Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([C:17]([F:20])([F:19])[F:18])=[N:7]2.C([Sn](CCCC)(CCCC)[C:26]([O:28]CC)=[CH2:27])CCC.Cl>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([NH:12][C:9]1[C:8]([C:17]([F:20])([F:19])[F:18])=[N:7][C:6]2[C:11]([N:10]=1)=[C:2]([C:26](=[O:28])[CH3:27])[CH:3]=[CH:4][CH:5]=2)([CH3:16])([CH3:15])[CH3:14]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc2nc(C(F)(F)F)c(NC(C)(C)C)nc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
A mixture of 8-bromo-N-(tert-butyl)-3-(trifluoromethyl)quinoxalin-2-amine (206 mg, 0.592 mmol), tributyl(1-ethoxyvinyl)stannane (300 μl, 0.888 mmol; Aldrich), and Pd(PPh3)4 (0) (68.4 mg, 0.059 mmol) in toluene (5.9 ml) was heated to 100° C. for 8 h; more Pd(PPh3)4 (0) (68.4 mg, 0.059 mmol) and tributyl(1-ethoxyvinyl)stannane (300 μl, 0.888 mmol) were added and the reaction was stirred at 100° C. for another 16 h. Concentrated HCl (61.6 μl, 0.740 mmol) was then added, and the resulting mixture was concentrated onto silica gel. Chromatographic purification (silica gel, 100% hexanes to 10% EtOAc in hexanes) provided 1-(3-(tert-butylamino)-2-(trifluoromethyl)quinoxalin-5-yl)ethanone (224e, >99% yield) as a light yellow solid. MS (ESI, pos. ion) m/z: 312.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:15])[CH2:7]/[C:8]/2=[CH:11]\[C:12](O)=[O:13])=[CH:4][CH:3]=1.[Cl:16]CCl>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH3:15])[CH2:7]/[C:8]/2=[CH:11]\[C:12]([Cl:16])=[O:13])=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: CC1C/C(=C\C(=O)O)c2cc(F)ccc21
Product: CC1C/C(=C\C(=O)Cl)c2cc(F)ccc21

Procedure:
This compound was prepared in an analogous manner to Example 15h with the replacement of (E)-2-(6-fluoro-3,3-dimethyl-1-indanylidene)acetic acid with (E)-2-(6-fluoro-3-methyl-1-indanylidene)acetic acid (9 g, 43.6 mmol). The product residue was dissolved in dichloromethane and used, without purification, in Example 17, 18, and 19.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:21])[NH:11][C:10]=3[O:9][C:8]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:4][CH:3]=1.[C:31]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CC(=O)OCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:21])[N:11]([CH3:31])[C:10]=3[O:9][C:8]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:29][CH:30]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2oc(-c3cccc(Cl)c3)c(Cc3ccc(Cl)cc3)c2c(=O)n1CCCO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)oc21
Temperature: 65 °C
Yield: 13.1 %

Procedure:
To a mixture of 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-3-(3-hydroxypropyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (22.25 mg, 0.05 mmol), K2CO3 (13.8 mg, 0.1 mmol) in DMF (1 mL) was added CH3I (8.5 mg, 0.06 mmol). The reaction was heated in a sealed tube at 65° C. for 2 h, cooled to RT then diluted with EA (10 mL) and water (3 mL). The organic layer was washed with brine (3 mL) dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-3-(3-hydroxypropyl)-1-methylfuro[2,3-d]pyrimidine-2,4(1H,3H)-dione (3 mg, 13% yield) as a white solid. 1H NMR (DMSO-d6) δ: 7.62 (s, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 4.47 (t, J=5.2 Hz, 1H), 4.32 (s, 2H), 3.97-3.81 (m, 2H), 3.53 (s, 3H), 3.43 (dd, J=11.8, 6.4 Hz, 2H), 1.75-1.60 (m, 2H). LCMS: MH+ 459 and TR=3.047 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH3:16])[C:10](=[O:17])[C:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[N:14]=1)[N:11]([CH3:16])[C:10](=[O:17])[C:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2C)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2C)c1O
Temperature: 120 °C
Yield: 48.8 %

