Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35](=[O:40])[CH2:36][CH2:37][CH:38]=[CH2:39])[CH3:33].C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:21]([O:20][C:19]([NH:18][C@H:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]([C:6]([C:5]2[CH:30]=[CH:31][C:2](/[CH:39]=[CH:38]/[CH2:37][CH2:36][C:35]([O:34][CH2:32][CH3:33])=[O:40])=[CH:3][CH:4]=2)=[O:7])[C@@H:9]([CH3:29])[CH2:10]1)=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=CCCC(=O)OCC
Reactant: C[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2ccccc2N1C(=O)c1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC(=O)CC/C=C/c1ccc(C(=O)N2c3ccccc3[C@H](NC(=O)OCc3ccccc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of benzyl [(2S,4R)-1-(4-iodobenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]carbamate (0.6 g, 1.14 mmol) in DMF (15 mL) at room temperature was added pent-4-enoic acid ethyl ester (0.292 g, 2.28 mmol), potassium acetate (0.67 g, 6.84 mmol), palladium acetate (0.05 g, 0.228 mmol), tetrabutylammonium chloride (0.32 g, 1.14 mmol), and triphenylphosphine (0.06 g, 0.228 mmol). The mixture was stirred at room temperature for 1 hour and then heated to 70° C. for 3 hours. The mixture was concentrated and ethyl acetate was added. The solution was washed with water, dried and concentrated. The residue was purified by silica gel chromatography (70% CH2Cl2/30% EtOAc) to afford ethyl (4E)-5-(4-{[(2S,4R)-4-{[(benzyloxy)carbonyl]amino}-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)pent-4-enoate (0.5 g, 83%), which was further converted into ethyl 5-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenyl)pentanoate following general procedure G.
Reaction SMILES: [H-].[Na+].[Br-].[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:31]=[CH:32][CH:33]=1)[CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7].[C:34]12([CH2:44][CH2:45][C:46]3[N:50]([CH3:51])[C:49]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=4[CH3:58])=[N:48][C:47]=3[CH:59]=O)[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][CH:36]([CH2:37]3)[CH2:35]1)[CH2:41]2.O>C1COCC1.C(OCC)(=O)C>[CH3:4][O:5][C:6](=[O:7])[C:8]1[CH:33]=[CH:32][CH:31]=[C:10]([CH:11]=[CH:59][C:47]2[N:48]=[C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[CH3:58])[N:50]([CH3:51])[C:46]=2[CH2:45][CH2:44][C:34]23[CH2:43][CH:38]4[CH2:37][CH:36]([CH2:42][CH:40]([CH2:39]4)[CH2:41]2)[CH2:35]3)[CH:9]=1
Reactant: Cc1ccccc1-c1nc(C=O)c(CCC23CC4CC(CC(C4)C2)C3)n1C
Reactant: COC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(C=Cc2nc(-c3ccccc3C)n(C)c2CCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% dispersion in oil) (122 mg, 3.05 mmol) was added to an ice cooled suspension of 3-methoxycarbonyl-benzyl-triphenylphosphonium bromide (1.25 g, 2.54 mmol) in THF (5 ml). The yellow suspension was stirred at room temperature for 10 min, cooled to 0° C. and the solution of the product of step b (7686 mg, 2.12 mmol) in THF (5 ml) was added. The suspension was allowed to warm to room temperature and stirred for 72 h. Water (2 ml), then ethyl acetate (40 ml) were added. The organic phase was washed with water (30 ml), brine (30 ml), dried (MgSO4) and the solvent was evaporated. The crude product was purified by flash column chromatography (silica, hexane/ethyl acetate 5:2) to afford the product as 2:1 mixture of trans/cis isomers (778 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@:9]1([OH:19])[CH2:17][C@H:16]([CH3:18])[CH2:15][C@@H:14]2[C@H:10]1[CH2:11][NH:12][CH2:13]2.[CH3:20][N:21]([CH3:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](O)=[O:30].O.ON1C2C=CC=CC=2N=N1.[ClH:44].CN(C)CCCN=C=NCC.Cl>ClCCl.O1CCOCC1.C(N(CC)CC)C>[ClH:44].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@:9]1([OH:19])[CH2:17][C@H:16]([CH3:18])[CH2:15][C@@H:14]2[C@H:10]1[CH2:11][N:12]([C:29](=[O:30])[CH2:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:21]([CH3:32])[CH3:20])[CH2:13]2
