Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21]C(=O)OC(C)(C)C)=[C:17]([F:29])[CH:16]=3)=[CH:13][N:14]=2)([OH:9])[CH2:5][CH2:4]1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[S:11][C:10]([C:6]3([OH:9])[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5]3)=[N:14][CH:13]=2)=[CH:16][C:17]=1[F:29]
Reactant: CCN1CCC(O)(c2ncc(-c3ccc(NC(=O)OC(C)(C)C)c(F)c3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1CCC(O)(c2ncc(-c3ccc(N)c(F)c3)s2)CC1
Reaction time: 2 h

Procedure:
To an ambient solution of Example 8A (0.20 g, 0.48 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred for 2 h, and was then concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×5 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound, which was used without further purification. MS (ESI) m/z 322 [M+H]+.
Reaction SMILES: N1C=CC=CC=1P([CH2:14][P:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)C1C=CC=CC=1.ClC[CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36]Cl>ClCCl>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[P:15]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:14][P:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClCCOCCOCCCl
Reactant: c1ccc(P(CP(c2ccccc2)c2ccccn2)c2ccccn2)cc1
Solvent: ClCCl
Product: c1ccc(P(CCOCCOCCP(c2ccccc2)c2ccccn2)c2ccccn2)cc1

Procedure:
Some 1,8-bis[(2-pyridyl)(phenyl)phosphino]-3,6-dioxaoctane was prepared substantially in the same way as the diphosphine of Example 2, except that instead of dichloromethane, 1,8-dichloro-3,6-dioxaoctane was employed.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:48])[CH2:19][CH2:20][C:21]1[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:25][CH:24]=[CH:23][C:22]=1[O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([O:46]C)=[O:45]>>[C:44]([CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:12]=[CH:11][C:5]3[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=3[C:3]=2[CH2:13][CH2:14][CH3:15])[C:21]=1[CH2:20][CH2:19][C:18]([OH:48])=[O:17])([OH:46])=[O:45]
Reactant: COC(=O)CCCCCOc1cccc(CCCCCCOS(C)(=O)=O)c1CCC(=O)OC
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCCc2cccc(OCCCCCC(=O)O)c2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 126, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 2-[(6-methoxy-6-oxohexyl)oxy]-6-[6-(methylsulfonyl)oxyhexyl]benzenepropanoic acid methyl ester from the preceding example, followed by saponification, in 79% overall yield. The product was a colorless solid, mp 86°-88° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][CH2:10][CH2:11][CH3:12])=O)=[CH:3][CH:2]=1.[CH:13]([NH:15][NH2:16])=[O:14].C1COCC1.C(O)C>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:1]1[CH:6]=[CH:5][C:4]([C:7](=[N:16][NH:15][CH:13]=[O:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][CH:2]=1
Reactant: NNC=O
Reactant: CCCCC(=O)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCC(=NNC=O)c1ccncc1
Yield: 26.2 %

Procedure:
A solution of 14.26 gm (0.0956 mole) of n-butyl 4-pyridyl ketone, 5.70 gm (0.0956 mole) of formylhydrazine, 50 ml of THF, 30 ml of absolute ethanol and 0.1 gm of p-toluenesulfonic acid is refluxed 24 hr. The reaction is chilled to give a white solid which is collected and discarded. The filtrate is concentrated in vacuo to furnish a solid. This material is dissolved in methylene chloride. The methylene chloride solution is washed with saturated sodium bicarbonate solution; then brine. The organic layer is dried over magnesium sulfate and concentrated in vacuo in the presence of excess hexane to yield 5.14 gm (26%) of the title compound having a melting point of 143.4° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:10][CH3:11].Cl>C(#N)C.C(OC)(OC)(OC)CCC>[CH3:11][N:10]1[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:7]1[CH2:2][CH2:3][CH3:4]
Reactant: CNN(Cc1ccccc1N)c1ccccc1
Agent: CCCC(OC)(OC)OC
Agent: Cl
Solvent: CC#N
Product: CCCC1=Nc2ccccc2CN(c2ccccc2)N1C
Temperature: 50 °C
Yield: 192.2 %

