Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].O1CCOCC1.O.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: CC(C)[C@@H](N)C(=O)O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of D-valine (15.0 g, 128.0 mmol) in 1:1 dioxane/water (200 mL) containing triethylamine (19.4 g, 192.0 mmol) at room temperature is added 4-methoxybenzenesulfonyl chloride (29.0 g, 141.0 mmol), and the reaction mixture is stirred at room temperature overnight. The mixture is then diluted with methylene chloride, washed with 1N aqueous hydrochloric acid and water. The organic layer is washed again with brine, dried (Na2SO4), and the solvent is evaporated to provide N-[4-methoxybenzenesulfonyl]-(D)-valine as a crude product. A solution of this crude product (15.0 g) in toluene (100 mL) containing N,N-dimethylformamide di-t-butyl acetal (50 mL, 206.5 mmol) is heated to 95° C. for 3 hours. The solvent is then evaporated. The crude product is purified by silica gel chromatography (30% ethyl acetate/hexanes) to provide N-[4-methoxybenzenesulfonyl]-(D)-valine t-butyl ester.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].[NH:11](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[CH2:12][C:13](O)=[O:14].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.C(OCC)(=O)C>[NH2:11][CH2:12][C:13]([NH:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[O:14]
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)CN
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of the glycine tert-butyl ester hydrogen chloride salt (70) (484 mg, 2.9 mmol) in dichloromethane (25 mL) was added Fmoc-Gly-OH (71) (0.861 mg, 2.99 mmol), DIPEA (756 mg, 4.35 mmol) and HATU (1.3 g, 3.5 mmol). The reaction mixture was stirred at an ambient temperature for 16 h and then poured into ethyl acetate and was washed with water (3×) and brine (1×). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified via radial chromatography on a 2 mm plate eluting with 5% methanol/dichloromethane. Product containing fractions were concentrated under reduced pressure and treated with 20% piperidine/dichloromethane (10 mL) for 1 h, before being concentrated under reduced pressure and then purified twice via radial chromatography on a 2 mm plate eluting with a gradient of 5 to 10% methanol/dichloromethane to provide (200 mg, 37%): 1H-NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 4.00 (s, 2H), 3.39 (s, 2H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].C([O-])([O-])=O.[K+].[K+].[CH3:19][C:20]([C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.O1CCOCC1>[CH3:27][C:20]([C:28]1[CH:29]=[C:30]([S:34]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:35])=[O:36])[CH:31]=[CH:32][CH:33]=1)([CH3:19])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(c1ccccc1)c1cccc(S(=O)(=O)Cl)c1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(c1ccccc1)c1cccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)c1

Procedure:
(S)-Arginine (12.6 g) and K2CO3 (12.03 g) are suspended in 50% water/dioxan (250 ml) with vigorous stirring and the reaction mixture is cooled to <5° C. 3-(α,α-Dimethylbenzyl)benzenesulphonyl chloride (21.4g) is added in 6 portions over 30 minutes at <5° C. The mixture is stirred at 20° C. for 2 hours. A colourless solid precipitates. The dioxan is removed by evaporation and the aqueous residue is acidified with cone. HCl. The mixture is extracted with ethyl acetate (3×50ml) and the aqueous phase and all solid materials are combined and neutralised (4M NaOH). The suspension is stirred for 16 hours at 20° C. The solid precipitate is collected by filtration and stirred for 16 hours with a little water. The solid is collected by filtration and dried (NaOH pellets) to give Nα -(3-(α,α-dimethylbenzyl)benzenesulphonyl)-(S)-arginine, m.p. 122°-124° C. (Found: C, 53.49; H, 6.81; N, 11.92; S, 6.93. C21H28N4O4S.2.3H2O requires C, 53.22; H, 6.93; N, 11.82; S, 6.77%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.Br[C:20]1[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Br:26])[N:25]=1.C(N(CC)CC)C>C(O)(C)C>[Br:26][C:24]1[N:25]=[C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11]3)=[CH:6][CH:7]=2)[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(N)cc2)C1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1cc(Br)nc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)c1=O
Yield: 78.5 %

