH3:50])=[O:47])=[CH:44][C:39]=2[CH:38]=[CH:37]1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1Cc2ccccc2C1
Reactant: CC(C)C[C@H](NC(C(=O)N(C)C)c1ccc2occc2c1)C(=O)O
Agent: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N(C)C)c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.3 %

Procedure:
To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (419 mg) in dry tetrahydrofuran (5 ml) at −20° C. under a nitrogen atmosphere was added N-methylmorpholine (158 μl) and a solution of isopropylchloroformate in toluene (1.0M, 1.44 ml). After 10 minutes, a solution of N-[1-(benzofuran-5-yl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (478 mg) in dimethylformamide (5 ml) was added and the reaction was allowed to warm to room temperature. After 20 hours, the solvent was removed in vacuo and the residue was dissolved in 4N hydrochloric acid in dioxan (4 ml). After 4 hours methanol (13 ml) was added and the reaction was left to stand for a further 18 hours. The solvent was then removed in vacuo and the residue was separated between dichloromethane and saturated sodium bicarbonate solution. The organic phase was evaporated in vacuo and the residue was applied to an SPE (10 g, silica). The product was eluted using an ethyl acetate: methanol gradient (3:1 to 1:3) to afford (2R)-2-(benzofuran-5-yl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide (51 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[N:22]1([CH2:21][C:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:18])[F:20])=[CH:15][CH:16]=3)[S:10][C:6]=2[CH2:4][OH:3])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 355 mg of 4-morpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester in 1 mL of tetrahydrofuran was added 0.88 mL of a 1M solution of lithium aluminium hydride in tetrahydrofuran. The resulting mixture was stirred at room temperature for 1 h. Water was slowly added and the mixture was extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of dichloromethane/methanol from 100/0 to 90/10) to give 276 mg of [4-morpholin-4-ylmethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26](O)=[O:27])[CH:18]=[CH:19][CH:20]=1)=[O:14])[CH3:11].P(Cl)(Cl)(Cl)=O.O(Cl)Cl>N1C=CC=CC=1.O>[CH2:10]([O:12][C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26](=[O:27])[NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:16]=1)[CH3:11]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOC(=O)c1cccc(N2CCC[C@@H]2C(=O)O)c1
Agent: ClOCl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cccc(N2CCC[C@@H]2C(=O)Nc2ccc(C#N)cc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Cool a solution of 4-aminobenzonitrile (0.05 g, 0.42 mmol) in pyridine (2 mL) to 0° C., and add (R)-1-(3-ethoxycarbonyl-phenyl)-pyrrolidine-2-carboxylic acid (0.10 g, 0.38 mmol), followed by phosphorous oxychloride (0.04 mL, 0.43 mmol). Stir the mixture at 0° C. for 2 h followed by addition of a second portion of phosphrous oxychloride (0.04 mL, 0.43 mmol). Stir the mixture at 0° C. for an additional 1 hour. Dilute the mixture with water and extract with EtOAc. Wash the combined organic phase with a saturated aqueous solution of sodium bicarbonate followed by a saturated aqueous solution of ammonium chloride and then brine. Dry the mixture over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.052 g of 3-[(R)-2-(4-cyano-phenylcarbamoyl)-pyrrolidin-1-yl]-benzoic acid ethyl ester as a solid.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][C:17]1[C:22]([C:23]([OH:25])=[O:24])=[C:21]([OH:26])[C:20]([Br:27])=[CH:19][CH:18]=1.[C:28](O)([CH3:31])([CH3:30])[CH3:29]>CN(C1C=CN=CC=1)C.C1COCC1>[NH2:16][C:17]1[C:22]([C:23]([O:25][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])=[C:21]([OH:26])[C:20]([Br:27])=[CH:19][CH:18]=1
Reactant: CC(C)(C)O
Reactant: Nc1ccc(Br)c(O)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)ccc(Br)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dicyclohexylcarbodiimide (4.14 g) was added to a stirred solution of 6-amino-3-bromo-2-hydroxybenzoic acid (Intermediate 63, 3.88 g) and DMAP (0.102 g) in tert-butanol (20 mL) and THF (150 mL). The mixture was stirred at room temperature for 4 hours. The resultant white precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 2.5-15% to give tert-butyl 6-amino-3-bromo-2-hydroxybenzoate (1.16 g) as a yellow solid.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:50][CH2:49][CH2:48][C@@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].Cl>C(O)(=O)C>[NH:1]1[CH2:50][CH2:49][CH2:48][C@@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:35])[CH3:36])=[O:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H]1CCCN1)C(N)=O