Procedure:
A mixture of 8-bromo-5-hydroxy-1-methyl-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (69 mg, 0.18 mmol), 3-tributylstannanyl-pyridine (0.085 mL, 0.27 mmol) and PdCl2(PPh3)2 (25 mg, 0.035 mmol) in 3 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified sequentially by flash chromatography (15-100% EtOAc/hexanes+1% AcOH), preparative TLC (5% MeOH/CH2Cl2), and flash chromatography (0-2% MeOH/CH2Cl2) to give 34 mg of the title compound. MS: (+) m/z 388.39 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:12][C:11]3[CH:26]=[CH:27][CH:28]=[CH:29][C:10]=3[C:9]=2[C:8]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]1=2.[NH2:30][CH2:31][CH2:32][N:33]([CH3:42])[CH2:34][CH2:35][CH2:36][N:37]([CH2:39][CH2:40][NH2:41])[CH3:38]>ClCCl>[NH2:41][CH2:40][CH2:39][N:37]([CH3:38])[CH2:36][CH2:35][CH2:34][N:33]([CH3:42])[CH2:32][CH2:31][NH:30][C:13]1[C:14]2[C:2](=[O:1])[C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:8]=3[C:9]=2[C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[N:12]=1
Reactant: CN(CCN)CCCN(C)CCN
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3ccccc3c3c2C(=O)c2cnccc2-3)cc1
Solvent: ClCCl
Product: CN(CCN)CCCN(C)CCNc1nc2ccccc2c2c1C(=O)c1cnccc1-2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A mixture of toluene-4-sulfonic acid 7-oxo-7H-5,9-diaza-benzo[c]fluoren-6-yl ester (102 mg) (the compound of Reference Example 6c-2) and N,N′-bis-(2-amino-ethyl)-N,N′-dimethyl-propane-1,3-diamine (0.8 ml) was stirred at 50° C. for 20 minutes. The reaction mixture was diluted with dichloromethane. The solution was washed with saturated NaHCO3 solution and dried over magnesium sulfate. The organic layer was evaporated to dryness. The residue was purified by silica gel column chromatography developed by dichloromethane-methanol-ammonia water (25%)=90:10:1. The desired product (37 mg) was obtained as a reddish oil.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH2:12])[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]1)=[O:4].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1>>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:12][C:5]2([C:3]([OH:2])=[O:4])[CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6]2)=[O:20])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(C)c1
Reactant: COC(=O)C1(N)CCC=CCC1
Product: COc1ccc(C(=O)NC2(C(=O)O)CCC=CCC2)cc1OCCc1cccc(C)c1

Procedure:
1-Amino-cyclohept-4-enecarboxylic acid methyl ester (K. Hammer et al., Tetrahedron 53 (1997), 2309-2322) was coupled to 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid analogy to step 1 of example 3. The ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](Cl)=[N:11][CH:12]=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH2:1]([O:8][C:9]1[C:10]([C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[F:20])=[N:11][CH:12]=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: COC(=O)c1cnc(Cl)c(OCc2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(-c2cc(OC)ccc2F)c(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 95.5 %

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 5-(benzyloxy)-6chloronicotinate (2.77 g) in 1,4-dioxane (100 mL) were added 2-fluoro-5methoxyphenylboronic acid (2.00 g), potassium carbonate (2.76 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (36 mg) and water (10 mL), and the mixture was stirred at 80° C. for 20 hr. The reaction mixture was concentrated, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (3.50 g) as a colorless oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)(=[O:25])=[O:24].[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:41][CH2:40][C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)(=[O:24])=[O:25]
Reactant: COc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: COc1cccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)c1
Yield: 25.9 %

