Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-])=O)[CH:24]=3)[NH:19][CH:18]=2)[CH2:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].O.NN>CO.O.[Ni]>[NH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9])[CH2:12]1
Reactant: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc([N+](=O)[O-])cc23)C1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(N)cc23)C1
Yield: 98.9 %

Procedure:
To a solution of tert-butyl ethyl(3-(5-nitro-1H-indol-3-yl)cyclohexyl)carbamate (0.70, g 1.81 mmol) in dry MeOH (15 mL) was added Raney-Ni (0.1 g as a slurry in water) and hydrazine hydrate (0.90 mL, 18.10 mmol). The resulting mixture was immersed in a preheated oil bath and refluxed for 15 minutes or until the solution became clear. The reaction was cooled and filtered trough Celite, washed with MeOH (20 mL), and the solvent evaporated. The crude was purified on column chromatography (2 M NH3 in MeOH:CH2Cl2, 2:98) to give the title compound as a brownish solid (0.64 g, quantitative). 1H-NMR (CDCl3) δ 1.12 (t, 3H, J=6.8 Hz), 1.45 (s, 9H), 1.53-1.69 (m, 3H), 1.71-1.79 (m 1H), 1.82-1.92 (m, 1H), 2.07-2.17 (m, 2H), 3.06-3.24 (m, 2H), 3.43-3.56 (m, 1H), 4.43 (s, 1H), 6.64 (dd, 1H, J=2.1, 8.4 Hz), 6.89 (d, 1H, J=2.1 Hz), 7.15 (d, 1H, J=8.4 Hz), 7.26 (s, 1H), 7.33 (s, 1H), 7.82 (s, 1H); EI-MS (m/z, %) 357 (M+, 70), 212 (100).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:47]=[CH:46][C:39]([C:40]([NH:42][CH2:43][CH2:44][OH:45])=[O:41])=[CH:38][C:37]=1[O:48][CH3:49].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:30]1([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]5[N:15]=[C:16]([CH3:18])[O:17][C:13]=5[CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:35][C:36]3[CH:47]=[CH:46][C:39]([C:40]([NH:42][CH2:43][CH2:44][OH:45])=[O:41])=[CH:38][C:37]=3[O:48][CH3:49])[N:3]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(C(=O)NCCO)ccc1N
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)NCCO)ccc1Nc1nc(OC2CCCC2)c2c(-c3ccc4nc(C)oc4c3)cn(COCC[Si](C)(C)C)c2n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a degassed mixture of 6-(2-chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-N-(2-hydroxyethyl)-3-methoxybenzamide (1.2 equiv) and cesium carbonate (5 equiv) in 1,4-dioxane (0.14 M) were added palladium acetate (0.1 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.2 equiv). The mixture was stirred at 120° C. overnight. The reaction was cooled to room temperature and filtered. The filtrate was concentrated and the residue obtained was purified by preparative thin layer chromatography (8% MeOH in DCM) to afford the title compound (30% yield). MS (ESI) m/z 673.1 [M+1]+.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](Cl)=[O:4].P(Cl)(Cl)(Cl)(Cl)Cl.C[C@@H](CCCC)C(O)=O.[NH2:25][C@H:26]([C:32]([C:34]1[C:35]([C:41]#[N:42])=[N:36][CH:37]=[C:38]([NH2:40])[CH:39]=1)=[O:33])[CH2:27][CH2:28][C:29](=[O:31])[OH:30].C([O-])(O)=O.[Na+]>O1CCCC1.O>[CH3:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([NH:25][C@H:26]([C:32]([C:34]1[C:35]([C:41]#[N:42])=[N:36][CH:37]=[C:38]([NH2:40])[CH:39]=1)=[O:33])[CH2:27][CH2:28][C:29](=[O:30])[OH:31])=[O:4]
Reactant: N#Cc1ncc(N)cc1C(=O)[C@@H](N)CCC(=O)O
Reactant: CCCC[C@H](C)C(=O)Cl
Agent: CCCC[C@H](C)C(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H](C)C(=O)N[C@@H](CCC(=O)O)C(=O)c1cc(N)cnc1C#N
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
