Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:15])[CH2:4][P:5]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:7])[OH:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>O.C1COCC1.C(OCC)(=O)C.Cl>[CH2:26]([O:25][C:23]([NH:1][CH2:2][C@@H:3]([OH:15])[CH2:4][P:5]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:6])[OH:7])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC[C@@H](O)CP(=O)(O)CC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC[C@@H](O)CP(=O)(O)CC1CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a mixture of ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid (7.05 g, 30 mmol) and potassium carbonate (12.42 g, 90 mmol) in water (90 mL) and THF (30 mL) was added benzyl chloroformate (7.65 g, 45 mmol). After stirring for 3 h at room temperature, the reaction mixture was diluted with ethyl acetate (150 mL) and 2N HCl (90 mL). After stirring vigorously for 10 min the aqueous layer was removed and the organic layer was diluted with heptane (200 mL). The resulting white precipitate was collected to yield ((R)-3-benzyloxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid (10.5 g, 28 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.32 (m, 5H), 5.45 (br s, 1H), 5.10 (s, 2H), 4.2 (m, 1H), 3.4 (dd, 1H), 3.20 (dd, 1H), 2.01-1.55 (m, 10H), 1.40-0.95 (m, 5H). 31P NMR (CDCl3, 300 MHz): δ 57.3. LC/MS m/z: [M+H]+=370.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[C:8]([CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][N:11]1C(=O)C1C=CC=CC=1)#N.[CH2:28]([C:32]1[CH:39]=[CH:38][C:35](CCl)=[CH:34][CH:33]=1)[CH2:29][CH2:30][CH3:31]>O>[CH2:28]([C:32]1[CH:39]=[CH:38][C:35]([CH2:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[CH:34][CH:33]=1)[CH2:29][CH2:30][CH3:31]
Reactant: N#CC1c2ccccc2C=CN1C(=O)c1ccccc1
Reactant: CCCCc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1ccc(Cc2nccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
To a dimethylformamide (1.8 ml) solution of 60% sodium hydride (16 mg, 0.40 mmol), a dimethylformamide (3.6 ml) solution of 1-cyano-2-benzoyl-1,2-dihydroisoquinoline (100 mg, 0.38 mmol) synthesized according to the literature of Org. Synth., VI, 115 (1988), and 4-n-butylbenzylchloride (70 mg, 0.38 mmol) was added dropwise under nitrogen atmosphere at −16° C., and was further stirred at room temperature for 30 minutes. Water was added, this was concentrated, and toluene and water were added to this residue. The toluene layer was washed with water, dried over potassium carbonate, and concentrated. To an ethanol (1.6 ml) solution of the residue, 50% aqueous sodium hydroxide solution (0.63 ml) was added, and this was refluxed for 2 hours. After concentration, toluene and water were added. The toluene layer was washed with water, then dried over calcium carbonate, and then concentrated. The residue was purified by silica gel column chromatography to give 18 mg of the aforementioned compound of the formula (Ia).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]([O:26]C(=O)C)[CH2:15][S:16][C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[NH:19][CH:20]=[N:21]3)[CH2:9][CH2:8]1.C(=O)(O)[O-].[Na+].CO>C(Cl)Cl>[OH2:26].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH:14]([OH:26])[CH2:15][S:16][C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[NH:19][CH:20]=[N:21]3)[CH2:11][CH2:12]1
Reactant: CC(=O)OC(CSc1ncnc2nc[nH]c12)CN1CCN(c2ccccn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O
Product: OC(CSc1ncnc2nc[nH]c12)CN1CCN(c2ccccn2)CC1
Yield: 184.2 %

Procedure:
To 6-[1-[1-[2-pyridyl)piperazin-4-yl]-2-acetoxy-3-propanylthio]purine (0.30 g, 0.725 mmol) from Example 8in methanol (5 mL), was added anhydrous sodium bicarbonate (0.10 g, 0.725 mmol) at room temperature. After one week the methanol was removed in vacuo to give the crude product as a white solid. Silica gel flash chromatography using 10% methanol:methylene chloride gave the pure product as a white solid (0.260 g, 96.6%). mp 159°-161° C. DCI/MS (M+1) 372. 300 MHz1H NMR (DMSO-d6 and D2O) δ: 8.6 (s, 1H), 8.4 (s, 1H), 8.1 (m, 1H), 7.5 (m, 1H) 6.8 (d, 1H, J=8.59 Hz), 6.6 (m, 1H), 4.0 (m, 1H), 3.3 and 3.7 (q of q, 2H), 2.5 (m, 10H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[CH:12]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:5]=1[F:31])(=[O:3])[NH2:2].C(Cl)CCl.[CH3:36][C:37]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:38]=1[C:39](O)=[O:40]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:36][C:37]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:38]=1[C:39]([O:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([CH:12]([CH2:13][NH:14][C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[NH2:2])=[C:5]([F:31])[CH:6]=2)=[O:30])=[CH:27][CH:26]=1)=[O:40]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc(C(N)=O)c(F)c1)c1ccc(CO)cc1
