Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C@@H:8]([OH:9])[C@H:7]([O:10][C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@H:14]([OH:19])[C@@H:13]3[O:20][C:21]4([O:27][C@H:26]([C@@H:28]([NH2:31])[CH2:29][OH:30])[C@H:25]([OH:32])[C@@H:24]([OH:33])[C@H:23]4[OH:34])[O:22][C@H:12]23)[C@@H:6]([OH:35])[C@H:5]([NH2:36])[CH2:4]1>O>[CH3:1][NH:2][C@H:3]1[C@H:8]([OH:9])[C@@H:7]([O:10][C@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@H:14]([OH:19])[C@@H:13]3[O:20][C@:21]4([O:27][C@H:26]([C@H:28]([NH2:31])[CH2:29][OH:30])[C@H:25]([OH:32])[C@H:24]([OH:33])[C@H:23]4[OH:34])[O:22][C@@H:12]23)[C@H:6]([OH:35])[C@@H:5]([NH2:36])[CH2:4]1
Reactant: CN[C@H]1C[C@@H](N)[C@H](O)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@@H]3OC4(O[C@H]23)O[C@H]([C@@H](N)CO)[C@H](O)[C@@H](O)[C@H]4O)[C@@H]1O
Solvent: O
Product: CN[C@@H]1C[C@H](N)[C@@H](O)[C@H](O[C@H]2O[C@H](CO)[C@H](O)[C@@H]3O[C@@]4(O[C@@H]23)O[C@H]([C@H](N)CO)[C@H](O)[C@H](O)[C@H]4O)[C@H]1O

Procedure:
After the incubation in Example 2, each culture was diluted with water to an OD600 of 0.5 (cell count 107 cells/ml) and further diluted by a factor of 10 (in the far left column marked with 10−1 in FIG. 3), and 7 μl of each dilution was spotted onto an YES medium (agar plate) and incubated at 30° C. (FIG. 3(a)) and 37° C. (FIG. 3 (c)) for 3 days. Similarly, each dilution was incubated on YES medium (5 mL) containing 20 μg/l hygromycin B (0.05 mass %) at 30° C. overnight (FIG. 3 (b)). If a rapid growth was observed in a short time, the dilutions were cultured under similar conditions after further serially diluted by a factor of 10. In FIG. 3 (a) to (c), cultures of serial 10-fold dilutions from OD600 of 0.5 (10−1, 10−2, 10−3 and 10−4) are shown.
Reaction SMILES: C1(O[C:8](=[O:19])[C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[C:11]([CH3:17])[C:10]=2[OH:18])C=CC=CC=1.[CH2:20]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:33]([N:32]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:8](=[O:19])[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[C:11]([CH3:17])[C:10]=1[OH:18])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCNCCCCCCCCCCCC
Reactant: Cc1cc(C)c(C(=O)Oc2ccccc2)c(O)c1C
Product: CCCCCCCCCCCCN(CCCCCCCCCCCC)C(=O)c1c(C)cc(C)c(C)c1O
Temperature: 120 °C
Yield: 91 %