Procedure:
To a solution of 2.37 g (0.01 m) of 1-[(2-aminophenyl)methyl]-2-methyl-1-phenylhydrazine of Example 9c in 40 ml of acetonitrile and 2.96 g (0.02 m) of trimethyl orthobutyrate, enough ethereal HCl was added to make the solution acidic. The mixture was warmed at 50° C. for 2.5 hours and then refluxed for 3.5 hours. The solvent was evaporated and the residue partitioned between 10% NaOH and ether. The ether solution was extracted with 5% HCl. The aqueous acidic solution was basified with 10% NaOH and the product was extracted with ether. The ether extract was dried (Na2SO4), filtered and evaporated to give 2.8 g (93%) of 4,5-dihydro-3-methyl-4-phenyl-2-n-propyl-3H-1,3,4-benzotriazepine as an oil.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[K].C1(=O)[NH:18]C(=O)C2=CC=CC=C12>CN(C)C=O>[NH2:18][CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCC1COc2ccccc2O1
Agent: [K]
Solvent: CN(C)C=O
Product: NCC1COc2ccccc2O1

Procedure:
Commercial grade of 2-chloromethyl-1,4-benzodioxane (10.0 g, 54.7 mmol) and phthalimide potassium salt (12.0 g, 65.0 mmol) were added to N,N-dimethylformamide (350 ml) and subjected to reaction overnight under reflux; thereafter, N,N-dlmethylformamide was distilled off under vacuum. Water (250 ml) was added to the residue and the mixture was stirred well, with the floating solids being subsequently recovered by filtration. The solids were dried, then recrystallized from methanol/methylene chloride, thereby yielding (1,4-benzodioxan-2-ylmethyl)phthalimide as a colorless tabular crystal in an amount of 8.43 g. The thus obtained crystal was dissolved in ethanol (500 ml); to the solution, hydrazine hydrate (4.3 g) was added, followed by refluxing under heating for 3 h. The resulting solids were filtered off and ethanol was distilled off under vacuum, followed by addition of water (300 ml). Thereafter, an aqueous solution of 6N sodium hydroxide was added to adjust pH to 12 and the mixture was subjected to 3 cycles of extraction with methylene chloride. The methylene chloride layers were dried with anhydrous sodium sulfate, and concentrated under vacuum, thereby yielding a crude product of 2-aminomethyl-1,4-benzodioxane as a colorless oil (crude product, 4.3 g).
Reaction SMILES: [Na].O[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C[O-].[Na+].Cl[CH2:14][C:15](CCl)=[CH2:16]>CO>[CH2:16]([S:9][C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1)[CH:15]=[CH2:14]
Reactant: Oc1ccc(S)cc1
Reactant: C=C(CCl)CCl
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: C=CCSc1ccccc1
Yield: 173.8 %

