Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[C:19]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:23]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[C:19]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:20][CH:21]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:23]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1cc(-c2ccccc2)cnc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cc(-c2ccccc2)cnc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.8 %

Procedure:
A suspension of 1E (560 mg, 1.11 mmol) and 5% wt. platinium on activated carbon (500 mg) in THF (90 mL) and MeOH (90 mL) was stirred at RT under H2 at 80 psi for 2 days. After this time, no starting material was detected by LC-MS. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as a foam (420 mg, 75%). LC/MS (method A): retention time=3.24 min, (M+H)+=506.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18](OC(=O)C)(=[O:20])[CH3:19].C([O-])(=O)C.[Na+]>S(=O)(=O)(O)O>[C:18]([NH:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])(=[O:20])[CH3:19]
Reactant: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
6.0 G. of 2-amino-4-phenylthio-1-nitrobenzene is dissolved in 80 ml. acetic anhydride and treated with a few drops of sulfuric acid. The mixture is left at 20°-30° C for 2 hours then a little sodium acetate added and the solvent removed under vacuum. The residue is treated with water, filtered and recrystallized from methanol yielding 2-acetamido-4-phenylthio-1-nitrobenzene. This material may also be obtained by reaction of 2-acetamido-4-chloro-1-nitrobenzene with sodium phenylmercaptide essentially as described above for the free amine.
Reaction SMILES: [CH2:1]([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]C1C(=O)C(Br)=CC(Br)(Br)C=1>ClCCl>[CH2:1]([N:8]([C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(Br)=CC(Br)(Br)C=C1Br
Reactant: CN(Cc1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CN(Cc1ccccc1)c1ccc(Br)cc1
Reaction time: 20 h
Yield: 56.7 %

Procedure:
N-benzyl-N-phenyl-N-methylamine (4.41 g, 0.0224 mol) was dissolved in anhydrous dichloromethane (150 mL) and 2,4,4,6-tetrabromocyclohexadiene-1-one(9.16 g, 0.0224 mol) was added in 10 equal portions over a 30 min. period. Stirring was continued at ambient temperature for 20 hours. The organic phase was successively washed with 0.5N solution of sodium hydroxide in water (100 mL), 1N solution of sodium hydroxide in water (100 mL), water (120 mL) and brine (120 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (1:99) as mobile phase to yield N-benzyl-N-(4-bromophenyl)-N-methylamine (3.52 g, 0.0127 mol) as a colorless oil.
Reaction SMILES: N[C:2]1[C:3]([O:13][CH3:14])=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Cu][C:16]#[N:17].[C-]#N.[K+].C(Cl)Cl>O.Cl>[C:16]([C:2]1[C:3]([O:13][CH3:14])=[C:4]([O:11][CH3:12])[CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1)#[N:17]
Reactant: N#C[Cu]
Reactant: COc1cc(C(C)=O)cc(N)c1OC
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(C)=O)cc(C#N)c1OC
Reaction time: 3 h