To prepare this compound, a solution of 1.2 g (0.008 mol) of (S)-2-methylhexanoyl chloride (prepared by reacting phosphorus pentachloride with (S)-2-methylhexanoic acid, itself obtained by the method described in J. Biol. Chem. 1926, 70, 211; ibid, 1932, 98, 1 and Chem. Pharm. Bull. 1979, 27, 747) in 30 cm3 of anhydrous tetrahydrofuran is added dropwise to a solution of 1 g (0.004 mol) of alpha-L-glutamyl-5-aminopyridine-2-carbonitrile (prepared according to J. Med. Chem. 1973, 16, 163) and 3.4 g (0.04 mol) of NaHCO3 in 30 cm3 of water. After stirring for 15 minutes at 20° C., the tetrahydrofuran is removed under vacuum and the remaining aqueous solution is acidified to pH 2-3 with a 6N solution of HCl, affording a precipitate of 1 g of N-[(S)-2-methylhexanoyl]-alpha-L-glutamyl-5-aminopyridine-2-carbonitrile (yield 69%, melting point 146° C., in the amorphous state) after filtration and trituration in hexane.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[OH-].[Na+].[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>C(Cl)Cl>[C:15]([O:14][C:12]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: OCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a stirred mixture of 22.2 g (193 mmol) of 4-hydroxymethylpiperidine in 100 mL of CH2Cl2 and 75 mL of a 15% solution of NaOH was added a solution of 63.2 g (289 mmol) of BOC2O in 50 mL of CH2Cl2 over 2 h. After stirring for a further 30 min, the reaction mixture was extracted with 15% NaOH solution and sat'd Nacl solution. The organic fraction was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ehtyl acetate, 19:1, then 4:1, then 1:1) to give 25 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=2)[C:9]([CH3:21])([CH3:20])[CH2:8]1)=[O:5].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([NH:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=2)[C:9]([CH3:21])([CH3:20])[CH2:8]1)=[O:5]
Reactant: COC(=O)c1ccc2c(c1)C(NC(=O)c1ccccc1Cl)CC2(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)CC(NC(=O)c2ccccc2Cl)c2cc(C(=O)O)ccc21
Reaction time: 4 h
Yield: 98 %

Procedure:
Methyl 3-(2-chlorobenzamido)-1,1-dimethyl-2,3-dihydro-1H-indene-5-carboxylate (B-39) (120 mg, 0.34 mmol, 1 eq.) was dissolved in a mixture of solvents THF:MeOH:H2O (5:3:1, 5 ml) and LiOH (70 mg, 1.67 mmol, 5 eq.) was added portionwise at 0° C. The reaction mixture was stirred for 4 h and then the solvent was evaporated under reduced pressure. Water (4 ml) was added to the reaction to get a clear solution and it was then acidified with citric acid. This was followed by extraction with EtOAc (2×50 ml). The organic part was washed with brine (20 ml), dried over Na2SO4, filtered and evaporated under reduced pressure to yield the crude product which was purified by column chromatography (silica gel, 5% MeOH/MC) to yield the desired product as a white solid. Yield: 98% (115 mg, 0.34 mmol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:7][N+:8]1[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][C:12]=2[N:11]=[C:10]([CH2:21][CH2:22][CH:23]=O)[N:9]=1)[CH2:18][CH2:17][CH2:16]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[N:1]1([CH2:23][CH2:22][CH2:21][C:10]2[N:9]=[N+:8]([O-:7])[C:13]3[CH:14]=[C:15]4[C:19]([CH2:18][CH2:17][CH2:16]4)=[CH:20][C:12]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: [O-][n+]1nc(CCCN2CCCCC2)nc2cc3c(cc21)CCC3
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