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: COc1ccccc1[C@]1(O)C[C@H](C)C[C@H]2CNC[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccccc1[C@]1(O)C[C@H](C)C[C@H]2CN(C(=O)Cc3ccccc3N(C)C)C[C@H]21
Temperature: 5 °C
Yield: 61.2 %

Procedure:
To a solution of 1.0 g of (3aS,4S,6R,7aR)-4-(2-methoxyphenyl)-6-methyl-4-perhydroisoindolol in 100 cm3 of dichloromethane are added 1.5 cm3 of triethylamine. The reaction mixture is cooled to 5° C. and 0.60 g of (2-dimethylaminophenyl)acetic acid, 0.10 g of 1-hydroxybenzotriazole monohydrate and 0.70 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added. The reaction mixture is maintained at 5° C. for 1 hour and at 20° C. for 16 hours and is then washed twice with 100 cm3 of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.060-0.200 mm, diameter 4 cm, height 50 cm), eluting under a pressure of 0.7 bar with a mixture of dichloromethane and methanol (97/3 by volume) and collecting 50 cm3 fractions. Fractions 14 to 19 are concentrated and, after drying at 40° C. and at 15 Pa, 1.0 g of (3aS,4S,6R,7aR)-4-(2-methoxyphenyl)-2-[(2-dimethylaminophenyl)acetyl]-6-methyl-4-perhydroisonindolol is obtained, in the form of a white powder which is dissolved in 50 cm3 of dioxane. 3 cm3 of 5M hydrochloric acid solution are added to the dioxane and, after 1 hour at room temperature, the solution is concentrated under reduced pressure (2.7 kPa), stirred in isopropyl ether, filtered and dried at 40° C. under 15 Pa. 0.94 g of (3aS,4S,6R,7aR)-4-(2-methoxyphenyl)-2-[(2-dimethylaminophenyl)acetyl]-6-methyl-4-perhydroisoindolol hydrochloride is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.O.B1([O-])O[O:34]1.O.O.O.O.[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:15])[CH3:16])[CH2:10][C@H:9]1[CH2:21][CH2:22][OH:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1Cc1ccccc1
Reactant: [O-]B1OO1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CCO)N(Cc2ccccc2)C1
Yield: 82.3 %

Procedure:
To a solution of (2S,4R)-1-benzyl-2-vinyl-4-(t-butyldimethylsilyloxy)pyrrolidine (24.03 g) in tetrahydrofuran (120 ml) was added 0.5M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (318 ml) at 0°~5° C. with stirring and then stirred at ambient temperature for 4 hours. To the reaction mixture were added water (200 ml) and sodium perborate tetrahydrate (87 g) at ambient temperature with stirring vigorously and then the mixture was stirred at the same temperature for 12 hours. The insoluble material was filtered off, and the filtrate was separated. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of n-hexane and ethyl acetate (1:1, V/V) to give (2R,4R)-1-benzyl-2-(2-hydroxyethyl)-4-(t-butyldimethylsilyloxy)pyrrolidine (20.89 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(=O)=O.CC(C)=O.[F:20][CH:21]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[F:22].[Br:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36]Br>C1CCCCC1.CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[Br:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][C:21]([P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])([F:22])[F:20]
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: BrCCOCCBr
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOP(=O)(OCC)C(F)(F)CCOCCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An oven dried round-bottom flask was charged with dry THF (1.07 M) and diisopropylamine (2.0 equiv.). The flask was cooled in an acetone-dry ice bath, and was treated with n-butyllithium (1.6 equiv.) solution in cyclohexane (1.52 M) in dropwised fashion via syringe. The flask was transferred to an ice-water bath upon completion of the addition, and stirred for 30 minutes. The flask was then cooled back down to the dry ice-acetone bath, and was treated with a solution of diethyl difluoromethylphosphonate (1.0 equiv.) in HMPA (1:1 v/v) via syringe. The stirring was allowed to proceed for an hour. To the above reaction mixture, a cooled solution of 1-bromo-2-(2-bromoethoxy)ethane (3.0 equiv.) in THF (3 M) was added quickly through a syringe, and the reaction was allowed to stir for another 3 hours before quenching with 1 N HCl. The flask was warmed to room temperature, and the pH was adjusted to <4 with 1 N HCl. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over anhydrous Na2SO4, and concentrated in vacuo. The crude material was purified by Combiflash using 0-75% EtOAc in hexanes, followed by RP-HPLC (0.035% TFA in ACN:0.05% TFA in H2O, C18 column), to afford diethyl 3-(2-bromoethoxy)-1,1-difluoropropylphosphonate as a pale yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15][CH:14]=1)([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.[OH-].[Na+]>CO>[C:22]([O:21][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:5]([OH:12])([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:4]([OH:26])=[O:3])=[CH:14][CH:15]=1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)C(O)(c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(C(O)(C(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of ethyl(4-tert-butyloxycarbonylphenyl)(hydroxy)phenylacetate from the previous step (78 mg, 0.218 mmol, HPLC RT=2.95 min.) in 2 mL CH3OH was added 0.3 mL of 1 N NaOH solution. Reaction was stirred at room temperature for 4 hours. HPLC analysis indicated rapid conversion to methyl ester but slow saponification to acid. Added 0.1 mL 1 N NaOH to drive reaction to completion. The solvent was removed on a rotary evaporator and the residue was partitioned between EtOAc (20 mL) and 1 N HCl (5 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed on a rotary evaporator. (4-tert-butoxycarbonylphenyl)(hydroxy)phenylacetic acid was obtained as a white solid. (62 mg, 87%); HPLC RT=2.53 min, method B. 1H NMR, 400 MHz, DMSO-d6, 13.4 ppm (br s, 1H); 7.85 ppm (d, J=7.5 Hz, 2H); 7.50 ppm (d, J=7.32 Hz, 2H); 7.34 ppm (m, 5H); and 1.53 ppm (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O>C(O)(=O)C>[C:14]1([N:12]=[N:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=Nc1ccccc1
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(N=Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
10.13 g (0.067 mol) of 4-aminophenylacetic acid Merck, pro analysis) was placed in a 250 mL one-necked round flask with a magnetic stirring bar and 100 mL of glacial acetic acid was added; during 15 minutes a light yellow suspension was formed. 7.22 g (0.067 mol) of nitrosobenzene (Fluka, purum) was added rapidly resulting in a green suspension. Stirring at room temperature was continued for 18 h. The resulting metallic shining needles in a brown solution was vacuum filtered and washed once with 50 mL of cold glacial acetic acid and five times with 50 mL portions of cold water. The orange precipitate was dissolved by heating to boiling in a mixture of 160 mL of ethanol and 40 mL of water. After unforced cooling to room temperature the mixture was cooled on an ice/water bath and vacuum filtered. The filtercake was washed six times with 25 mL of externally cooled ethanoL After drying 16 h at 50° C. under vacuum 7.23 g (yield 45%) of 2-[4(phenylazo)phenyl]-ethanoic acid was obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:22]([O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.ClCCl>[CH2:22]([O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][C:5](=[O:6])[OH:7])[NH2:1])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