Procedure:
To a 1 L flask at 0 C was added 160 mL of methanol. The solution was kept under 30 C as Na metal (5.10 g, 221.24 mmol) was added in small portions. After all the sodium had reacted, 4-hydroxythiophenol (25.0 g, 2.2 eq) was added to the solution of sodium methoxide. The solution was heated to reflux and 3-chloro-2-chloromethyl-1-propene (11.26 g, 1 eq) was added dropwise over 1 hour. The solution was allowed to reflux overnight. The solution was cooled to 25 C, filtered, and reduced in vacuo to remove the methanol. The crude material was taken up in 500 mL of water and extracted with ether (4×150 mL). The ether layer was washed with 1N HCl, water, brine, and dried over sodium sulfate. The organic layer was reduced in vacuo to a crude orange oil. The oil was purified by flash chromatography 90:10 hexanes/ethyl acetate to yield 23.52 g of a colorless oil. Yield 85.8%. 1H NMR (400 MHz, CDCl3, δ): 7.23 (m, 4H, Ar—H), 6.74 (m, 4H, Ar—H), 5.84 (s, 2H, Ar—OH), 4.70 (s, 2H, C═CH2), 3.57 (s, 4H, CH2); 13C NMR (400 MHz, CDCl3, δ): 155.3 (C1), 140.45 (C10), 138.6 (C5), 134.3 (C8), 132.7 (C4), 126.0 (C7), 116.5 (C3), 116.0 (C6), 40.63 (C11); MS (ESI, m/z): [M+Li]+ calcd for C16H16O2S2, 344.3; found, 344.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:19][C:20]3[N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH3:38])[C:22](=[O:31])[C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:30])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=3)[C:3]=12.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:19][C:20]3[N:21]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH3:38])[C:22](=[O:31])[C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:30])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)[C:3]=12
Reactant: COc1cccc(-c2nn(Cc3cc4cccc(C)c4c(=O)n3-c3ccccc3C)c3ncnc(N)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccccc1-n1c(Cn2nc(-c3cccc(O)c3)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Temperature: -78 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 3-((4-amino-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1702) (100 mg, 0.2 mmol) in CH2Cl2 (20 mL) at −78° C. under a nitrogen atmosphere, BBr3 (1 mL) was added and the resulting mixture was stirred at −78° C. for 3 h. The mixture was allowed to warm to RT, poured into ice-water (200 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (10-50% MeOH/CH2Cl2) to afford the desired product, 3-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (1613) (87 mg, 91% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[Cl:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH2:25])=[N:21]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][N:20]2[CH:24]=[N:23][C:22]([NH:25][CH:10]3[CH2:11][CH2:12][N:7]([C:5]4[S:4][N:3]=[C:2]([CH3:1])[N:6]=4)[CH2:8][CH2:9]3)=[N:21]2)=[CH:17][CH:16]=1
Reactant: Nc1ncn(Cc2ccc(Cl)cc2)n1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Product: Cc1nsc(N2CCC(Nc3ncn(Cc4ccc(Cl)cc4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(4-chloro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].C([O-])([O-])=O.[Na+].[Na+].[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O.O>[CH2:13]([O:20][C:21]([NH:1][C@@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC[C@H](N)CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a cold (0° C.) solution of (S)-2-amino-1-butanol (2.0 g, 22.5 mmol) in acetone/H2O 1:1 (50 mL), Na2CO3 (8.7 g, 81.9 mmol) and BnOCOCl (5.8 g, 33.8 mmol) were added. After stirring at 0° C. for 1 h, the solid was filtered off and washed with acetone (2×30 mL). The filtrates were concentrated in vacuo and the residue was purified by column chromatography on silica (100% CH2Cl2 to CH2Cl2/MeOH 20:1) to obtain alcohol 7 as a white solid (2.14 g, 43% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:27][CH:26]=2)=[O:23])[CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1)[CH3:2]>CCO.[Pd]>[CH2:31]([C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:22](=[O:23])[NH:21][C:6]2([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:39])[CH2:10][CH2:9][NH:8][CH2:7]2)=[CH:30][CH:29]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCN(C(=O)OCc3ccccc3)C2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCNC2)cc1
Reaction time: 24 h
Yield: 80.1 %