Piperidine (3.0 g, 35 mmol) was added to a stirred solution of propanal 75 (1.5 g, 6.2 mmol) in MeOH (100 mL) at 0° C. and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0° C. for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 mL), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 86 (1.33 g, 69%) as a yellow oil: 1H NMR δ 8.24 (s, 1H, H-9), 7.74 (s, 1H, H-5), 3.09-3.15 (m, 4H, H-6, H-8), 3.02-3.07 (m, 2H, CH2), 2.82-2.95 (m, 6H, 3×CH2), 2.27-2.38 (m, 2H, CH2), 2.17-2.26 (m, 2H, H-7), 1.76-1.87 (m, 4H, 2×CH2), 1.50-1.60 (m, 2H, CH2); 13C NMR δ 164.3, 155.0, 149.2, 147.4, 132.3, 122.7, 114.2, 57.1, 53.5 (2), 34.3, 33.2, 32.8, 25.7 (2), 23.7, 22.9, 22.6; HRMS (FAB+) calcd for C18H25N4O (MH+) m/z 313.2025, found 313.2025.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1OCc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1cc(Br)ccc1OCc1cccc(Cl)c1
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-(3-chloro-benzyloxy)-benzaldehyde (6.0 g, 18.4 mmol) in MeOH (90 mL) at rt was added NaBH4 (1.07 g, 27.7 mmol) over 1 h. After 18 h at rt, H2O was added (5 mL) and the reaction concentrated to a residual mass, which was dissolved into EtOAc (150 mL). This EtOAc solution was washed with H2O (2×100 mL) and dried to yield the title compound as a light yellow (6.0 g, 100%). MS (ESI): mass calcd. for C14H12BrClO, 327.6; m/z found, 328.3 [M+H]+. 1H NMR (CDCl3) 7.48 (d, J=2.5 Hz, 1H), 7.42-7.20 (m, 5H), 6.76 (d, J=8.7 Hz, 1H), 5.07 (d, J=19.2 Hz, 2H), 4.69 (d, J=17.5 Hz, 2H), 2.15 (t, J=10.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:14]1=[O:24].Br[C:26]1[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][CH:31]=1.CC1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:26]3[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][CH:31]=3)[CH2:20][CH2:19]2)[C:14]1=[O:24]
Reactant: FC(F)(F)c1ncc(Br)cn1
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc3ccccc3c2-c2c(P(c3ccc(C)cc3)c3ccc(C)cc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4cnc(C(F)(F)F)nc4)CC3)C2=O)c(F)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
A mixture of (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (Preparation E; 0.20 g, 0.56 mmol), 5-bromo-2-(trifluoromethyl)pyrimidine (0.15 g, 0.68 mmol), (S)-(−)-2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl (0.076 g, 0.11 mmol), Pd(OAc)2 (0.025 g, 0.11 mmol), and Cs2CO3 (0.92 g, 2.8 mmol) were combined in degassed toluene (6 mL) and stirred in a sealed tube at 110° C. overnight. The solution was cooled, quenched with water, extracted with EtOAc, dried over MgSO4, and concentrated. Flash chromatography of the crude product on silica followed by trituration of the isolated material with 9:1 hexanes:DCM gave a white solid that was filtered and dried. The material was characterized as (S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-1-(1-(2-(trifluoromethyl)pyrimidin-5-yl)piperidin-4-yl)pyrrolidin-2-one (0.064 g, 0.13 mmol, 23% yield). Mass spectrum (apci) m/z=502.1 (M+H). Optical purity was not determined.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].[C:16]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(OC)C=CC=CC=1>[Pd].C(N(CC)CC)C>[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[NH:6][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16](=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: [Pd]
Agent: Cl
Solvent: COc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1

Procedure:
A mixture of tyrosine methyl ester hydrochloride (4.8 g), 2-benzoylcyclohexanone (5.0 g), palladium on carbon (1.0 g, 10%), triethylamine (2.9 ml) and anisole (70 ml) was heated at reflux for 20 hours. The reaction mixture was filtered and the filtrate was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane: ethyl acetate=3:1 as the eluant to afford the title compound (1.83 g, Rf=0.39: thin layer chromatography on a silica gel plate using hexane: ethyl acetate=3:1 as the eluant).