Procedure:
A solution of 5.2 g of sodium nitrile in 20 ml of water is added dropwise at 0° within 20 minutes to 14.0 g of 5'-amino-3',4'-dimethoxyacetophenone dissolved in 155 ml of 1N hydrochloric acid. After stirring at -2° for 30 minutes the cold diazonium salt solution is added dropwise within 30 minutes at 5°-10° to a solution of 8.7 g of copper(I) cyanide and 5.45 g of potassium cyanide in 60 ml of water. After completion of the addition 200 ml of methylene chloride are added, and the reaction mixture is stirred at 23° for 3 hours and then filtered. The organic phase is separated, washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride/petroleum ether. There is obtained 5'-cyano-3',4'-dimethoxyacetophenone of m.p. 125°-126°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[C:4]([O:13]C)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[C:4]([OH:13])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(C)(C)CO
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CO)c1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
To a solution of 2-(4-bromo-2-methoxyphenyl)-2-methylpropan-1-ol (300 mg, 1.16 mmol) in dichloromethane (5 mL) was added dropwise boron tribromide (580 mg, 2.32 mmol) at −78° C. under nitrogen. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction was quenched with water (10 mL) and extracted with dichloromethane (20 mL). The organic layer was washed with aq. sodium bicaronate (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a crude residue, which was purified by flash chromatography to give the title compound (90 mg, 32%) as a white solid.
Reaction SMILES: N[C@H:2]([C:8](O)=[O:9])CCCCN.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][C:21]([C@H:23]([N:30]([CH3:55])[C:31]([C@H:33]([NH:45][C:46](=[O:54])/[CH:47]=[CH:48]/[CH2:49][C:50]([NH2:53])([CH3:52])[CH3:51])[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)=[O:32])[CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[O:22])[C:17](=[O:19])[NH2:18]>>[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:20][C:21]([C@H:23]([N:30]([CH3:55])[C:31]([C@H:33]([NH:45][C:46](=[O:54])/[CH:47]=[CH:48]/[CH2:49][C:50]([NH2:53])([CH3:52])[CH3:51])[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)=[O:32])[CH2:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)=[O:22])[C:17](=[O:19])[NH2:18])(=[O:9])[CH3:2]
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)/C=C/CC(C)(C)N)[C@H](Cc1cccs1)C(=O)N[C@@H](CCCCN)C(N)=O
Reactant: NCCCC[C@H](N)C(=O)O
Product: CC(=O)NCCCC[C@H](NC(=O)[C@@H](Cc1cccs1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)/C=C/CC(C)(C)N)C(N)=O

Procedure:
This compound was prepared by acetylation of the epsilon amino group in the lysine fragment using the general method described above and using the compound prepared in example 22 as starting material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:17])[CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:23]([OH:25])=[O:24].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:21]2[C:20]([F:19])=[C:28]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])[CH:5]=[CH:6][C:7]=1[C:8](=[O:17])[CH:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC(C)C(=O)c1ccc(O)cc1F
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)O)c(-c2ccc(C(=O)C(C)CCCCCC)c(F)c2)c1F
Yield: 56.5 %

Procedure:
Into a flask were charged 1.2 g (4.76 mmol) of (+)-3-fluoro 4-(2-methyloctanoyl) phenol, 1.51 g (5.94 mmol) of 3-fluoro-4-heptyloxy benzoic acid, 76.7 mg (0.63 mmol) of N,N-dimethylamino pyridine and 30 ml of dried methylene chloride, which were slightly heated with stirring to form a homogeneous solution. Then, the solution was added with 1.40 g (6.79 mmol) of dicyclohexyl carbodiimide and stirred over a night. The precipitated white crystal was filtered off, and the resulting filtrate was washed with 2 normal hydrochloric acid, an aqueous solution of 5% sodium hydrogen carbonate and water in this order and dried on magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated and dried under a reduced pressure to obtain an oil. This oil was purified through a column chromatography and recrystallized with ethanol to obtain 1.02 g (2.69 mmol, yield: 44%) of a white crystal of the objective compound having the aforementioned physical and chemical properties.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[I:13]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[C:9]([I:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(C)(C)C)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1ccc(C(C)(C)C)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-tert-butyl-4-methoxybenzene (0.10 g, 0.61 mmol) in MeOH (2 mL) was added to a mixture of silver sulfate (0.19 g, 0.61 mmol) and iodine (0.154 g, 0.61 mmol) in MeOH (1 mL). The mixture was stirred at room temperature for 1 h. The mixture was filtered. The filtrate was concentrated. The title compound was obtained. 1H NMR (CDCl3, 500 MHz): δ 7.82 (d, J=2.5 Hz, 1H), 7.36 (dd, J=8.5, 2.5 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 1.35 (s, 9H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[H-].[Na+].[F:19][C:20]([F:24])=[C:21](F)[F:22]>C1C=CC=CC=1.O1CCCC1>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:21]([F:22])=[C:20]([F:24])[F:19])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: FC(F)=C(F)F
Reactant: CCC[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](c2ccc(OC(F)=C(F)F)cc2)CC1
Temperature: 140 °C