Procedure:
Condensation of BocDPro-Phe-PheNHNH2 (0.932 g.) and HGly-Leu-MetNH2 hydrochloride salt (Example 7, 0.630 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocDPro-Phe-Phe-Gly-Leu-MetNH2 in 58% yield. De-t-butoxycarbonylation of BocDPro-Phe-Phe-Gly-Leu-MetNH2 (0.838 g.) using hydrogen chloride in acetic acid gave HDPro-Phe-Phe-Gly-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt sesquihydrate in 72% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10]Br.CCN(CC)CC>COCCOC>[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][NH:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCN
Reactant: BrCc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: COCCNCc1cccc(Br)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
To a solution of 2-methoxyethanamine (900 mg, 12 mmol) in DME (15 mL) was added 3-bromobenzylbromide (2.5 g, 10 mmol) and the reaction mixture was stirred at 40° C. (scheme 14). After 30 minutes, Et3N (1.01 g, 10 mmol) was added and the reaction was allowed to stir for another 10 minutes, filtered and the filtrate was concentrated to afford bromide 64 as a colorless oil (2.0 g, 80% yield). MS (m/z): 244.1/246.1 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C-:10]#[N:11].[Na+].O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:10]([CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9])#[N:11]
Reactant: N#Cc1ccsc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: N#CCc1sccc1C#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
2-Bromomethyl-3-cyanothiophene (2.746 g) was dissolved in toluene (40 ml), followed by the addition of a solution of sodium cyanide (2.002 g)/water (15 ml), and the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of saturated sodium bicarbonate, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a pale yellow solid (823 mg, yield; 43%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:17][CH:16]=2)=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:29]([N:31]=[C:32]=[S:33])[CH3:30].C(O)C>C(OCC)(=O)C>[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:3]2[C:2]([NH:1][C:32]([NH:31][CH2:29][CH3:30])=[S:33])=[CH:12][CH:11]=[CH:10][C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:16][CH:17]=1)#[N:28]
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Reactant: CCN=C=S
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCNC(=S)Nc1cccc(C(=O)OCC)c1NCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of ethyl 3-amino-2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]benzoate (1.61 g), ethyl isothiocyanate (1.5 ml) and ethanol (1 ml) was stirred at room temperature for 3 days. The reaction mixture was dissolved in ethyl acetate and the solution was washed with water, dried and concentrated to dryness to give crystals. Recrystallization from ethyl acetate-hexane afforded pale yellow crystals (1.92 g, 91%), m.p. 108-110° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[NH:5][CH3:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[F:1][C:2]1[CH:3]=[C:4]([N:5]([CH3:6])[CH:13]([C:15]2[CH:16]=[C:17]([C:32]([NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CC(Br)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNc1ccc(F)c(F)c1
Agent: Br
Product: CC(c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1ccc(F)c(F)c1
Yield: 45.8 %

Procedure:
3,4-difluoro-N-methylaniline (161 mg, 1.13 mmol) was reacted with 8-(1-bromoethyl)-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (150 mg, 0.28 mmol) using a procedure similar to the one described in Example 3.00 to give 8-(1-((3,4-difluorophenyl)(methyl)amino)ethyl)-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (66.0 mg, 45.6%). Mass Spectrum: M+H+ 515. NMR Spectrum: (DMSOd6) 1.56 (d, 3H), 2.18 (s, 6H), 2.41 (t, 2H), 2.63 (s, 3H), 3.21-3.28 (m, 2H), 3.34-3.41 (m partially hidden by H2O, 4H), 3.41-3.49 (m, 2H), 3.49-3.56 (m, 2H), 5.53 (q, 1H), 5.55 (s, 1H), 6.61 (d, 1H), 6.87 (ddd, 1H), 7.24 (dd, 1H), 8.09 (d, 1H), 8.43 (d, 1H), 8.74 (t, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:26])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])[CH2:3][CH2:2]1.[BH3-]C#N.[Na+].[CH:31]([C:34]1[C:39]([CH:40]=O)=[C:38]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[C:37]([CH2:49][O:50][CH3:51])=[C:36]([CH:52]([CH3:54])[CH3:53])[N:35]=1)([CH3:33])[CH3:32].O>CO>[CH:31]([C:34]1[C:39]([CH2:40][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:26])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])[CH2:3][CH2:2]2)=[C:38]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[C:37]([CH2:49][O:50][CH3:51])=[C:36]([CH:52]([CH3:54])[CH3:53])[N:35]=1)([CH3:32])[CH3:33]
Reactant: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCNCC1
Reactant: COCc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCN(Cc2c(C(C)C)nc(C(C)C)c(COC)c2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.7 %