A solution of 0.52 g of pyro-L-glutamic acid, 1.72 g of L-phenylalanine benzyl ester toluenesulfonic acid and 0.55 mg of N-ethylmorpholine in 5 ml of dimethylformamide (DMF) and 20 ml of dichloromethane was cooled in an ice bath with stirring. A solution of 0.826 g of dicyclohexylcarbodiimide in 2 ml dichloromethane was added to the above reaction mixture. The reaction mixture was stirred in an ice water bath for 1 hour and then at room temperature overnight. Dicyclohexylurea was removed by filtration and the product was washed in ethyl acetate. Solvents of the combined filtrates were removed under reduced pressure with a rotary evaporator at 40° C. Ethyl acetate (25 ml) was added to the residue and the organic solution was washed until neutral. The organic phase was dried over anhydrous MgSO4, filtered and then the solvent was removed with a rotary evaporator. The material was crystalized from isopropanol and ether, yield: 1.01 g of white needles, m.p. 103°-104.5° C. The material was homogeneous on all TLC and electrophoresis systems.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[N:12]12CCN(CC1)C[CH2:13]2>>[C:13]([C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])#[N:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CN2CCN1CC2
Product: N#CC(=O)OCc1ccccc1
Yield: 12180.4 %

Procedure:
Benzyl chloroformate (13.7 g; 0.08 mol) and 1,4-diazabicyclo [2.2.2] octane (60 mg; 0.54 mmol) were added to a dry reaction vessel under a dry nitrogen atmosphere. Trimethylsilyl nitrile (8 g; 0.08 mol) was added dropwise over about 1 hr. The mixture was maintained at between 20°-30° C. until the reaction reached completion in about 3 hr. After distilling off the trimethylsilyl chloride, 10.6 g product was isolated as a clear liquid (bp 70-72/1 mm Hg.) Yield: 82%; purity 98% 1H-NMR: δ7.3,m(5H); δ5.26, s(2H); IR: 2250 cm-1 (CN), 1760 cm-1 (CO).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)[C:8](=[O:29])[CH2:9][CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=1)[CH3:2].[Li+].[OH-].CCOC(C)=O>C1COCC1.O>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:38])[CH3:39])=[CH:33][CH:32]=1)[C:8](=[O:29])[CH2:9][CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOCCCN(Cc1ccc(C(C)C)cc1)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOCCCN(Cc1ccc(C(C)C)cc1)C(=O)CCc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 69.5 %

Procedure:
Methyl 2-[(4-{3-[(3-ethoxypropyl)(4-isopropylbenzyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (0.16 g, 0.30 mmol) was dissolved in THF/water (2/1, 2 ml) and LiOH (14.4 mg, 0.60 mmol) was added. The reaction was performed in a single node microwave oven (150° C., 7 min). Workup was done by adding EtOAc (10 ml) and washing the organic phase with two portions of HCl (2×5 ml, 1 M). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.108 gram of 2-[(4-{3-[(3-ethoxypropyl)(4-isopropylbenzyl)amino]-3-oxopropyl}phenoxy)methyl]benzoic acid (yield 69.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[NH:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[O:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:20]2[NH:14][C:15](=[O:16])[NH:17][C:18]2=[O:19])[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: O=C1CNC(=O)N1
Product: COc1cc(C=C2NC(=O)NC2=O)cc(OC)c1O
Yield: 75.7 %

Procedure:
Prepared according to the procedure described in Example 90 using 3,5-dimethoxy-4-hydroxybenzaldehyde (5.6 g, 30 mmoles), hydantoin (3.0 g, 30 mmoles), and μ-alanine (1.4 g, 16 mmoles), to afford the pure product (6.0 g), mp 296°-297° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([C:20]#[N:21])([CH:17]1[CH2:19][CH2:18]1)[C:12](OCC)=[O:13])=O)(C)(C)C.[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH:17]1([C:11]2([C:20]#[N:21])[CH2:10][CH2:9][NH:8][C:12]2=[O:13])[CH2:19][CH2:18]1
Reactant: CCOC(=O)C(C#N)(CCNC(=O)OC(C)(C)C)C1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#CC1(C2CC2)CCNC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of ethyl 4-((tert-butoxycarbonyl)amino)-2-cyano-2-cyclopropylbutanoate (45 g) obtained in Step B of Example 103 in tetrahydrofuran (1.2 L) was added sodium hydride (60% in mineral oil, 7.3 g) in an ice bath, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution (100 mL), the solvent (tetrahydrofuran) was evaporated under reduced pressure, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (18 g).