Procedure:
A solution of 10 g of p-(trans-4-n-propylcyclohexyl)phenol in a mixture of 40 ml of benzene and 10 ml of tetrahydrofuran is reacted with sodium hydride analogously to Example 1. After tetrafluoroethene has been condensed in, the mixture is heated at 140° C. for about 20 hours and treated as described in Example 1. p-(trans-4-n-propylcyclohexyl)trifluorovinyloxybenzene is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=1)([O-])=O.O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:12])[CH3:13])=[O:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C)(C)CC(C)(C)NC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)CC(C)(C)NC(=O)c1ccc(N)cc1
Yield: 76.1 %

Procedure:
4-nitro-N-(tert-octyl)benzamide (30 g, 0.108 mol) dissolved in 200 ml of ethyl acetate was hydrogenated in a 500 ml hydrogenator in the presence of 4.8 g of palladium, 10% on charcoal with 50% water as the catalyst (hydrogen pressure: 8-10 bar) at a temperature of 70-75° C. for 1 hour and 15 minutes. After filtering, concentrating the solvent and vacuum drying, 20.4 g (yield: 76%) of 4-amino-N-(tert-octyl)benzamide were obtained in the form of a pale yellow powder and used as is in the next step.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4]([C:12]([OH:14])=[O:13])=[CH:3]1>[Pd].C(O)(=O)C.C(OCC)(=O)C>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH:4]1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(=O)c2ccccc2o1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)C1CCc2ccccc2O1
Yield: 96.2 %