Procedure:
Step 2): N-(Piperidin-4-yl)-2-(N'-n-heptylureido)benzamide (0.96 g, 2.7 mmol) and NaBH3CN (0.17 g, 2.7 mmol) were added into a solution of 2.6-diisopropyl-4-(4-fluorophenyl)-3-formyl-5-methoxymethylpyridine (0.9 g, 2.7 mmol) in MeOH (30 ml). The mixture was stirred at room temperature for 72 hours, and then water was added at 0° C. extracted with dichloromethane, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (10 to 50% ethyl acetate in hexane) to give N-[1-[2,6-diisopropyl-4-(4-fluorophenyl)-5-(methoxymethyl)pyridin-3-yl]methylpiperidin-4-yl]-2-(N'-n-heptylureido)benzamide (0.65 g, 35.7%): mp 123° C.: 1NMR (CDCl3)ppm: 0.88 (3H, t), 1.17-1.46 (22H, m), 1.49-1.66 (2H, m), 1.80-2.00 (4H, m), 2.57 (2H, d), 3.09-3.53 (9H, m), 3.68-3.89 (1H, m), 3.49 (2H, s), 4.53 (1H, t), 5.98 (1H, d), 6.93 (1H, t), 7.05-7.24 (4H, m), 7.33-7.48 (2H, m), 8.41 (1H, d), 10.30 (1H, s).
Reaction SMILES: C([O:8][C@H:9]([C@@H:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[OH:20])[C@H:10]([O:15][C:16](=[O:18])[CH3:17])[C@@H:11]([OH:14])[CH:12]=[O:13])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:16]([O:15][C@@H:10]([C@@H:9]([C@@H:19]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[OH:20])[OH:8])[C@@H:11]([OH:14])[CH:12]=[O:13])(=[O:18])[CH3:17]
Reactant: [H][H]
Reactant: CC(=O)OC[C@@H](O)[C@@H](OCc1ccccc1)[C@H](OC(C)=O)[C@@H](O)C=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OC[C@@H](O)[C@@H](O)[C@H](OC(C)=O)[C@@H](O)C=O

Procedure:
Degussa 10% Pd/C (50% wet) (0.4 g) was added to the solution of 4-O-benzyl-3,6-di-O-acetyl-D-glucose (5 mmol) in ethanol (50 mL). Obtained mixture was hydrogenated at room temperature using Paar apparatus with hydrogen (45 psi) After 12 hr reaction was completed (TLC), catalyst was filtered off and the solvent was evaporated to give a crude product. Product was purified by column chromatography (SilicaGel 60 Merck), using hexanes:ethyl acetate as eluent.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][CH3:13].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: COCCCOc1ccccc1I
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COCCCOc1ccccc1-n1ccc2ccccc21
Temperature: 125 °C
Reaction time: 26 h
Yield: 40.2 %

Procedure:
A mixture of the compound of step 1 (8.00 g, 27.4 mmol), indole (3.21 g, 27.4 mmol), copper(I) iodide (522 mg, 2.74 mmol), L-proline (636 mg, 5.48 mmol) and potassium carbonate (7.68 g, 54.8 mmol) in DMSO (50 ml) was stirred for 26 h at 125° C. The mixture was quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC. The eluate was lyophilized overnight to give 3.10 g of the title compound.