Reaction SMILES: [CH2:1]([CH:8]1[CH:13]=[CH:12][NH:11][NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=O.O>C(O)C>[CH2:1]([C:8]1[C:9](=[O:14])[NH:10][N:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NNC=CC1Cc1ccccc1
Agent: O=[Se]=O
Solvent: O
Solvent: CCO
Product: O=c1[nH]nccc1Cc1ccccc1
Yield: 52.4 %

Procedure:
To a solution of 1-methyl 2-benzylsuccinate (0.78 g) in tetrahydrofuran (12 mL) was added borane tetrahydrofuran complex (0.93 mol/L solution in tetrahydrofuran, 3.8 mL) at 0° C. The temperature was raised to room temperature, and the mixture was stirred for 15 hours. To the reaction mixture were added water and potassium carbonate, and the mixture was extracted with diethyl ether. After the organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. After the residue was dissolved in dichloromethane (20 mL), a Dess-Martin reagent (1,1,1-tri-acetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one)(1.2 g), and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. After the organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. After the residue was dissolved in ethanol (5 mL), hydrazine monohydride (0.14 mL) was added to the solution, and the mixture was heated under reflux for 30 minutes. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1-1/1) to give 4-benzyl-3,4-dihydro-2H-pyridazin-3-one (0.31 g). To a solution of the obtained 4-benzyl-3,4-dihydro-2H-pyridazin-3-one (0.16 g) in ethanol (5 mL-) was added selenium dioxide (0.48 g), and the mixture was heated under reflux for 41 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added diethyl ether, and the resulting precipitated crystals were collected by filtration and dried under reduced pressure to give 4-benzyl-2H-pyridazin-3-one (0.083 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH3:25][S:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([S:26][CH3:25])=[CH:28][CH:29]=2)=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: CSc1ccc(CCl)cc1
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(SC)cc2)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 86(b)] with 4-methylthio-benzyl chloride [J.Org.Chem. (1988),53(3), 561-569] there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-(4-methylsulphanyl-benzyloxy)-piperidine-1-carboxylate, from which by cleavage of the allyl group by means of bis-(triphenylphosphine)-palladium(II) diacetate analogously to Example 152(e) there was obtained tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(4-methylsulphanyl-benzyloxy)-piperidine-1-carboxylate. Subsequent alkylation with 5-bromomethyl-3-(2-methoxy-phenyl)-[1,2,4]oxadiazole analogously to Example 44(e) gave tert-butyl (3RS,4RS)-4-{4-[3-(2-methoxy-phenyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-3-(4-methylsulphanyl-benzyloxy)-piperidine-1-carboxylate as a pale yellow, viscous oil; MS: 618 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([O:19][CH2:20][CH3:21])=[C:13]([CH3:22])[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([C:26]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:27]=1[O:28][CH2:29][CH2:30][NH2:31])([CH3:25])[CH3:24]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([O:19][CH2:20][CH3:21])=[C:13]([CH3:22])[C:10]=1[CH2:11][NH:31][CH2:30][CH2:29][O:28][C:27]1[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:26]=1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(C)C)c(OCCN)c1
Reactant: CCOc1c(C)c(C)c(OCc2ccccc2)c(C=O)c1C
Solvent: c1ccccc1
Product: CCOc1c(C)c(C)c(OCc2ccccc2)c(CNCCOc2cc(C)ccc2C(C)C)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