Procedure:
A mixture of the compound from Example 8 (20.0 g, 105 mmol), and 10% palladium on activated carbon (2.0 g) in acetic acid (200 mL) was placed under hydrogen pressure (60 psig) in a Parr hydrogenation apparatus. After 22.5 hours the mixture was removed from the hydrogen atmosphere and filtered through a pad of Celite. The Celite pad was washed with ethyl acetate (800 mL), and the combined filtrate concentrated to give a brown oil. The oil was dissolved in ethyl acetate (500 mL) and extracted with saturated NaHCO3 (4×125 mL). The aqueous phase was acidified to pH=2 with concentrated HCl and extracted with ethyl acetate (4×100 mL). The combined organic phase was washed with saturated aqueous sodium chloride solution (100 mL), dried (MgSO4), and concentrated to give a colorless solid (18.0 g, 96%). Mp 97.5-99° C.; 1H NMR (300 MHz, DMSO-d6) δ12.96 (br s, 1H), 7.03 (m, 2H), 6.78 (m, 2H), 4.74 (dd, J=6.4 Hz, J=3.9 Hz, 1H), 2.73 (m, 1H), 2.63 (m, 1H), 2.03 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[N:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[CH:24]=[N:23][C:22]([C:31]3[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=3)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2cnc(Br)cn2)cs1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2cnc(-c3ccc(Cl)cc3)cn2)cs1
Yield: 90.9 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(5-bromopyrazin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (10.5 g) synthesized in Example 226-1 and 4-chlorophenylboric acid (5.36 g) were dissolved in dioxane (80 mL) and aqueous sodium carbonate solution (2 mol/L, 40 mL), tetrakis(triphenylphosphine)palladium (1.32 g) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer 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 chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (10.2 g) as a brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:43])[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C@@H:12]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([NH:19][C:20](=[O:41])[C@@H:21]([NH:33]C(=O)OC(C)(C)C)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[CH:32])=[CH:25][CH:24]=2)[C@H:13]1[OH:42]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:33][C@@H:21]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[CH:32])=[CH:25][CH:24]=1)[C:20]([NH:19][C@H:14]1[C@@H:13]([OH:42])[C@H:12]([N:7]2[CH:6]=[N:5][C:4]3[C:8]2=[N:9][CH:10]=[N:11][C:3]=3[N:2]([CH3:43])[CH3:1])[O:16][C@@H:15]1[CH2:17][OH:18])=[O:41]
Reactant: C#CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N(C)C)ncnc43)O[C@@H]2CO)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCOc1ccc(C[C@H](N)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N(C)C)ncnc43)O[C@@H]2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
O-Propargyl Boc-Puromycin 4 (480 mg, 0.81 mmol) was dissolved in a 1:1 TFA (4 mL) and CH2Cl2 (4 mL) mixture and then stirred at room temperature for 30 min. Volatiles were evaporated in vacuo and the residue was dissolved in CH2Cl2. The solution was poured into saturated aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated to dryness in vacuo. The residue was purified by flash chromatography (SiO2, step-wise gradient from 5-15% MeOH in CH2Cl2) to afford the O-propargyl-puromycin 5 (111 mg, 28%) as a white solid. 1H NMR (600 MHz, DMSO-d6): δ 8.44 (s, 1H), 8.24 (s, 1H), 8.06 (br, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.13 (d, J=5.4 Hz, 1H), 5.98 (d, J=3.0 Hz, 1H), 5.13 (t, J=5.4 Hz, 1H), 4.74 (d, J=1.8 Hz, 2H), 4.42-4.51 (m, 2H), 3.91-3.96 (m, 1H), 3.66-3.72 (m, 1H), 3.26-3.58 (m, 9H), 2.92 (dd, J=14.4, 4.8 Hz, 1H), 2.52-2.58 (m, 1H), 2.02 (br, 2H); 13C NMR (150 MHz, DMSO-d6): δ 174.6, 155.7, 154.3, 151.8, 149.6, 137.9, 131.3, 130.2, 119.6, 114.5, 89.4, 83.5, 79.4, 78.0, 73.2, 61.0, 56.1, 55.3, 50.0, 40.4, 40.0; HRMS: (ESI, m/z) calcd [M+H]+ for C24H29N7O5: 496.2303. found 496.2308.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][C:37]2[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=2[F:44])=[O:35])=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[O:17])[CH:12]=2)[CH:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:16]([C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:30]=[C:31]([C:34]([NH:36][C:37]4[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=4[F:44])=[O:35])[CH:32]=[CH:33][C:2]=3[F:1])[CH:10]=[CH:9][N:8]=2)[NH:15][CH:14]=1)=[O:17]
