Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH2:10])=[O:9])=[O:5])[CH3:3].N(C(OC[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=O)[C@@H](C(NCC(N)=O)=O)CCC(=O)O.N(C(OCC1C=CC=CC=1)=O)[C@@H](C(NCC(N)=O)=O)CCCCN.N(C(C)=O)[C@@H](C(NCC(N)=O)=O)CC1C=CC=CC=1>>[NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH2:10])=[O:9])=[O:5])[CH2:3][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NC(=O)CNC(=O)[C@@H](CCC(=O)O)NC(=O)OCc1ccccc1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Agent: CC(=O)N[C@H](Cc1ccccc1)C(=O)NCC(N)=O
Agent: NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Product: NC(=O)CNC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 66 %

Procedure:
For accurate comparison, the D-isomers Z-D-Phe-OBn, Z-D-Ala-OBn, Z-D-Glu-OMe, Z-D-Lys-OBn, and Ac-D-Phe-OBn (15-19) of the representative L-amino acids Z-L-Phe-OBn, Z-L-Ala-OBn, Z-L-Glu-OMe, and Z-L-Lys-SBn (1-4) examined in the previous ligation examples were used. The stereoselectivity of SBL-WT for L-amino acids was clear (Table 4), because none of the D-amino acid esters evaluated gave dipeptide products with WT as the catalyst. All of the S166C-MEs yielded dipeptide products containing D-amino acids Z-D-Phe-Gly-NH2, Z-D-Ala-Gly-NH2, Z-D-Glu-Gly-NH2, Z-D-Lys-Gly-NH2, and Ac-D-Phe-Gly-NH2 (20-24). While each of these enzymes still showed a preference for L-amino acids, yields of up to 66% of Z-D-Phe-Gly-NH2, using S166C—SCH2C6H5, over 0% for WT, demonstrated a dramatic improvement in SBL's acceptance of D-amino acids.
Reaction SMILES: FC1C=CC(CN)=CC=1.[NH2:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36](O)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36]([NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 57 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 3-(aminomethyl)pyridine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 57% yield: mp 153-154° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.56-8.40 (m, 3H), 7.66 (d, J=7.8 Hz, 1H), 7.35-7.19 (m, 6H), 4.46-4.35 (m, 4H), 3.96 (t, J=7.5 Hz, 2H), 3.41 (t, J=7.5 Hz, 2H), 2.50 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.3, 157.8, 155.5, 151.7, 149.3, 148.4, 136.7, 135.6, 135.5, 129.1, 128.2, 127.9, 123.9, 117.9, 47.3, 42.9, 42.4, 40.8, 14.5; MS (ES+) m/z 408.1 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][C:5]=1[CH3:18])(=[O:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[O:25][CH:26]=[CH:27][CH:28]=1)CCC.[Cl-].[Li+]>O1CCOCC1.O.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>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:7]1[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:18])[CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2ccco2)cc1C
Temperature: 25 °C
Yield: 91.9 %

Procedure:
To a stirred solution of trifluoromethanesulfonic acid 4-acetyl-3-methylphenyl ester (1.76 g, 6.25 mmol) in dioxane (60 ml) was added 2-(tributylstannyl)furan (2.68 g, 7.5 mmol), lithium chloride (0.66 g, 15.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.722 g, 0.62 mmol) under nitrogen. The mixture was heated at reflux temperature for 2 hours, and cooled down to room temperature. The reaction mixture was diluted with water and the whole was extracted with diethylether. The organic layer was washed with saturated potassium fluoride aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:10) to give title compound (1.15 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]3[CH2:16][C:15](=O)[CH2:14]3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(O)C>N1C=CC=CC=1>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]3[CH2:16][C:15](=[N:21][OH:22])[CH2:14]3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CC(c2cccc(Oc3ccc(F)cc3)c2)C1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CC(c2cccc(Oc3ccc(F)cc3)c2)C1