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OCc2ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc3ccc(C(N)=O)c(F)c3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-(4-carbamoyl-3-fluorophenylamino)-2-(4-(hydroxymethyl)phenyl)-3-oxopropylcarbamate (E337-1) in pyridine was added was added EDC, DMAP, and 2,4-dimethylbenzoic acid, and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-5% MeOH/CH2Cl2 gradient) gave pure 4-(3-(tert-butoxycarbonylamino)-1-(4-carbamoyl-3-fluorophenylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E337-2).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([C@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C.CN(C=O)C>[CH2:29]([N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([C@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH:3]=[N:2]1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCCc1ccccc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(-c2cn[nH]c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(-c2cnn(CCc3ccccc3)c2)c1
Temperature: 50 °C
Yield: 77.3 %

Procedure:
To a vial was added Intermediate 11B (110 mg, 0.383 mmol) in acetonitrile (0.7 mL) and DMF (0.7 mL) and potassium carbonate (159.0 mg, 1.148 mmol). The reaction was stirred for 10 min before (2-bromoethyl)benzene (106 mg, 0.574 mmol) was added. The resulting mixture was heated at 50° C. for 16 h. The reaction was quenched with water and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated. The crude was purified by flash chromatography to give Intermediate 11C (116 mg, 0.296 mmol, 77.0% yield) as a white solid. LCMS=2.20 min [M+1]=392.3 (Method B).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5])#[N:2].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Br:26])=[C:22]([O:24][CH3:25])[CH:23]=1.[CH2:27](OC(OCC)OCC)C>C(O)(C)C>[Br:26][C:21]1[CH:20]=[CH:19][C:18]([NH:17][CH:27]=[C:3]([C:1]#[N:2])[C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=2[Cl:16])=[O:5])=[CH:23][C:22]=1[O:24][CH3:25]
Reactant: COc1cc(N)ccc1Br
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(NC(=O)CC#N)c(Cl)cc1Cl
Solvent: CC(C)O
Product: COc1cc(NC(=O)C(C#N)=CNc2ccc(Br)c(OC)c2)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 73.2 %

Procedure:
To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide (6.1 g, 23.5 mmol) in 500 mL of isopropanol was added 5-amino-2-bromoanisole (5.0 g, 24.8 mmol). This mixture was heated to reflux to give a clear yellow solution. To this solution, triethylorthoformate (10.6 mL, 63.5 mmol) was added dropwise and the reaction mixture was heated at reflux for 5 hours. An additional 10.6 mL of triethylorthoformate was added and the mixture was heated at reflux overnight. The mixture was allowed to cool to room temperature. The solid was collected by filtration, washed with isopropanol and ethyl acetate, and then dried overnight at ˜40° C. under reduced pressure to give 8.1 g (73%) of 4-bromo-3-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide as a yellow solid, mp >250° C.; MS (ES) m/z470.0, 472.0 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)#[N:13].O=[C:23]([CH3:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].Cl>C1COCC1>[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([CH3:30])[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[C:9](=[O:10])[NH:11]2)=[CH:16][CH:15]=1)#[N:13]
Reactant: Cc1cccc(NC(N)=O)c1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)N(c2cccc(C)c2)C(=O)NC1c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
150 mg (1.0 mmol) N-[3-methylphenyl]urea, 101 mg (0.77 mmol) 4-cyanobenzaldehyde and 100 mg (0.77 mmol) ethyl 3-oxobutanoate are suspended in 2 ml of THF, and catalytic amounts of concentrated hydrochloric acid are added. The mixture is stirred at reflux for 18 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate as eluent.
Reaction SMILES: [C:1]([Li])(C)(C)C.CCCCC.Br[C:12]1[C:13]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:14][N:15]([CH3:26])[C:16]=1[C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21].CI>C1COCC1>[C:20]([SiH2:19][O:18][C:17]([CH3:25])([CH3:24])[C:16]1[N:15]([CH3:26])[N:14]=[C:13]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[C:12]=1[CH3:1])([CH3:23])([CH3:22])[CH3:21]
Reactant: [Li]C(C)(C)C
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)c(Br)c1C(C)(C)O[SiH2]C(C)(C)C
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCC
Product: Cc1c(-c2ccc(C(F)(F)F)cc2)nn(C)c1C(C)(C)O[SiH2]C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1.5 M solution of tert-butyllithium in pentane (0.5 ml, 748 μmol) was added dropwise to a solution of 4-bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole (280 mg, 623 μmol; example 8 b]) in THF (2 ml) at −78° C. under an argon atmosphere. After 15 min methyl iodide (177 mg, 1.2 mmol) was added at −78° C. The reaction mixture was stirred for another 30 min at −78° C. and then for 2 h at RT. After quenching with saturated aqueous NaHCO3 solution the reaction mixture was partitioned between tert-butyl methyl ether and water. The ether phase was dried over sodium sulfate and concentrated in vacuo to give 240 mg (620 μmol, quant.) 5-(tert-butyl-dimethyl-silanyloxymethyl)-1,4-dimethyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole as yellow oil which was used in the next step without further purification.