Procedure:
A solution of benzyl 3-(2-ethoxy-2-oxoethyl)-3-(3-(4-octylphenyl)ureido)pyrrolidine-1-carboxylate (140 mg, 0.26 mmol) in EtOH (5 mL) was purged with nitrogen and Pd/C (25 mg) was added and the flask was purged with hydrogen and stirred for 24 h. The mixture was filtered through celite and concentrated. The residue was dissolved into H2O and lyophilized to give the title compound as a white solid (84 mg, 80%). 1H NMR (400 MHz, CD3OD) δ 7.25 (d, 2H, J=7.9 Hz), 7.08 (d, 2H, J=8.1 Hz), 4.16 (q, 2H, J=7.1 Hz), 4.05-4.02 (m, 1H), 3.51-3.47 (m, 2H), 3.23-3.19 (m, 1H), 2.91-2.87 (m, 1H), 2.57-2.50 (m, 3H), 2.26-2.20 (m, 1H), 1.60-1.57 (m, 2H), 1.31-1.23 (m, 15H), 0.90 (t, 3H, J=6.6 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([S:15]([CH2:18]C)(=[O:17])=[O:16])=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1.[H-].[Na+].[CH3:34][O:35][C:36](=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([CH2:43]Br)=[CH:39][CH:38]=1>CN(C=O)C.C(Cl)Cl.C([O-])(O)=O.[Na+].[Cl-].[Na+].O>[CH3:1][N:2]1[C:6]2[C:7]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:8][C:9]([C:11]([F:13])([F:12])[F:14])=[CH:10][C:5]=2[N:4]([CH2:43][C:40]2[CH:41]=[CH:42][C:37]([C:36]([O:35][CH3:34])=[O:45])=[CH:38][CH:39]=2)[C:3]1=[N:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:31])[F:30])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCS(=O)(=O)c1cc(C(F)(F)F)cc2nc(Nc3ccc(OC(F)(F)F)cc3)n(C)c12
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2c(=Nc3ccc(OC(F)(F)F)cc3)n(C)c3c(S(C)(=O)=O)cc(C(F)(F)F)cc32)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A flask containing the title compound from Example 10, Step A (30 mg, 0.066 mmol) was charged with sodium hydride (60% suspension in mineral oil, 4.0 mg, 0.10 mmol), and the mixture was dissolved in DMF (1.5 mL). After ten minutes, methyl4-(bromomethyl)benzoate (18 mg, 0.077 mmol) was added and the mixture was stirred at room temperature. After 15 h, the mixture was diluted with CH2Cl2 and poured in saturated aq. NaHCO3/brine. The phases were separated, and the organic phase was dried over Na2SO4 and concentrated. The crude reaction mixture, containing both N-benzyl regioisomers, was taken forward directly: LC-MS (ESI, Method B) 2.25 min, m/z 602.3 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4]O.[I-].[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[H-].[Na+]>C(Cl)Cl.C1COCC1.CCOCC>[CH3:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:7][O:8][CH2:4][CH2:3]1
Reactant: CC(CCO)(CCO)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(c2ccccc2)CCOCC1
Reaction time: 16 h

Procedure:
3-Methyl-3-phenyl-pentane-1,5-diol (3.88 g, 20 mmol), Ag2O (6.95 g (30 mmol), potassium iodide (0.66 g, 4 mmol) were suspended in 50 mL DCM and treated with a solution of p-toluenesulfonyl chloride (4.19 g, 22 mmol) in 30 mL DCM. The mixture was allowed to stir under nitrogen atmosphere for 16 h. The crude reaction mixture was applied on a short plug of silica gel column and the product was collected by washing with DCM. The solvent was evaporated and the residue was dissolved in dry THF (30 mL) and added drop wise to a suspension of NaH (0.8 g of 60% suspension in mineral oil, 20 mmol) in THF (30 ml). The reaction mixture was allowed to stir at room temperature for 24 h and was then diluted with 60 mL ether and washed with water (60 mL). The aqueous phase was washed once with ether (30 mL) and the organic extracts were combined, washed with brine, dried over Na2SO4 and the solvent was evaporated by rotary evaporation. The product was purified by flash chromatography on silica gel column using 0-5% hexane/ethylacetate solvent mixture as the mobile phase. MS: m/z 177.1 (M++1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[N+]1([O-])CC[O:24]CC1.O>C(#N)C>[CH:2]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:24]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(CBr)c1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccccc2)c(C=O)c1
Reaction time: 4 h
Yield: 66.7 %