Procedure:
A solution of 3-(3-(4-fluorophenoxy)phenyl)cyclobutanone (2.59 g, 10.1 mmol) and hydroxylamine hydrochloride (844 mg, 12.1 mmol) in 1:1 ethanol:pyridine (50 mL) was stirred for 36 hours. It was then concentrated in vacuo. The residue was taken up in brine (50 mL) and extracted with ethyl acetate (3×50 mL). The organics were combined, dried over MgSO4 and concentrated to afford 3-(3-(4-fluorophenoxy)phenyl)cyclobutanone oxime which was used as is.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[C:17]1([CH2:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:8]([NH:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: CN1CCC(C(=O)Cl)(c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN1CCC(C(=O)NCc2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
1-Methyl-4-phenyl-4-piperidinecarbonyl chloride (0.49 mol) was added portionwise at room temperature to a stirring mixture of benzenemethanamine (0.49 mol) and triethyl amine (1.223 mol) in CH2Cl2 (2500 ml). The mixture was stirred at room temperature for 1 hour. K2CO3 (150 g) and H2O were added. The mixture was stirred and separated into its layers. The aqueous layer was extracted with CH2Cl2. The combined organic layer was dried (MgSO4), filtered and the solvent was evaporated, yielding 144 g of 1-methyl-4-phenyl-N-(phenylmethyl)-4-piperidinecarboxamide (95%) (interm. 12).
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:33]([CH3:36])=[C:34]=[O:35]>O1CCOCC1>[C:27]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([C:34]([NH:33][CH3:36])=[O:35])[C:18]3=[O:26])[CH2:10][CH2:9]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CN=C=O
Solvent: C1COCCO1
Product: CNC(=O)n1c(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21

Procedure:
A mixture of 3 parts of 1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one, 1 part of isocyanatomethane and 25 parts of 1,4-dioxane is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2'-oxybispropane, yielding 3-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-2,3-dihydro-N-methyl-2-oxo-1H-benzimidazole-1-carboxamide; mp. 153.1° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.CN(C=O)C.F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[O:26][CH3:27]>C(OCC)(=O)C.O>[N:7]1([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=2[O:26][CH3:27])[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: c1c[nH]cn1
Reactant: COc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1-n1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
Potassium carbonate (2.0 g) and imidazole (662 mg) were added to a DMF (20 mL) solution of 4-fluoro-3-methoxybenzaldehyde (1.50 g). The reaction solution was agitated at 80° C. overnight, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane:ethyl acetate=3:1->ethyl acetate->ethyl acetate:methanol=10:1), and 960 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [H-].[Na+].[C:3]([O:16][CH3:17])(=[O:15])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[CH3:28].C(OCC)(=O)C>CN(C)C=O.O>[CH3:17][O:16][C:3](=[O:15])[CH:4]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[CH3:28])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: COC(=O)CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])cc1C

Procedure:
Sodium hydride (1.29 g of 60% dispersion in oil) was added portionwise to a stirred solution of malonic acid, methyl benzyl ester (5.84 ml) in dry N,N-dimethylformamide (40 ml). After 2.5 h 2-fluoro-5-nitro-toluene (5.0 g) was added, and the mixture was warmed to 100° for 18 h. The mixture was cooled then partioned between ethyl acetate and water. The aqueous phase was separated and extracted further with ethyl acetate. The combined organic extracts were dried, concentrated, and purified by chromatography eluting with cyclohexane:ethyl acetate (6:1) to give 2-(2-methyl-4-nitro-phenyl)-malonic acid benzyl ester methyl ester, admixed with the starting malonate ester, as a yellow oil (4.60 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12]([CH:15]([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][N:14]=2)=[CH:7][CH:8]=1
Reactant: CCCCCCC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCC(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-[2-(4-Trifluoromethyl-phenyl)-pyrimidin-5-yl]-heptan-1-one (1.47 g, 4.36 mmol) is dissolved in ethanol and cooled to 0° C. while stirring under nitrogen. To the flask is added sodium borohydride (165 mg, 4.36 mmol), and the reaction is kept at 0° C. for 1 h., then slowly warmed to room temperature. The reaction is monitored by HPLC. Upon complete consumption of starting material, the reaction is carefully quenched with water, the ethanol removed by rotary evaporator, and extracted with diethyl ether, washed, dried, and concentrated. The title compound is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])(O)[CH3:26])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])=[CH2:26])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C(C)(O)c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1)c1ccccc1OC
Yield: 78 %