Procedure:
Reaction of oxalyl chloride (50 λL, 0.57 mmol) and benzoic acid 38 (146 mg, 0.38 mmol) with subsequent coupling to 3-pyridinylmethylamine (43 λL, 0.42 mmol) gave benzamide 39 (47 mg, 26%) as a white powder: mp (EtOAc) 143-145° C.; 1H NMR δ 9.23 (t, J=5.8 Hz, 1H, CONH), 8.56 (d, J=1.6 Hz, 1H, H-2′), 8.46 (dd, J=4.7, 1.4 Hz, 1H, H-6′), 8.00 (br d, J=8.5 Hz, 2H, H-2, H-6), 7.91 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.74 (br d, J=7.9 Hz, 1H, H-4′), 7.53 (br dd, J=8.9, 7.6 Hz, 1H, H-5″), 7.34-7.39 (m, 2H, H-5′, H-2″), 7.25-7.29 (m, 2H, H-4″, H-6″), 4.70 (s, 2H, CH2SO2), 4.51 (d, J=5.8 Hz, 2H, CH2N), 3.79 (s, 3H, OCH3), 2.17 (s, 3H, CH3); 13C NMR δ 165.5, 159.4, 158.0, 150.1, 148.9, 148.1, 139.7, 135.4, 135.2, 134.9, 130.4, 128.8, 128.1 (2), 125.9, 125.4 (2), 123.5, 120.3, 120.1, 112.8, 55.6, 52.7, 40.5, 9.7; MS m/z 478.6 (MH+, 100%). Anal. calcd for C25H23N3O5S.½CH3OH: C, 62.06, 5.11; N, 8.51. Found: C, 62.23; H, 4.90; N, 8.66%.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>C(Cl)(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:2][CH:3]2[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC1CCC(O)CC1)c1ccc(Cl)cc1
Yield: 95 %

Procedure:
To 100 g of trans-4-aminocyclohexanol hydrochloride suspended in 11 of chloroform are added, at 5° C., 184 ml of triethylamine, followed by a solution containing 143 g of 4-chlorophenylsulfonyl chloride in 150 ml of chloroform. After reaction for 2 hours, the reaction mixture is poured onto 500 ml of water. The expected product is obtained by filtration of the precipitate.
Reaction SMILES: CN(/[CH:4]=[C:5]1/[C:6](=O)[CH:7]=[CH:8][C:9]2([CH2:22]/1)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)C.[CH:24]([NH:27][NH2:28])([CH3:26])[CH3:25].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:24]([N:27]1[C:6]2[CH:7]=[CH:8][C:9]3([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:13][CH2:14]3)[CH2:22][C:5]=2[CH:4]=[N:28]1)([CH3:26])[CH3:25]
Reactant: CC(C)NN
Reactant: CN(C)/C=C1\CC2(C=CC1=O)CCN(C(=O)OC(C)(C)C)CC2
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)n1ncc2c1C=CC1(CCN(C(=O)OC(C)(C)C)CC1)C2
Temperature: 25 °C
Yield: 98.5 %

Procedure:
(E)-tert-Butyl 10-((dimethylamino)methylene)-9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (107 g) was taken up in toluene (700 mL) and isopropyl hydrazine (44.4 g) was added. The reaction was stirred at reflux for 4 hours. The reaction was cooled to room temperature and ethyl acetate was added (500 mL). The reaction solution was washed with citric acid (2×300 mL, 10% aqueous), and water (400 mL). The organic layer concentrated in vacuo to afford tert-butyl 1-isopropyl-1,4-dihydrospiro[indazole-5,4′-piperidine]-1′-carboxylate as a yellow solid (109 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.25 (s, 1H) 6.42 (dd, J=10.05, 0.49 Hz, 1H) 5.84 (d, J=9.95 Hz, 1H) 4.42-4.52 (m, 1H) 3.36-3.53 (m, 4H) 2.62 (s, 2H) 1.56-1.68 (m, 2H) 1.45-1.55 (m, 17H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]3[CH2:25][C:24]([O:26]CC(C)C)=[C:23]([CH2:31][CH3:32])[C:22]3=[O:33])[CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]3[CH2:25][C:24]([OH:26])=[C:23]([CH2:31][CH3:32])[C:22]3=[O:33])[CH:15]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCC1=C(OCC(C)C)CC(Cc2cccc(CCNS(=O)(=O)c3ccc(Cl)cc3)c2)C1=O
Agent: Cl
Solvent: CC(C)=O
Product: CCC1=C(O)CC(Cc2cccc(CCNS(=O)(=O)c3ccc(Cl)cc3)c2)C1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 75 %