Reaction SMILES: NC1N=CC(N2CCN(C(OC(C)(C)C)=O)CC2)=CC=1.[CH3:21][C@@H:22]1[N:27]([C:28]2[CH:29]=[N:30][C:31]([N+:34]([O-])=O)=[CH:32][CH:33]=2)[CH2:26][CH2:25][N:24]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]1>>[NH2:34][C:31]1[N:30]=[CH:29][C:28]([N:27]2[CH2:26][CH2:25][N:24]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23][C@@H:22]2[CH3:21])=[CH:33][CH:32]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Agent: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(N)nc1
Yield: 93.1 %

Procedure:
Following the procedure described for compound 101h and starting with (3S)-tert-butyl 3-methyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 191e (5.8 g, 18 mmol) afforded 191f as a brown solid (4.9 g, 93%). MS-ESI: [M+H]+ 293
Reaction SMILES: [CH3:1][Si:2]([CH3:5])(Cl)[Cl:3].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:10][SiH:11]([CH3:13])[CH3:12].C[Mg][Cl:16].C[SiH](Cl)Cl.C1(OC)C=CC=CC=1>>[CH3:1][SiH:2]([CH3:5])[Cl:3].[CH3:10][Si:11]([CH3:13])([CH3:12])[Cl:16]
Reactant: C[Mg]Cl
Reactant: C[SiH](C)C
Reactant: C[Si](C)(Cl)Cl
Agent: C[SiH](Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: C[SiH](C)Cl
Product: C[Si](C)(C)Cl
Reaction time: 1 h

Procedure:
A four-necked flask equipped with a condenser, thermometer, gas feed tube, and stirrer was charged with 129.1 g (1.0 mol) of dimethyldichlorosilane and 1.3 g (0.01 mol) of AlCl3, which were agitated with the stirrer. To the flask at room temperature, trimethylsilane which had been synthesized in a separate flask from methylmagnesium chloride and 57.5 g (0.5 mol) of methyldichlorosilane was fed. Agitation was continued for one hour. 2.2 g (0.02 mol) of anisole was added to the reaction solution which was agitated for a further one hour. Dimethylchlorosilane and trimethylchlorosilane were isolated from the reaction solution by distillation. There were obtained 42.0 g of dimethylchlorosilane and 48.9 g of trimethylchlorosilane in a yield of 89% and 90%, respectively.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([CH3:9])[CH:8]=1.O1CCCC1.C([Li])CCC.CCCCCC.C(O[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1)(C)C>>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[N:6][N:7]([CH3:9])[C:8]=1[B:30]1[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]1
Reactant: COCc1cnn(C)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(methoxymethyl)-1-methyl-1H-pyrazole (261.0 mg, 2.069 mmol) in tetrahydrofuran (5 mL, 60 mmol) at 0° C. was added 1.6 M n-butyllithium in hexane (3.88 mL, 6.21 mmol). The solution was stirred at room temperature for 1 h and cooled to −78° C. To the solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.46 mL, 2.3 mmol). The reaction was stirred at −78° C. for 0.5 h and then warmed up to 0° C. (taking 0.5 h). The reaction mixture was quenched with brine, adjusted to pH=6-7 with 1 N HCl aqueous solution, and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to give brown oil, which was purified by combi-flash chromatography. LC/MS found: 253.1 (M+1)+.