Procedure:
A solution of crude 37 (2.23 mmol) in toluene (80 mL) was treated with p-toluenesulfonic acid (100 mg) and refluxed under a Dean-Stark trap for 3 hr. After cooling, the reaction mixture was diluted with ethyl acetate (150 mL) and washed with saturated sodium bicarbonate (150 mL) and water (2×100 mL). The organic extract was dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator and the crude product was purified by chromatography on silica (75 g) with 2% ethyl acetate in heptane (4 L) to afford 38 (0.78 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][N:17]3[C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].[NH4+].[Cl-]>C1COCC1.CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][N:17]3[C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=[C:16]3[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccn12
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccn3c(C(=O)O)cnc3c2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirring suspension of ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate (90) (84 mg, 0.23 mmol) in THF:MeOH:H2O (3:2:1, 1 mL) was added 6N LiOH (0.13 mL). The reaction was stirred at room temperature for 2.5 hours then neutralized with NH4Cl and concentrated to afford 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (91) which was immediately used without purification. MS (m/z) 346.1 (M+1)+.
Reaction SMILES: [C@H:1]1([O:12][C@@H:13]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[C@@H](O)C=O)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[CH2:24]([OH:46])[C@H:25]1[O:30][C@@H:29]([O:31][C@H:32]2[C@H:37]([OH:38])[C@@H:36]([OH:39])[C@H:35]([OH:40])[O:34][C@@H:33]2[CH2:41][OH:42])[C@H:28]([OH:43])[C@@H:27]([OH:44])[C@@H:26]1[OH:45]>>[C@H:1]1([O:12][CH2:13][C@@H:18]([OH:19])[C@@H:20]([OH:21])[C@H:22]([OH:23])[C@@H:28]([OH:43])[CH:29]=[O:30])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@@H:2]1[OH:3].[CH2:24]([OH:46])[C@H:25]1[O:30][C@@H:29]([O:31][C@H:32]2[C@H:37]([OH:38])[C@@H:36]([OH:39])[C@H:35]([OH:40])[O:34][C@@H:33]2[CH2:41][OH:42])[C@H:28]([OH:43])[C@@H:27]([OH:44])[C@@H:26]1[OH:45]
Reactant: O=C[C@H](O)[C@@H](O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O)[C@H](O)[C@H](O)CO
Agent: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O

Procedure:
In addition to glycerol (2.0 mol) and erythritol (0.14 mol) given in Table 3 above, 2-O-β-D-glucosyl-D-erythritol (0.74 mol) and 2,4-bis-hydroxymethyl-5-O-β-D-glucosyl-1,3-dioxane (0.35 mol) were obtained as the controlled Smith-degradation products of mannoglucan. Furthermore, acetolysis of mannoglucan gave 3-O-α-D-mannosyl-D-glucose and cellobiose, and partial acid hydrolysis of mannoglucan (0.33N sulfuric acid, 100° C., 7 hrs.) yielded 6-O-α-D-mannosyl-D-glucose and cellobiose.
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH:18]([CH3:20])[CH3:19])=[C:12]([O:21][CH3:22])[CH:11]=1)(=O)OCC)C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]=[CH:28][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)[CH:11]=[C:12]([O:21][CH3:22])[C:13]=1[CH:18]([CH3:19])[CH3:20]
Reactant: CCOP(=O)(Cc1cc(OC)c(C(C)C)c(OC)c1)OCC
Reactant: O=Cc1ccc(F)cc1
Product: COc1cc(C=Cc2ccc(F)cc2)cc(OC)c1C(C)C