Procedure:
A mixture of 38 (0.005 g, 0.11 mmol) in acetone (5 mL) was added with 2 N hydrochloric acid (5 mL). The reaction mixture was stirred at rt for 13 h and then concentrated, extracted with ethyl acetate (10 mL×2), and washed with brine (5 mL×2). The organic layer was dried with sodium sulfate anhydrous, filtered and concentrated and the residue so obtained was purified by reverse phase preparative HPLC to give the desired compound.
Reaction SMILES: C(CCC([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)C(O)=O)#N.[CH2:20]([O:22][C:23](=[O:34])[CH:24]([CH2:30][CH2:31][C:32]#[N:33])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:21].[H-].[Na+].ClCC1C2C(=CC=CC=2)C=CC=1>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[C:24]([CH2:30][CH2:31][C:32]#[N:33])([CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)[C:23]([O:22][CH2:20][CH3:21])=[O:34])[CH3:29]
Reactant: N#CCCC(Cc1cccc2ccccc12)C(=O)O
Reactant: CCOC(=O)C(CCC#N)C(=O)OCC
Agent: ClCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCC#N)(Cc1cccc2ccccc12)C(=O)OCC
Reaction time: 2 h

Procedure:
4-Cyano-2(R,S)-α-naphthylmethylbutyric acid: 2.13 g of 2-cyanoethylmalonic acid diethyl ester are added to a suspension of 0.48 g of sodium hydride dispersion in 25 ml of DMF. The reaction mixture is stirred for 2 hours at 80° and then, at room temperature, 1.77 g of α-chloromethylnaphthalene in 5 ml of DMF are added. The mixture is further stirred for 16 hours at 50° and then concentrated by evaporation. The residue is dissolved in ethyl acetate, washed with 0.1N hydrochloric acid and water, dried over sodium sulphate and concentrated by evaporation, leaving 2-cyanoethyl-α-naphthylmethylmalonic acid diethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CS(O[CH2:17][C@@H:18]([CH3:21])[CH2:19][CH3:20])(=O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:17][C@@H:18]([CH3:21])[CH2:19][CH3:20])=[O:5]
Reactant: CC[C@H](C)COS(C)(=O)=O
Reactant: O=C(O)c1cc(O)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@H](C)COC(=O)c1cc(O)ccc1O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-dihydroxybenzoic acid (15.4 g) in DMF (50 ml) DBU (15.3 ml) was drop wise added. After complete addition (10 min) stirring was continued for 30 min at room temperature, then a solution of (2S)-2-methylbutyl methanesulfonate (16.4 g) in DMF (20 ml) was added drop wise. After complete addition (30 min) the reaction mixture was heated to 80° C. for 6 h. It was then cooled to room temperature, poured into saturated solution of NaHCO3 (200 ml) and extracted with ethyl acetate (2×300 ml). The combined extracts were dried over Na2SO4 and evaporated to dryness. The obtained dark oily residue was purified over silica gel column to give nearly pure (2S)-2-methylbutyl 2,5-dihydroxybenzoate as beige oil.
Reaction SMILES: [C:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([NH:12][C:13]2[C:14](=[O:39])[N:15]([CH2:25][C:26]([NH:28][CH:29]([CH:36]([CH3:38])[CH3:37])[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[O:27])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl.[CH3:43][N:44]([CH3:53])[CH2:45][CH2:46]CN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN(C)CCO>O1CCCC1.C(OCC)(=O)C>[CH3:43][N:44]([CH3:53])[CH2:45][CH2:46][O:2][C:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([NH:12][C:13]2[C:14](=[O:39])[N:15]([CH2:25][C:26]([NH:28][CH:29]([CH:36]([CH3:38])[CH3:37])[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])=[O:27])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccc(C(=O)O)cc2)c1=O)C(=O)C(F)(F)F
Agent: CN(C)CCO
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccc(C(=O)OCCN(C)C)cc2)c1=O)C(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 2-[3-(4-carboxybenzyloxycarbonylamino)-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide (0.281 g) in dry tetrahydrofuran (5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0,141 g), 1-hydroxybenzotriazole hydrate (0,066 g) and 2-dimethylaminoethanol (0.06 mL). The reaction mixture was stirred overnight before it was diluted with ethyl acetate, washed (twice with saturated sodium bicarbonate solution, then brine), dried and evaporated before purification by chromatography, eluting with dichloromethane:methanol (97:3), to afford the title compound; TLC: Rf =O.18, dichlormethane:methanol (97:3); HPLC: tR =6.51, FR=1, column A, water:acetonitrile (3:2); MS: m/z=645(M+1).
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH:29]([C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C@H:30]([C:38]([NH:40][C@H:41]([C:43]([OH:45])=O)[CH3:42])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[CH:56]1[C:64]2[C:63]3[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][C:62]=3[O:61][C:60]=2[CH:59]=[CH:58][C:57]=1[NH2:70]>>[CH2:49]([O:48][C:46]([NH:29][C@H:30]([C:38]([NH:40][C@H:41]([C:43]([NH:70][C:57]1[CH:58]=[CH:59][C:60]2[O:61][C:62]3[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][C:63]=3[C:64]=2[CH:56]=1)=[O:45])[CH3:42])=[O:39])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:47])[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 25.6 %