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCCNC(=O)OC(C)(C)C)c[nH]4)c3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCCN)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of tert-butyl {3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propyl}carbamate (100 mg, 0.165 mmol) in 10 ml of methylene chloride was added 1 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 60 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8-9. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-aminopropyl)-5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxamide as grey solid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:35])[CH2:32][CH2:33][CH3:34]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]3[O:28][N:35]=[C:31]([CH2:32][CH2:33][CH3:34])[N:30]=3)[CH2:10]2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CCCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
150 mg (0.373 mmol) of the compound from Example 44A and 70 mg (0.746 mmol) of N′-hydroxybutanimidamide were reacted according to the General Method 2. Yield: 174 mg (93% of theory).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]([CH:9]1[CH:13]([C:14]([F:17])([F:16])[F:15])[O:12][C:11](=[O:18])[NH:10]1)([CH3:8])[CH3:7]>CCCCCC.C1COCC1>[CH:6]([C@H:9]1[C@H:13]([C:14]([F:15])([F:17])[F:16])[O:12][C:11](=[O:18])[N:10]1[C:11]([O:18][C@H:1]1[C@H:9]([CH:6]([CH3:8])[CH3:7])[CH2:13][CH2:14][C@@H:3]([CH3:4])[CH2:2]1)=[O:12])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)C1NC(=O)OC1C(F)(F)F
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)N1C(=O)O[C@@H](C(F)(F)F)[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (20 ml of a 10M solution in hexane) was added to a solution of (4RS),5SR)-4-isopropyl-5-trifluoromethyl-oxazolidin-2-one (35.8 g) in THF (600 ml) at -78° C., followed by stirring for 0.5 hours. (-)-Menthyl chloroformate (41 ml, freshly distilled) was added followed by continuation of stirring at -78° C. for 0.5 hours. The solution was warmed to 25° C. and the reaction quenched by addition of saturated aqueous sodium bicarbonate solution. The product was extracted into ether and washed with water and brine. The solution was dried (MgSO4) and the solvent removed under vacuum. The resulting oil crystallized upon standing to give a solid which was collected by filtration. The solid was washed with ether:hexane (1:1) and dried to give (4S,5R)-4-isopropyl-3-[(1R,3R,4S)-3-p-menthyloxycarbonyl]-5-trifluoromethyloxazolidin-2-one (23.15 g); m.p. 138-140° C.; 1H NMR (300 MHz, DMSO):5.51 (dd, 1H), 4.68 (m, 1H), 4.26 (m, 1H), 2.27 (m, 1H), 1.94 (d, 1H), 1.78 (m, 1H), 1.62 (d, 2H), 1.42 (m, 2H), 1.01 (dd, 2H), 0.95-0.84 (m, 24H), 0.71 (d, 3H); 19FNMR (376.5 MHz,DMSO): -76.9910; 99% d.e. (A further crop of 4.3 g (99% d.e.) was obtained from the mother liquor). [Note: the (4R,5S) isomer has m.p. 80-82° C. and 19FNMR (376.5 MHz, DMSO): -77.0019.
Reaction SMILES: [K].CC(C)([O-])C.[OH:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH2:10]P(=O)(OCC)OCC.[C:23]1([CH3:45])[CH:28]=[CH:27][C:26]([N:29]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=2)=[CH:25][CH:24]=1.Cl>O1CCCC1.O>[OH:7][C:8]1[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=1[CH:10]=[CH:44][C:41]1[CH:40]=[CH:39][C:38]([N:29]([C:30]2[CH:37]=[CH:36][C:33]([CH3:34])=[CH:32][CH:31]=2)[C:26]2[CH:27]=[CH:28][C:23]([CH3:45])=[CH:24][CH:25]=2)=[CH:43][CH:42]=1
Reactant: CCOP(=O)(Cc1ccccc1O)OCC
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=O)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C=Cc3ccccc3O)cc2)cc1
Reaction time: 2 h
Yield: 72 %

Procedure:
14.8 g of kalium-tert-butoxide and 50 ml of tetrahydrofuran were put in a reaction reservoir having a mixer, a thermometer and a dropping funnel. Under a nitrogen stream, a solution wherein 9.90 g of the diethyl 2-hydroxybenzylphosphonate and 5.44 g of 4-(di-para-tolylamino)benzaldehyde were dissolved in tetrahydrofuran was slowly dropped therein at a room temperature, and the reaction therein is further performed for 2 hrs at the same temperature. Then, water was added therein while cooling the reaction product with water, a hydrochloric acid solution having a normal concentration of 2 was added therein to acidize the reaction product, and the tetrahydrofuran was removed by an evaporator to extract a crude product with toluene. The toluene phase was washed with water, a sodium hydrogen carbonate solution and a saturated saline in this order, and magnesium sulfate was further added thereto to dehydrate the toluene phase. After filtered, the toluene was removed therefrom to prepare an oily crude product, and the oily crude product was further column-refined with silica gel to crystallize 5.09 g of 2-hydroxy-4′-(di-para-tolylamino)stilbene in hexane at a yield of 72%, having a boiling point of 136.0 to 138.0° C.