Procedure:
A mixture of 298a (500 mg, 2.02 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (536 mg, 2.02 mmol) and triethylamine (0.6 mL, 4.04 mmol) in isopropanol (10 mL) was heated at reflux for 4 days. The solvent was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to afford 298b (690 mg, 66%). MS: [M+H]+ 435.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)=[O:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH2:23]1COC[CH2:24]1.C([Mg]Br)#C.CC(C)=O.CCCCCC>C(OCC)C>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C:11]([C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([OH:12])[C:23]#[CH:24])[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: C1CCOC1
Reactant: COc1cc(OC)cc(C(=O)c2cc(OC)cc(OC)c2)c1
Agent: C#C[Mg]Br
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CCCCCC
Product: C#CC(O)(c1cc(OC)cc(OC)c1)c1cc(OC)cc(OC)c1
Yield: 73 %

Procedure:
In a 100 mL flask, bis(3,5-dimethoxy-phenyl)methanone (compound B, 1.2 g, 3.9 mmol) was dissolved in 20 mL diethyl ether. Approximately 5 mL THF was added to help solvate the ketone followed by the slow addition of ethynylmagnesium bromide (0.5 M in THF, 12 mL). The reaction was monitored by TLC and upon consumption of starting material, 2N HCl was added to the flask. The mixture was extracted 3 times with ethyl acetate and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give a yellow oil. Purification was achieved with column chromatography using a gradient of 30% to 50% acetone/hexane. The product was obtained as a pale yellow oil in 73% yield: Rf 0.14 (30:70 acetone/hexane); IR (cm−1): 3441, 3280, 2940, 2837, 1598, 1460, 1289, 1205, 1156, 1053, 834, 748, 689; 1H NMR (250 MHz, C6D6): δ 2.38 (s, 1H), 2.94 (br s, 1H), 3.27 (s, 12H), 6.42 (t, J=2.5 Hz, 2H), 3.99 (d, J=2.5 Hz, 4H); 13C NMR (63 MHz, C6D6): 54.8 (4C), 74.5, 75.3, 86.8, 100.1 (2C), 104.9 (4C), 147.6 (2C), 161.2 (4C).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>>[C:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C:21]1[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2)([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1cc2cc(C(C)(C)C)ccc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: CC(C)(C)c1ccc2c(c1)cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-tert-butyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale brown solid. MS: 356.3 ([M−H]−).
Reaction SMILES: [H-].[Na+].[C:3]1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=C)C=CC=CC=1.[I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:44][N:45]1[C:54](=[O:55])[C:53]2[N:52]([CH2:56][CH2:57][CH2:58][CH2:59][C:60](=O)[CH3:61])[CH:51]=[N:50][C:49]=2[N:48]([CH3:63])[C:46]1=[O:47]>CS(C)=O.O>[CH3:44][N:45]1[C:54](=[O:55])[C:53]2[N:52]([CH2:56][CH2:57][CH2:58][CH2:59][C:60]([CH3:3])=[CH2:61])[CH:51]=[N:50][C:49]=2[N:48]([CH3:63])[C:46]1=[O:47]
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)CCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: C=C(C)CCCCn1cnc2c1c(=O)n(C)c(=O)n2C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
0.5 g of sodium hydride are reacted with 15 ml of anhydrous dimethyl-sulphoxide under a nitrogen atmosphere with stirring at 80° C. and cooled to 15° C. after 25 minutes. To prepare triphenyl-methylene-phosphorane, 8.1 g of methyl-triphenyl phosphonium iodide in 20 ml of anhydrous dimethyl-sulphoxide are added to this solution. After stirring for 10 minutes at room temperature, 5.6 g of 1,3-dimethyl-7-(5-oxohexyl)-xanthine in 10 ml of dimethylsulphoxide are added dropwise over 10 minutes, and the temperature is not allowed to exceed 20° C. After standing overnight, the mixture is dissolved in water, extracted with diethyl ether and the ether phase is separated and dried over Na2SO4. The product obtained after evaporation at reduced pressure is subsequently subjected to a purification by column chromatography on silica gel with methylene chloride/acetone (1:1) as eluent. The resulting product is in the form of an oil after distillation under reduced pressure. Yield: 3.5 g (63.3% of theory relative to the starting product used); refractive index: nD20 =1.5445.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH3:24][C:25]([CH3:30])([CH3:29])[C@@H:26]([NH2:28])[CH3:27]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:28][C@H:26]([C:25]([CH3:30])([CH3:29])[CH3:24])[CH3:27])=[O:2])([CH2:5][CH2:6]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: C[C@H](N)C(C)(C)C
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: C[C@H](NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2)C(C)(C)C