A solution of 2-benzyloxy-5-ethoxy-3,4,6-trimethylbenzaldehyde (2.98 g) and 2-(2-isopropyl-5-methylphenoxy)ethylamine (1.93 g) in benzene (50 ml) was refluxed under heating for 5 hours in a Dean-Stark extractor. The solvent was distilled off under reduced pressure and the residue was suspended in ethanol (100 ml). Sodium borohydride (0.40 g) was added with ice-cooling and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure and water was added. The mixture was extracted with ethyl acetate and the obtained extract was purified by silica gel column chromatography (eluent; ethyl acetate/benzene=1/1) to give 4.16 g of a colorless solid. The solid was recrystallized from methanol to give 1.62 g of the title compound (colorless needle crystals).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:77])[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:73]([CH3:76])[CH2:74][CH3:75])[C@H:35]([O:71][CH3:72])[CH2:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C@H:44]([O:69][CH3:70])[C@@H:45]([CH3:68])[C:46](=[O:67])[NH:47][C@H:48]([C:56]1[O:57][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[N:59][N:60]=1)[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:22])[CH3:21])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:77])[C@H:19]([C:23]([NH:25][C@H:26]([C:30]([N:32]([C@@H:34]([C@@H:73]([CH3:76])[CH2:74][CH3:75])[C@H:35]([O:71][CH3:72])[CH2:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[C@H:44]([O:69][CH3:70])[C@@H:45]([CH3:68])[C:46](=[O:67])[NH:47][C@H:48]([C:56]1[O:57][C:58]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[N:59][N:60]=1)[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:38])[CH3:33])=[O:31])[CH:27]([CH3:29])[CH3:28])=[O:24])[CH:20]([CH3:21])[CH3:22]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCNC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C

Procedure:
15 mg (14 μmol) of N-(6-{[(benzyloxy)carbonyl]amino}hexyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 234) were taken up in 3 ml of methanol, and 1.8 mg of palladium on charcoal (5%) were added. The reaction mixture was subsequently hydrogenated under standard hydrogen pressure at RT for 2 h. The catalyst was then filtered off and the solvent was removed under reduced pressure. The residue was lyophilized from 1:1 acetonitrile/water. 11 mg (86% of theory) of the title compound were obtained as a foam.
Reaction SMILES: ClCCCl.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:16]=2[C:17](O)=[O:18])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].S(Cl)(Cl)=O.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>O1CCCC1.CN(C)C=O>[CH2:32]([N:34]([CH2:35][CH3:36])[C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:15]=1[C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH3:5])[CH:8]=1)[CH3:33]
Reactant: CCNCC
Reactant: COc1ccc(-c2cc(C(F)(F)F)ccc2C(=O)O)cc1OC
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(C(F)(F)F)cc1-c1ccc(OC)c(OC)c1
Temperature: 0 °C
Yield: 88.8 %

Procedure:
500 ml of 1,2-dichloroethane, 60 g (0.184 mol) of 2-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)benzoic acid and 5 ml of N,N-dimethylformamide are introduced successively into a 1000 ml round-bottomed flask. 20 ml of thionyl chloride (0.276 mol) are then run in dropwise with stirring and while cooling at 0° C. When the addition is finished, the reaction mixture is heated progressively to 55° C. over 2 hours and then evaporated to dryness. The residue is taken up in 200 ml of tetrahydrofuran and then poured dropwise into a solution containing 58 ml (0.55 mol) of diethylamine in 200 ml of tetrahydrofuran maintained at a temperature below 10° C. When the addition is finished, the reaction mixture is stirred at room temperature for one hour and then evaporated to dryness. The residue is taken up in dichloromethane and washed successively with 1N HCl and distilled water. After drying over magnesium sulfate, the organic phase is evaporated under reduced pressure to provide 62.3 g (yield: 89%) of N,N-diethyl-2-(3,4-dimethoxyphenyl)-4-(trifluoromethyl)benzamide in the form of a white solid melting at 109°-110° C.