Procedure:
This material was prepared from diethyl(3,5-dimethoxy-4-i-propylbenzyl)phosphonate and 4-fluorobenzaldehyde in the same procedure as described in example 21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:23]([OH:25])=O)=[C:8]([C:19]([O:21][CH3:22])=[O:20])[N:9]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:5][CH:4]=1.C(Cl)(C(Cl)=O)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][NH2:37].CCN(CC)CC>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][NH:37][C:23]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:8]=1[C:19]([O:21][CH3:22])=[O:20])=[O:25]
Reactant: NCc1ccc(F)c(F)c1
Reactant: COC(=O)c1c(C(=O)O)c2ccc(OC)cc2n1Cc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC)cc2n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-methoxy-2-(methoxycarbonyl)-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 92, 1.59 g, 4.7 mmol) in anhydrous CH2Cl2 (50 ml) was added DMF (3 drops, catalytic amount) and (COCl)2 (2M in CH2Cl2, 5.9 ml, 11.8 mmol). The resulting mixture was stirred at room temperature for 1 h, and was concentrated in vacuo. To a solution of the crude product in CH2Cl2 (50 ml) was added 3,4-difluorobenzylamine (0.84 ml, 7.05 mmol), followed by Et3N (2.0 ml, 14.1 mmol). The reaction was stirred at room temperature for 1 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:26]([O-:28])=[O:27])=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13](O)[CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:26]([O-:28])=[O:27])=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2C(O)c3ccc(OC)c([N+](=O)[O-])c3C3CCCCC32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(C2=Cc3ccc(OC)c([N+](=O)[O-])c3C3CCCCC23)cc1
Reaction time: 1 h
Yield: 65 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-5-nitro-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-ol (378.6 mg, 0.987 mmol), p-toluene sulfonic acid (38.0 mg, 0.197 mmol), toluene (8 mL), stir, and reflux under nitrogen atmosphere. After 1 hour, cool reaction to ambient temperature, add ethyl acetate, wash sat sodium bicarbonate solution (aq), and then with brine, dry over sodium sulfate, and concentrate in vacuum. Flash chromatograph using 0% to 30% ethyl acetate/hexanes to yield the titled compound (234.5 mg, 68%) as a clear oil. TLC Rf=0.40 in 2:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.25 (d, 2H, J=8.4 Hz), 6.91 (d, 2H, J=8.4 Hz), 6.67 (d, 1H, J=8.4 Hz), 6.58 (d, 1H, J=8.4 Hz), 6.37 (d, 1H, J=2.6 Hz), 3.88 (m, 614), 3.18 (s, 1H), 2.90 (m, 1H), 2.19 (d, 1H, J=14.1 Hz), 1.60 (m, 4H), 1.33 (m, 2H), 0.99 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:52])[CH2:7][CH:6]([N:8]([CH:40]2[CH2:45][C:44]([CH3:47])([CH3:46])[NH:43][C:42]([CH3:49])([CH3:48])[CH2:41]2)[C:9]([CH2:11][CH2:12][N:13]([CH2:15][CH2:16][C:17]([N:19]([CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[NH:33][C:32]([CH3:39])([CH3:38])[CH2:31]2)[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)=[O:18])[OH:14])=[O:10])[CH2:5][C:4]([CH3:51])([CH3:50])[NH:3]1.CC1(C)CC(N(C2CC(C)(C)NC(C)(C)C2)C(=O)C=C)CC(C)(C)N1.NO>>[CH3:26][C:24]1([CH3:27])[CH2:25][CH:20]([N:19]([CH:30]2[CH2:31][C:32]([CH3:39])([CH3:38])[NH:33][C:34]([CH3:37])([CH3:36])[CH2:35]2)[C:17]([CH2:16][CH:15]=[N+:13]([CH2:12][CH2:11][C:9]([N:8]([CH:40]2[CH2:41][C:42]([CH3:48])([CH3:49])[NH:43][C:44]([CH3:47])([CH3:46])[CH2:45]2)[CH:6]2[CH2:7][C:2]([CH3:1])([CH3:52])[NH:3][C:4]([CH3:50])([CH3:51])[CH2:5]2)=[O:10])[O-:14])=[O:18])[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23]1
Reactant: CC1(C)CC(N(C(=O)CCN(O)CCC(=O)N(C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Agent: C=CC(=O)N(C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Agent: NO
Product: CC1(C)CC(N(C(=O)CC=[N+]([O-])CCC(=O)N(C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1

Procedure:
Following the general procedure of Example 6, the title compound is prepared from N,N-bis[2-(N,N-bis(2,2,6,6-tetramethylpiperidin-4-yl)aminocarbonyl)ethyl]hydroxylamine. This intermediate is prepared from N,N-bis(2,2,6,6-tetramethylpiperidin-4-yl)acrylamide and hydroxylamine.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[C:13](O)([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>FC(F)(F)C(O)=O>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:11]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O
Reactant: CCC(C)(C)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Yield: 39 %

Procedure:
4-t-amylphenol (80 g, 0.49 mole) was dissolved in 200 ml anhydrous trifluoroacetic acid (TFA). T-butyl alcohol (39 g, 0.53 mole) was added with stirring. The mixture was stoppered and stirred for 19 hours at ambient (~22° C.) temperature. The solution was then poured into 400 ml of 1M NaOH, and the resulting upper organic layer was isolated in a separatory funnel. The crude product was dried over anhydrous magnesium sulfate. The product, 4-t-amyl-2-t-butylphenol, was purified by eluting 35 g of the mixture the mixture with 60:40 hexanes:dichloromethane (v/v) in a 5×20 cm silica column and eluted with 300 to 700 ml of solvent and collected in aliquots of 50 ml. Aliquots showing a single spot by Thin Layer Chromatography (TLC) (on silica eluted with 60:40 hexanes:dichloromethane (v/v)) were combined and rotoevaporated to a thick syrup. The yield was 39%.
Reaction SMILES: C([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[N:13][C:14]([CH3:20])=[N:15][C:16]=32)[CH2:9]1)C1C=CC=CC=1.C(N)(=N)C1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[N:25]1[CH:26]=[CH:27][C:20]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]4[CH2:19][CH:17]([CH2:18][NH:8][CH2:9]4)[C:16]=3[N:15]=2)=[CH:23][CH:24]=1
Reactant: N=C(N)c1ccncc1
Reactant: Cc1ncc2c(n1)C1CC2CN(Cc2ccccc2)C1
Product: c1cc(-c2ncc3c(n2)C2CNCC3C2)ccn1

Procedure:
Following the method described in Example 13, 10-benzyl-4-methyl-3,5,10-triaza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene and isonicotinamidine were converted to the title compound in 7.5% overall yield. APCl MS m/z 239.1 (M+H)+.