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and (2S)-3,3-dimethyl-2-butylamine (41.4 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[(2S)-3,3-dimethyl-2-butyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (20.5 mg).
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:16])([CH3:15])[C:5](=[O:14])[NH:6]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:24]([CH3:26])[CH3:25].[Cl-].[NH4+]>CN(C=O)C>[NH2:11][C:10]1[C:2]([F:1])=[C:3]2[C:7](=[CH:8][CH:9]=1)[N:6]([CH:24]([CH3:26])[CH3:25])[C:5](=[O:14])[C:4]2([CH3:16])[CH3:15]
Reactant: CC(C)Br
Reactant: CC1(C)C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(C)(C)c2c1ccc(N)c2F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (500 mg) and cesium carbonate (1.82 g) in DMF (10 mL) was added dropwise 2-bromopropane (0.523 mL) at room temperature, and the mixture was stirred at 80° C. for 2 hr under a nitrogen atmosphere. To the reaction mixture was added saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (10 mL), palladium on carbon (containing water (50%), 237 mg) was added thereto, and the mixture was stirred at room temperature for 2 hr under a hydrogen atmosphere. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (330 mg).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][CH2:25][N:26]3[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:21][CH:20]=2)=[N:13][C:14]=1[C:15]([O:17][CH3:18])=[O:16])C1C=CC=CC=1>CCOC(C)=O.CCO.C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][CH2:25][N:26]3[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:21][CH:20]=2)=[N:13][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)ccc1O
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 7-(5-(benzyloxy)-6-(methoxycarbonyl)pyridin-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (29C) (2.72 g, 5.74 mmol) in EtOAc (80 mL) and EtOH (80 mL) and glacial acetic acid (˜30 drops) was added 10% Pd—C (420 mg). The reaction mixture was stirred under an atmosphere of hydrogen for 24 hrs, filtered through a bed of Celite, and concentrated to provide the desired product tert-butyl 7-(5-hydroxy-6-(methoxycarbonyl)pyridin-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (29D): 1H NMR (300 MHz, CDCl3) δ 10.67 (1H, s), 8.30 (1H, d), 7.86 (1H, d), 7.56 (1H, dd), 7.42 (1H, d), 7.15 (1H, d), 4.05 (3H, s), 3.74 (2H, m), 2.80 (2H, t), 1.95 (2H, m), 1.56 (9H, s).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11][CH3:12])[CH2:7][CH2:8][CH3:9].[NH2:13][C:14]([NH2:16])=[S:15].C(OCC)(=O)C>C(O)C>[ClH:2].[ClH:1].[CH2:7]([N:6]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:4][CH2:3][S:15][C:14](=[NH:13])[NH2:16])[CH2:8][CH3:9]
Reactant: CCCN(CCC)CCCCl
Reactant: NC(N)=S
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCN(CCC)CCCSC(=N)N
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.6 %