Reaction SMILES: COCCOC[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O.O>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[NH:12][CH2:11][C:10]1[CH:9]=[C:8]([OH:7])[CH:15]=[CH:14][CH:13]=1
Reactant: COCCOCOc1cccc(CN)c1
Reactant: Clc1ccc2ccccc2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CS(C)=O
Product: Oc1cccc(CNc2ccc3ccccc3n2)c1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
To a solution of 3-[(2-methoxyethoxy)-methoxy]-benzylamine (422 mg, 2 mmol, example 9) in DMSO (4 mL) is added 2-chloroquinoline (328 mg, 2 mmol). The resulting solution is warmed to 140° C. and stirred at this temperature for 3 h. The resulting mixture is cooled, diluted with water, then extracted with ethyl acetate. The organic extract is washed with brine, dried over MgSO4 and concentrated. The residue is taken up in methanol (10 mL) then p-toluene sulphonic acid monohydrate (190 mg, 1 mmol) is added. This mixture is warmed to 60° C. and stirred at this temperature for 2 h. The reaction mixture is then cooled, concentrated under reduced pressure and the residue purified by flash chromatography (silica, 30% ethyl acetate in dichloromethane) to give the title compound. MS (ESI) 251 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([O:15][C:16]1[CH:17]=[C:18]([NH:24][C:25](=[O:37])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:35]#[N:36])([CH3:34])[CH3:33])[CH:27]=3)[CH:19]=[CH:20][C:21]=1[CH2:22][CH3:23])[N:9]=2)=[O:4].C(N(CC)CC)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>O1CCCC1.C(OCC)(=O)C>[C:35]([C:32]([C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[C:25]([NH:24][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH3:23])=[C:16]([O:15][C:10]2[N:9]=[C:8]3[S:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:49]4[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]4)=[N:14][C:13]3=[CH:12][CH:11]=2)[CH:17]=1)=[O:37])([CH3:33])[CH3:34])#[N:36]
Reactant: CN1CCNCC1
Reactant: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CCl)sc2n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CN3CCN(C)CC3)sc2n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
N-[3-({2-[(Chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-ethylphenyl]-3-(1-cyano-1-methylethyl)benzamide synthesized above was dissolved in tetrahydrofuran (4.0 mL), triethylamine (135 μL, 0.98 mmol) and 1-methylpiperazine (108 μL, 0.98 mmol) were added, and the mixture was stirred at 60° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→85/15), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether/hexane to give the title compound (114 mg, 59%) as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:14].[Na+]>>[O:8]=[CH:9][CH:10]([NH:11][C:7](=[O:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:12]=[O:13]
Reactant: [OH-]
Reactant: O=Cc1coc(-c2ccccc2)n1
Agent: [Na+]
Product: O=CC(C=O)NC(=O)c1ccccc1
Yield: 88 %

Procedure:
2-phenyloxazole-4-carbaldehyde (5.0 g, 28.9 mmol) and 2.0 M aqueous sodium hydroxide solution (50 ml) were heated to 70° C. in a 250 mL Erlenmeyer flask until dissolved. Some insoluble dark material remained which was removed by filtration. The reaction was cooled in an ice bath and acidified (sulfuric acid) with swirling. The resulting solid was collected by filtration, washed with water, and dried under vacuum to provide the title compound (4.85 g, 88%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[O:10][CH2:9][C:8](=O)[N:7]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5])[CH3:2].CO>O1CCCC1.ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[O:10][CH2:9][CH2:8][N:7]1[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(C)OCC(=O)N1Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C1C(C)OCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-benzyl-2-methyl-5-oxo-morpholine-3-carboxylic acid ethyl ester (0.24 g, 0.865 mmol; prepared according to the procedure described in Meinzer A. et al., Helv. Chim. Acta 2004, 87, 90-105) in tetrahydrofuran (7 ml) was cooled to −20° C. and borane-methyl sulfide complex (0.246 ml, 2.595 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred overnight. After the addition of methanol (5 ml), stirring was continued for 1 h. The solution was diluted with dichloromethane, washed with brine, and concentrated in vacuo. The resulting 4-benzyl-2-methyl-morpholine-3-carboxylic acid ethyl ester was used in the next step without further purification. LC/MS (method 8): Rt=0.54 min; m/z=264.25 (M+H+).