Procedure:
In a 250 ml flask fitted with a mechanical stirrer and a reflux condenser, were placed 30.7 g (0.12 mole) of the 2-hydroxy-3,4,6-trimethylbenzoic acid phenyl ester prepared in step (2) and 42.36 g (0.12 mole) of didodecylamine. This mixture was heated in a nitrogen atmosphere at 120° C. for 12 hours. The phenol formed was distilled off under vacuum (7 g were thus collected). After cooling, the crystallization of the desired product was started by scraping.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH2:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[C:12]([O:16][O:17][C:18](=[O:24])[CH2:19][CH2:20][C:21](Cl)=[O:22])([CH3:15])([CH3:14])[CH3:13].C(OOC(=O)CCC(O)=O)(C)(C)C.O=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH:8][C:21](=[O:22])[CH2:20][CH2:19][C:18]([O:17][O:16][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:24])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(C)(C)OOC(=O)CCC(=O)Cl
Agent: CC(C)(C)OOC(=O)CCC(=O)O
Agent: O=O
Solvent: ClCCl
Product: CC1(C)CC(NC(=O)CCC(=O)OOC(C)(C)C)CC(C)(C)N1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
Into a 250 ml flask equipped with a magnetic stirrer, thermometer, condenser, addition funnel and calcium chloride drying tube were placed 2,2,6,6-tetramethyl-4-aminopiperidine (20.3 g, 0.13 mole) and 50 ml of methylene chloride. The addition funnel was charged with 4-t-butylperoxy-4-oxobutanoyl chloride (13.2 g, 0.06 mole) and 50 ml methylene chloride. The acid chloride was added dropwise at 20°-23° C. over a 20 minute period, causing a slight exotherm. The reaction mixture was warmed to 30° C. over 60 minutes and then stirred at 30° C. for another 30 minutes. The reaction mixture was poured into a jacketed reactor and washed at 20°-25° C. with eight 50 ml portions of water. The organic material was dried with anhydrous magnesium sulfate and the solvent stripped under reduced pressure to give 9.3 g of a light amber-straw liquid. Liquid chromatography of this product showed it to contain two components, one of which was 4-t-butylperoxy-4-oxobutanoic acid. Iodometric analysis indicated 5.65% active oxygen content which corresponds to a mixture of 22% perester-acid and 78% perester-amide (C-VII). The infrared spectrum (neat) showed three carbonyl absorptions at 1650, 1700 and 1770 cm-1 (amide, acid and perester) and a broad absorption at 3300 cm-1. Based on the 78% assay, the product was prepared in 37% corrected yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.ClCCl.[OH-].[Na+].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:17]=1[CH2:18]Cl>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[NH2:1][C:2]1[C:7]([O:8][CH2:18][C:17]2[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:16]=2[Cl:15])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Fc1cccc(Cl)c1CCl
Reactant: Cc1ccc(O)c(N)n1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(OCc2c(F)cccc2Cl)c(N)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-amino-3-hydroxy-6-methylpyridine (4.3 g, 0.035 mol), dichloromethane (26 ml) and 40% aqueous sodium hydroxide solution (26 ml) was stirred for five minutes at room temperature, then 2-chloro-6-fluorobenzyl chloride (6.8 g, 0.038 mol) and Adogen 464 (2.5 ml) were added and stirring continued for 16 hours. The mixture was diluted with water and extracted with dichloromethane. Drying and evaporation of the organic extracts and trituration with ethanol gave the desired product. Yield 6.3 g (67%), m.p. 108°-109 ° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][C:10](=[O:13])[NH:9][C:8]=2[C:7]([OH:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CN(C=O)C.C(N(CC)C(C)C)(C)C.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.O>[C:1]([C:4]1[C:12]2[S:11][C:10](=[O:13])[NH:9][C:8]=2[C:7]([O:14][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(O)c2[nH]c(=O)sc12
Reactant: BrCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)sc12
Reaction time: 72 h

Procedure:
To a solution of 7-acetyl-4-hydroxy-1,3-benzothiazol-2(3H)-one (153 mg), in dry THF (3 ml) and dry DMF (0.5 ml) under nitrogen, was added N,N-diisopropylethylamine (0.13 ml) and benzyl bromide (0.09 ml), and the mixture stirred for 72 h. Water (10 ml) was added and the mixture extracted with ethyl acetate. The organic phases were combined, washed with brine, dried (MgSO4), and evaporated in vacuo. The residue was purified on a 5 g silica SPE cartridge, eluting with a stepped gradient of 10% to 50% ethyl acetate-cyclohexane mixtures, to give the title compound (68 mg). LCMS RT=3.14 min.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[C:18]([CH3:33])=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=4)=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:33][C:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:34])=[O:3])=[CH:10][CH:11]=2)=[CH:22][CH:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=2)[N:19]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3ccc(-c4cccc(C(F)(F)F)c4)nc3C)cc21
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 5 g], {6-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as off-white crystals.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([Cl:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:28][C:29]([CH3:33])([CH3:32])[CH2:30][NH2:31]>C(#N)C>[Cl:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH3:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(Cl)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CC(C)(C)CN
Solvent: CC#N
Product: CC(C)(C)CNC[C@H]1COc2c(Cl)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 57 using [(2R)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.027 g, 0.062 mmol), 2,2-dimethylpropan-1-amine (0.5 ml), ACN (3 ml). MS m/z (rel. intensity, 70 eV) 347 (M+, 2), 332 (20), 292 (30), 290 (78), 100 (bp), 70 (16).
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([Si:8]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:9]1[O:10][CH:11]=[C:12]([CH:14]=O)[CH:13]=1)[CH3:7]>CCCCCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:6]([Si:8]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:9]1[O:10][CH:11]=[C:12]([CH:14]=[CH2:1])[CH:13]=1)[CH3:7]
Reactant: CC[Si](CC)(CC)c1cc(C=O)co1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=Cc1coc([Si](CC)(CC)CC)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
n-Butyl lithium (a 2.5M solution in hexane; 4.4 ml, 11.0 mmol) was added dropwise to a suspension of methyltriphenylphosphonium bromide (3.93 g, 11 mmol) in THF (40 ml) at 0 degrees C under argon. After 2 hours stirring at 0 degrees C., a solution of 2-triethylsilyl-4-furaldehyde (1.54 g, 7.33 mmol) in THF (2 ml) was added. Stirring was continued at room temperature for 14 hours and the mixture was quenched with methanol/water 40 ml (1:1). Extraction (pentane) and evaporation of the dried (magnesium sulfate) extracts gave a residue, which was purified by flash chromatography on silica using pentane to give the titled furan. Rf (pentane) 0.75. 1H NMR (CDCl3) 0.81 (q, 6H, J=8.1 Hz), 0.99 (t, 9H, J=7.4 Hz), 5.14 (d, 1H, J=12.1 Hz), 5.48 (d, 1H, J=17.6 Hz), 6.64 (dd, 1H, J=10.8 Hz, 17.5 Hz), 6.81 (s, 1H) and 7.64 (s, 1H). HRMS exact mass calculated for C12H20SiO(M+) 208.1283, found 208.1280.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH3:9])=[N:3][CH:2]=1.O.NN>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:10])[CH2:8][CH3:9])=[N:3][CH:2]=1
Reactant: CCC(c1ccncn1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: CCC(N)c1ccncn1
Yield: 84 %