Procedure:
A stirred mixture of 1-chloro-3-(dipropylamino)-propane hydrochloride (42 g), thiourea (15.5 g) and ethanol (250 ml) was heated under reflux for 24 hours then allowed to cool to ambient temperature. Ethyl acetate was added until a faint opalescence was observed, then the mixture was stored at 4° C. for 24 hours. After this time it had deposited an oil which was isolated by decantation of the bulk of the solvent followed by removal of residual solvent in vacuo. The oil was triturated with ethanol, the solvent was removed by decantation, and the residue was dried in vacuo at ambient temperature for 24 hours to give a pale brown solid. The ethanol solution decanted from the oil was concentrated in vacuo, and the residue was triturated with ethanol as described above to give a second crop of pale brown solid. The ethanol solution remaining after isolation of the second crop was concentrated in vacuo and the residue was triturated with propan-2-ol to give a third crop of solid. The three crops were combined to give S-[3-(dipropylamino)propyl]isothiourea dihydrochloride as a pale brown solid (51 g), m.p 143°-145° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20].CCCCC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]([C:19](=[O:20])[CH2:18][Cl:17])[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Solvent: CCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(N(C(=O)CCl)c2c(F)cccc2Cl)cc1
Temperature: -15 °C

Procedure:
A mixture of 25 g (0.11 mol) N-(2′-chloro-6′-fluorophenyl)-4-methylaniline and 40 ml (0.5 mol) of chloroacetylchloride is heated under a nitrogen atmosphere for 15 minutes at 60°. The solvent is evaporated under reduced pressure to give an oil which is dissolved in 25 ml of ethyl acetate. Pentane (250 ml) is added dropwise over 15 minutes to precipitate the product. The mixture is cooled to −15° C. and the solid is filtered and washed with pentane to give N-(2′-chloro-6′-fluorophenyl)-N-chloroacetyl-4-methylaniline, m.p. 80-83°.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O.C(OCC)(=O)C>[N:14]1([CH2:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C1Cc2cc(CCCl)ccc2N1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2cc(CCN3CCOCC3)ccc2N1
Yield: 31 %

Procedure:
5-Chloroethyl-2-oxindole (2.3 g), 1.2 mL of morpholine and 1.2 mL of diisopropylethylamine were heated overnight at 100° C. in 10 mL of dimethylsulfoxide. The mixture ws cooled, poured into water and extacted with ethyl acetate. The organic layer was washed with brine, dried and evaporated. The residue was chromatographed on silica gel in 5% methanol in chloroform to give 0.9 g (31%) of the title compound as a white solid.
Reaction SMILES: ClC1C=CC=CC=1.[F:8][C:9]([F:25])([F:24])[C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.Br[CH:27]([CH:34](Br)[CH3:35])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CC)CCC.O>[F:8][C:9]([F:24])([F:25])[C:10]1[CH:23]=[CH:22][C:13]([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH:34]([CH3:35])[CH:27]=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:19][CH:20]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)CC(Br)C(C)Br
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: CCCC[N+](CC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: Clc1ccccc1
Product: CCOC(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 95.2 %

Procedure:
In a reactor, 15 g of chlorobenzene and 15 g of water were charged, and 12.7 g (0.05 mole) of 4-(4-trifluoromethylphenoxy)phenol, 15.8 g (0.055 mole) of ethyl 3,4-dibromopentanoate and 8.7 g (0.063 mole) of potassium carbonate and 0.3 g (0.001 mole) of tributylethylammonium bromide were added. They were refluxed for 6 hours to react them. The water phase was separated and the organic phase was washed with 5% hydrochloric acid and with water and then, chlorobenzene, ethyl 3,4-dibromopentanoate and low boiling by-products were distilled off at 100° C. under a reduced pressure (0.02-0.05 mmHg) to obtain 18.1 g of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-2-pentenoate (nD20 1.5175). The yield was 95.1%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: ClCCN1CCOCC1
Reactant: COc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Temperature: 140 °C