Procedure:
In 100 ml of acetonitrile was dissolved 9.3 g of ethyl 2-(bromomethyl)biphenyl-4-carboxylate, and 7.0 g of N-methylmorpholine-N-oxide was added thereto at room temperature, followed by 4 hours of stirring. Water was added to the reaction solution, which was then extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate. After the solvent was removed by evaporation, the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 4.94 g of ethyl 2-formylbiphenyl-4-carboxylate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:17]2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:16]=2[Cl:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(Cl)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])cc(Cl)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (6.3 9), methyl 3-chloro-5-nitrosalicylate (2.4 g) and triphenylphosphine (10.8 g) in dichloromethane (100 ml) was added diethyl azodicarboxylate (6.6 ml) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/1 as an eluant to give the desired compound (3.4 g, yield 79%) as a pink solid.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:45])[C:7](=[CH2:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][C@@H:12]([CH:32]([CH3:34])[CH3:33])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([O:24]CC2C=CC=CC=2)[CH:15]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([NH:5][C:6](=[O:45])[C@H:7]([CH3:44])[CH2:8][C@H:9]([OH:43])[C@@H:10]([NH:35][C:36]([O:38][C:39]([CH3:40])([CH3:42])[CH3:41])=[O:37])[CH2:11][C@@H:12]([CH:32]([CH3:33])[CH3:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([OH:24])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCc2ccccc2)c1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Agent: [Pd]
Solvent: CO
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(O)c1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
860 mg of N-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-benzyloxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide are hydrogenated for 3 hours at room temperature and under normal pressure in the presence of 860 mg of 50% Pd/C in 30 ml of methanol. The reaction mixture is filtered and concentrated by evaporation. The residue is purified by means of FC (100 g of silica gel, dichloromethane/ethyl acetate=9:1) with separation of the diastereoisomers. The title compound is obtained: Rf (dichloromethane/ethyl acetate=8:2)=0.23.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([NH:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][C@H:9]1[C:10](O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.[C@H:55]1([NH2:65])[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH2:58][CH2:57][CH2:56]1>CN(C=O)C.O>[CH:32]1[C:33]2[CH:21]([CH2:20][O:19][C:17]([NH:16][C@@H:14]3[CH2:15][N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[C@H:9]([C:10](=[O:11])[NH:65][C@H:55]4[C:64]5[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=5)[CH2:58][CH2:57][CH2:56]4)[CH2:13]3)=[O:18])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]=2[CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)O
Reactant: N[C@@H]1CCCc2ccccc21
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reaction time: 0.33 h
Yield: 86.6 %

Procedure:
To a solution of (2S,4S)-Boc-4-(Fmoc-amino)-proline (Chem-Impex, 6.00 g, 13.3 mmol) in DMF (20 mL) at 0° C. were added EDC (3.05 g, 15.9 mmol), HOAt (2.17 g, 15.9 mmol) and NMM (4.38 mL, 39.8 mmol). The reaction mixture was stirred at ice bath temperature for 20 min then treated with a solution of (R)-1,2,3,4-tetrahydronaphthalen-1-amine (Alfa Aesar, 2.15 g, 14.6 mmol) in DMF (2 mL). The reaction mixture was stirred at rt for 1 h and cold water (100 mL) was added to the reaction mixture. The solid that formed was collected by filtration and washed with cold water (100 mL). The solid was dissolved in CH2Cl2 (200 mL) and the organic solution was washed with 5% aq. citric acid solution and brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 and purified by flash column chromatography (gradient elution from 10 to 30% EtOAc in CH2Cl2) provided the title compound (6.70 g, 87%) as a light tan solid. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=7.5 Hz, 2H), 7.67 (d, J=7.3 Hz, 2H), 7.42 (td, J=7.2, 4.0 Hz, 2H), 7.37-7.03 (m, 6H), 5.22 (br. s., 1H), 4.57-4.23 (m, 5H), 3.68-3.49 (m, 2H), 2.91-2.74 (m, 2H), 2.52 (d, J=13.4 Hz, 1H), 2.35-2.21 (m, 1H), 2.14 (d, J=5.1 Hz, 1H), 1.97-1.80 (m, 3H), 1.44 (s, 9H); MS(ESI+) m/z 582.2 (M+H)+.