Procedure:
2-[1-(Pyrimidin-4-yl)propyl]isoindoline-1,3-dione (292 mg, 1.09 mmol) in methanol (2 mL) was stirred with hydrazine monohydrate (153 μL, 3.15 mmol) at room temperature for 16 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure repeatedly to give the desired product (84% yield).
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([O:32][CH2:33][CH3:34])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])=[CH:8][C:7]=1[CH3:31].[Li+].[OH-]>>[CH3:31][C:7]1[CH:8]=[C:9]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:30])[CH:10]=[C:11]([CH3:12])[C:6]=1[CH2:5][C@H:4]([O:32][CH2:33][CH3:34])[C:3]([OH:35])=[O:2]
Reactant: CCO[C@@H](Cc1c(C)cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], (S)-3-{2,6-dimethyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-{2,6-dimethyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-2-ethoxy-propionic acid as yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][C@H:16]([NH:18]C(OC(C)(C)C)=O)[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])[CH3:2].C(OCC)C.[ClH:36]>C(OCC)(=O)C>[ClH:36].[NH2:18][C@H:16]([CH3:17])[CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[O:10][C:6]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:7][C:8]=2[CH:14]=1
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)NC(=O)OC(C)(C)C)cc2O1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N)cc2O1

Procedure:
A solution of (R)-5-[N-(t-butyloxycarbonyl)-2-aminopropyl]-1,3-benzodioxole-2,2-dicarboxylic acid diethyl ester (3.0 g, 7 mMol) in ethyl acetate (40 ml) and hydrogen chloride solution in diethyl ether (1M, 56 ml, 56 mMol) was stirred at ambient temperature under an argon atmosphere for 48 hours. The solvent was evaporated and the residue was dried giving the title compound as a glass.
Reaction SMILES: [F:1][C:2]([F:16])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][N:6]=1>[O-2].[O-2].[Mn+4]>[F:16][C:2]([F:1])([CH:13]([F:15])[F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][N:6]=1
Reactant: OCc1ccc(OCC(F)(F)C(F)F)nc1
Agent: [Mn+4]
Agent: [O-2]
Product: O=Cc1ccc(OCC(F)(F)C(F)F)nc1
Yield: 96 %

Procedure:
2-(2,2,3,3-Tetrafluoropropoxy)-5-(hydroxymethyl)pyridine was treated with active manganese dioxide in the same manner as in Reference example 22 to obtain the title compound as an oil in a yield of 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1Cl