Procedure:
Following the procedure of Example 30, triethylamine (0.43 mL, 3.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.31 g, 1.6 mmol), N-hydroxybenzotriazole (0.22 g, 1.6 mmol), N-Cbz-Phe-Ala-OH (0.51 g, 1.4 mmol), and 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol) provided N-[(benzyloxy)carbonyl]-L-phenylalanyl-N1-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl-L-alaninamide (0.17 g). MS (ESI) m/z 554 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[O:22])=[CH:19][CH:20]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(CO)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
To a suspension of 518 mg (1.72 mmol) of 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-(4-hydroxymethyl-phenyl)-urea in methylene chloride (25 mL) is added 2.7 g of MnO2. The mixture is stirred at room temperature for 3 hours. Then the mixture is filtered over Celite® and evaporated to obtain 353 mg (1.2 mmol, 68%) of the title compound as a white solid. (ES+(m/z) 301 [M+H]).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:9][O:10][CH2:11][CH2:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.Cl.[NH:37]1[CH2:42][CH2:41][CH:40]=[C:39]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:38]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(OCC)(=O)C>[CH2:46]([O:45][C:43]([C:39]1[CH2:38][N:37]([CH2:12][CH2:11][O:10][CH2:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:42][CH2:41][CH:40]=1)=[O:44])[CH3:47]
Reactant: CCOC(=O)C1=CCCNC1
Reactant: OCCOCCC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CCCN(CCOCCC(c2ccccc2)c2ccccc2)C1
Temperature: 10 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
A solution of 2-(3,3-diphenyl-1-propyloxy)ethanol (3.9 g, 15 mmol) in dry THF (30 ml) kept under a nitrogen atmosphere was cooled to 10° C. and a solution of n-butyllithium in hexanes (6.0 ml, 2.5 M) was added dropwise. The reaction mixture was stirred for 1 h at room temperature and heated at reflux temperature for 1.5 h and then cooled to room temperature. p-Toluenesulphonyl chloride (2.9 g, 15 mmol) was added and the mixture was stirred at room temperature for 1.5 h. Ethyl 1,2,5,6-tetrahydro-3-pyridinecarboxylate hydrochloride (3.8 g, 20 mmol) and potassium carbonate (5.0 g, 38 mmol) were added and the mixture was stirred at room temperature for 0.5 h and then heated at reflux temperature for 4 h. The reaction mixture was allowed to stand overnight and was diluted with ice water (25 ml) and ethyl acetate (100 ml). The separated organic phase was extracted with a 10% citric acid solution (4×50 ml) and the combined aqueous extracts was washed with ethyl acetate (25 ml). The acidic aqueous phase was adjusted to pH 5 with a sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was washed with a diluted sodium bicarbonate solution, dried over sodium sulphate and the solvent evaporated in vacuo to give 1.9 g (32%) of the title compound as an oil. TLC: rf=0.21 (SiO2 ; n-heptane/THF=7:3). 1H NMR (CDCl3)δ 4.12 (t, 1H); 7.00 (m, 1H).