Procedure:
A mixture of 2-methoxy-4-nitro-phenol Compound 36a (0.92 g, 5.4 mmol), potassium carbonate (1.5 g, 10.8 mmol) and 4-(2-chloro-ethyl)-morpholine hydrochloride Compound 56a (1.04 g, 5.65 mmol) in DMF (10 mL) was heated under microwave conditions to 140° C. for 30 minutes. The reaction mixture was filtered, diluted with EtOAc and subsequently washed with water, then brine. The organic layer was dried over sodium sulfate and concentrated to yield 4-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-morpholine Compound 56b (1.46 g). 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, 1H); 7.77 (d, 1H); 6.93 (d, 1H); 4.26 (t, 2H); 3.97 (s, 3H); 3.79-3.69 (m, 4H); 2.91 (t, 2H); 2.66-2.55 (m, 4H). MS 283 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl.[NH2:20][CH2:21][C:22]([NH2:24])=[O:23].C(N(CC)CC)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CO>[NH2:24][C:22](=[O:23])[CH2:21][NH:20]/[C:11](/[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][OH:1])=[CH:12]\[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(=O)c1ccccc1OCCO
Reactant: NCC(N)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\NCC(N)=O)c1ccccc1OCCO
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 3-(2-(2-hydroxyethoxy)phenyl)-3-oxopropanoate (2 g, 7.94 mmol) and glycinamide hydrochloride (3.5 g, 31.7 mmol) in methanol (20 mL) was added triethylamine (3.21 g, 31.7 mmol) at room temperature. The mixture was stirred at 40° C. for 20 min. Acetic acid (1.9 g, 31.7 mmol) was added, and the mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled to room temperature and saturated sodium bicarbonate (200 mL) was added. The organic layer was separated, dried (Na2SO4) and concentrated to give a yellow solid. The solid was washed with EtOAc (20 mL), and the residue was dried under reduced pressure to give the title compound as a white solid. This material was used without further purification.
Reaction SMILES: NCC(N[C@H](C(O)=O)CC1C=CC(O)=CC=1)=O.[CH2:18]([O:20][C:21](=[O:32])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[NH2:23])[CH3:19].[Cl:33][CH2:34][C:35](Cl)=[O:36]>>[CH2:18]([O:20][C:21](=[O:32])[C@H:22]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1)[NH:23][C:35](=[O:36])[CH2:34][Cl:33])[CH3:19]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(Cl)CCl
Agent: NCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CCl

Procedure:
A process for producing N-glycyl-L-tyrosine is disclosed in Berichte der Deutschen Chemischen Gesellschaft, p. 2486 (1904). In the process, L-tyrosine is subjected to a reaction with 1.1 equivalents of chloroacetyl chloride and an aqueous solution of sodium hydroxide to obtain N-chloroacetyl-L-tyrosine, which is then made to react with aqueous ammonia to prepare N-glycyl-L-tyrosine. This process gives N-chloroacetyl-L-tyrosine, which is an intermediate for the synthesis of N-glycyl-L-tyrosine, in a 50% yield. The above literature also discloses a process in which L-tyrosine ethyl ester is made to react with 1.0 equivalent of chloroacetyl chloride to form N-chloroacetyl-L-tyrosine ethyl ester, which is then hydrolyzed to prepare N-chloroacetyl-L-tyrosine. In this process, the overall yield of N-chloroacetyl-L-tyrosine based on L-tyrosine ethyl ester is 91%, and that based on L-tyrosine is 77% as the yield in the step of conversion into ethyl ester from L-tyrosine is 85%. The process for producing N-glycyl-L-tyrosine via L-tyrosine ethyl ester is thus advantageous in respect of yield over the process in which L-tyrosine is directly chloroacetylated. However, when applied to the production on an industrial scale, the former process which requires the steps of esterification and hydrolysis is inefficient compared with the latter process requiring a smaller number of steps.