Procedure:
A mixture of 3-chloro-4-nitrophenol (10 g, 0.058 mole), benzyl bromide (11.8 g, 0.069 mole), and potassium carbonate (16 g, 0.116 mole) in acetone is stirred, heated at reflux temperature for 17 hours, cooled and filtered. The filtrate is concentrated in vacuo to give a solid residue which is recrystallized from absolute ethanol to give the title compound, mp 82°-84.5° C., identified by elemental and NMR analyses.
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)=[CH2:4].[CH3:11][C:12]([Si:15]([CH3:23])([CH3:22])[O:16][C@@H:17]([CH3:21])[C:18](Cl)=[O:19])([CH3:14])[CH3:13]>O1CCCC1.C(Cl)Cl>[CH3:13][C:12]([Si:15]([CH3:23])([CH3:22])[O:16][C@@H:17]([CH3:21])[C:18]([N:9]1[C@H:5]([CH:3]=[CH2:4])[CH2:6][CH2:7][C:8]1=[O:10])=[O:19])([CH3:11])[CH3:14]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Cl
Reactant: C=CC1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=C[C@@H]1CCC(=O)N1C(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 52.3 %

Procedure:
To 60% sodium hydride (336 mg, 10 mmol) in mineral oil) in tetrahydrofuran (20 mL) at 0° C. was added dropwise a solution of 5-vinylpyrrolidin-2-one (1.0 g, 9.0 mmol) in tetrahydrofuran (10 mL) over a 5 minute period. The cooling bath was removed and the solution was allowed to warm to 25° C. to ensure complete anion generation. To the anion at 25° C. was added dropwise a solution of (2S)-2-((1,1-dimethylethyl)dimethylsilyloxy)propanoyl chloride (2.23 g, 10 mmol) in tetrahydrofuran (10 mL) over a 5 minute period. TLC indicated that the reaction was complete upon addition of the acid chloride (silica gel plates; hexane and ethyl acetate, 9:1). The solvent was removed by rotary evaporation affording a thick slug. The slug was dissolved in methylene chloride (75 mL) and washed with water (1×50 mL) and dried (MgSO4). Concentration and purification by flash chromatography on silica gel (EM 60, 0.040-0.063 partical size, 230-400 Mesh, column size: 4.5 cm diameter×15 cm length) using hexane and ethyl acetate (19:1) afforded 1.40 g (47%) of (5S)-N-((2S)-2-((1,1-dimethylethyl)dimethylsilyloxy)propanoyl)-5-ethenylpyrrolidin-2-one (9a) as clear liquid: 1H NMR (CDCl3) δ0.0300 (s,3 H), 0.0656 (s, 3 H), 0.877 (s, 9 H), 1.37 (d, J=6.5 Hz, 3 H), 1.82-1.88 (m, 1 H) 2.21 (p, J=10.7 Hz, 1 H), 2.34-2.47 (m, 1 H), 2.60 (p, J=9.8 Hz, 1 H), 4.88 (br, 1 H), 5.05-5.11 (m, 2 H), 5.36-5.38 (m, 1 H), 5.70-5.79 (m, 1 H); 13C NMR (CDCl3) δ174.86, 174.77, 135.5, 115.4, 66.8, 57.9, 31.6, 25.5, 24.4, 21.1, 18.1, -4.87, -5.16.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([C:18]#N)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[O:31]1CCCC1>>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:17])([CH:18]=[O:31])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C#N)O2
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C=O)O2

Procedure:
(± )-6-acetoxy-2-cyano-2,5,7,8-tetramethylchroman was reduced with diisobutylaluminum hydride as described in Example 101, with tetrahydrofuran as reaction solvent. TLC of the crude product indicated that it was partially deacetylated. The material was thus reacetylated by the process described in Example 2 give (±)-6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxaldehyde as a white solid, m.p. 88°-90°, from 30°-60° petroleum ether.
Reaction SMILES: CS[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5].O.C(OCC)C>C(O)(=O)C.[Zn].S([O-])([O-])(=O)=O.[Cu+2]>[Cl:16][C:11]1[CH:10]=[C:9]([CH:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: COC(=O)C(C)(SC)c1ccc(N)c(Cl)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)C(C)c1ccc(N)c(Cl)c1
Yield: 95.7 %

Procedure:
Methyl α-methylthio-α-(3-chloro-4-aminophenyl)propionate (380 mg) was dissolved in 4 ml of acetic acid, and an intimate mixture of 406 mg of zinc powder and 1.5 mg of anhydrous copper sulfate was added. The entire mixture was heated under reflux for 1 hour. Water (40 ml) and 15 ml of diethyl ether were added to the reaction mixture. The insoluble matter was separated by filtration, and then the organic layer was separated. Furthermore, the aqueous layer was extracted with 5 ml of diethyl ether. The organic layer and the extract were combined, washed with 15 ml of a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 299 mg of methyl α-(3-chloro-4-aminophenyl)propionate in a yield of 95.6% as a colorless oil.
Reaction SMILES: [N:1]1([C:51](OC(C)(C)C)=O)[CH2:50][CH2:49][CH2:48][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].Cl>C(O)(=O)C>[NH:1]1[CH2:51][CH2:50][CH2:49][CH2:48][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:32]([C:37]([NH:39][C@@H:40]([C:45]([NH2:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CSCC[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-Phe-PheNHNH2 (Example 1, 1.93 g.) and HGly-Leu-DMetNH2 (1.31 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-Gly-Leu-DMetNH2 in 60% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-Gly-Leu-DMetNH2 (1.6 g.) using hydrogen chloride in acetic acid gave HPro-Phe-Phe-Gly-Leu-DMetNH2, which was isolated as the amorphous white solid phosphate (1:1) slat sesquihydrate in 72% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:24][O:25][C:26](=[O:32])[CH2:27][C@@H:28]([NH2:31])[CH2:29][CH3:30]>N1C=CC=CC=1>[CH3:24][O:25][C:26](=[O:32])[CH2:27][C@@H:28]([NH:31][C:8]([C:3]1[C:2]([NH2:1])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10])[CH2:29][CH3:30]
Reactant: Nc1cccnc1C(=O)O
Reactant: CC[C@H](N)CC(=O)OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Product: CC[C@@H](CC(=O)OC)NC(=O)c1ncccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of 321 mg of 3-aminopyridine-2-carboxylic acid in pyridine (5.0 mL) is added 377 mg of 1,1′-carbonyldiimidazole and the mixture is stirred for 2 h at room temperature. The resulting mixture is treated with 300 mg of (S)-3-aminopentanoic acid methyl ester hydrochloride and the mixture is stirred for 16 h at room temperature. Then the solvent is removed under vacuum and the residue is purified by flash chromatography on silica gel to give 250 mg (56%) of (S)-3-[(3-amino-pyridine-2-carbonyl)-amino]-pentanoic acid methyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)C(C)C)(C)C.Cl.[N:21]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][N:23]=[CH:22]1>C(#N)C>[N:21]1([CH:26]2[CH2:31][CH2:30][N:29]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N+:8]([O-:10])=[O:9])[CH2:28][CH2:27]2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: c1cn(C2CCNCC2)cn1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1N1CCC(n2ccnc2)CC1
Temperature: 25 °C
Yield: 81.5 %

Procedure:
A solution of 1-fluoro-2-nitro-benzene (0.32 mmol, 34 μL), N,N-diisopropylethylamine (1.6 mmol, 0.28 mL) and HCl salt of 4-Imidazol-1-yl-piperidine (0.53 mmol, 0.10 g) in ACN (2 mL) was irradiated using microwave for 10 minutes at a temperature of 180° C. The solution was then cooled to room temperature and concentrated in vacuo and the resulting residue was purified using column chromatography on silica gel to provide 4-Imidazol-1-yl-1-(2-nitro-phenyl)-piperidine (71 mg, 81% yield). To the solution of this nitro compound in EtOAc (15 mL) was added Pd on carbon (5% Pd, 55 mg). The resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature for about 15 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to provide compound 41A (54 mg, 86% yield). HPLC-MS RT=0.63 minutes, mass calculated formula C14H18N4 242.15, observed LCMS m/z 243.30 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[C:16]([Li])(C)(C)C.IC>O1CCCC1.CCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:16])[C:3]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cccc(F)c1NC(=O)OC(C)(C)C
Temperature: -15 °C
Yield: 99.5 %

Procedure:
A solution of tert-butyl 2-fluorophenylcarbamate (99.5 g, 471 mmol) in anhydrous tetrahydrofuran (900 mL) was placed under a nitrogen atmosphere, cooled in a dry ice-acetone bath, and stirred while t-butyllithium (666 mL of a 1.7M solution in pentane, 1132 mmol) was added slowly. The resulting mixture was slowly warmed up to −15° C. in 2 hours, then cooled back to −78° C. and treated with iodomethane (32.3 mL, 518 mmol). After warming up to −15° C. in 30 minutes, the mixture was removed from the cooling bath and treated with aqueous saturated NH4Cl (20 mL). The resulting slurry was diluted with CH2Cl2 (2000 mL), dried over MgSO4, filtered through a pad of silica, and concentrated under vacuum to afford tert-butyl 2-fluoro-6-methylphenylcarbamate(105 g, 99.5%) as a yellow solid.