Reaction SMILES: B.CSC.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[CH3:26][C:27]1([CH3:48])[O:32][C:31]2[CH:33]=[CH:34][C:35]([C:37](=[O:47])[CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:36][C:30]=2[CH2:29][O:28]1.Cl>C1COCC1.C1(C)C=CC=CC=1>[CH3:26][C:27]1([CH3:48])[O:32][C:31]2[CH:33]=[CH:34][C:35]([C@@H:37]([OH:47])[CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[CH:36][C:30]=2[CH2:29][O:28]1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc2c(c1)COC(C)(C)O2
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: CSC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H](O)c1ccc2c(c1)COC(C)(C)O2
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A 2M solution of borane-dimethyl sulphide in THF (28 ml) was added slowly to a 1M solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole in toluene (56 ml) at 0° under nitrogen. A solution of tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate, (108.2 g) in THF (1.3 liters) was added slowly keeping the temperature below 5° followed by 2M solution of borane-dimethyl sulphide in THF (252 ml) over 50 min. After 1 h, 2M HCl (170 ml) was added with cooling and the mixture was partitioned between EtOAc and water. The organic layer was washed with saturated NaHCO3 solution and brine and dried (MgSO4). The solution was concentrated and the product purified by chromatography on flash silica gel (800 g), eluting successively with hexane:EtOAc (4:1 then 3:1) to give the title compound (93.3 g), LCMS RT=3.31 min.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[N:12]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:21]([CH2:24][C:25](=[O:27])[CH3:26])(=[O:23])[CH3:22]>C(O)(=O)C.Cl.O.C(O)C>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([NH:7][N:12]=[C:24]([C:25](=[O:27])[CH3:26])[C:21](=[O:23])[CH3:22])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(OC(F)F)c1
Reactant: CC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(=O)C(=NNc1cccc(OC(F)F)c1)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of 3-(difluoromethoxy)aniline (1000 mg, 6.25 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (518 mg, 7.50 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (1538 mg, 18.75 mmol) and acetylacetone (812 mg, 8.12 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-{[3-(difluoromethoxy)phenyl]hydrazono}pentane-2,4-dione (1500 mg, 89%).
Reaction SMILES: C[CH:2]([OH:6])[CH:3](O)[CH3:4].[C:7]([O-:12])(=[O:11])[CH:8](C)O.C([OH:15])C>>[C:7]([O-:12])(=[O:11])[CH3:8].[C:2]([O-:6])(=[O:15])[CH2:3][CH2:4][C:7]([O-:12])=[O:11]
Reactant: CCO
Reactant: CC(O)C(=O)[O-]
Reactant: CC(O)C(C)O
Product: CC(=O)[O-]
Product: O=C([O-])CCC(=O)[O-]
Reaction time: 15 h

Procedure:
The initial concentrations of substrates in the medium containing 0.5% sweetgum hemicellulose hydrolysate were determined by HPLC to be 20 mM xylose, 1.4 mM MeGAX and a small amount of MeGAX2. Previous studies indicated that MeGAX was metabolized by E. asburiae JDR-1 into methanol, glucuronate and xylose (Bi et al. 2009). In these previous studies glucuronate fermentation by E. asburiae JDR-1 generated acetate in nearly 100% yield, indicating fermentation products more reduced than acetate could only be produced from the free xylose and the xylose released from MeGAX in the hydrolysate. The theoretical maximum yield of lactate from this hydrolysate medium was 35.7 mM based on the total xylose initially present. In the fermentation of methylglucuronoxylan hydrolysate, E. asburiae JDR-1 utilized all of the MeGAX within 30 h and xylose within 40 h. Similar amounts of ethanol (15.6 mM) and acetate (20 mM) were produced but no 2,3-butanediol or lactate was detected (Table 6, FIG. 5A). When supplemented with LB, E. asburiae JDR-1 fermented the 0.5% hydrolysate more rapidly than with ZH minimal salts. Substrates were utilized within 15 h, producing 16.2 mM ethanol, 22 mM acetate, and 3.2 mM succinate, again with no 2,3-butanediol or lactate detected. (Table 6, FIG. 5C).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:36]([NH:38][C@H:39]([C:45]([OH:47])=[O:46])[CH2:40][CH2:41][C:42](=[O:44])[NH2:43])=[O:37])[CH3:35])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[C@H:11]([CH2:13][CH3:14])[CH3:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(O)(=O)C>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:36]([NH:38][C@H:39]([C:45]([OH:47])=[O:46])[CH2:40][CH2:41][C:42](=[O:44])[NH2:43])=[O:37])[CH3:35])=[O:32])[CH2:27][CH:28]([CH3:29])[CH3:30])=[O:24])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:16])[C@H:11]([CH2:13][CH3:14])[CH3:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](N)CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
0.50 Gram of Z-Leu-Ile-Leu-Leu-Ala-Gln-OH was dissolved in 50 ml of methanol and 10 ml of 10%-acetic acid, and the mixture was catalytically reduced by using palladium as a catalyst to obtain H-Leu-Ile-Leu-Leu-Ala-Gln-OH. Hereinafter, this product is referred to as [Peptide A].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([OH:29])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([OH:28])=[CH:23][CH:24]=3)[CH2:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([N:33]([CH2:37]C)[CH:34](C)C)(C)[CH3:31].FC(F)(F)C(OC(=O)C(F)(F)F)=[O:42].O>ClCCl.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]([OH:29])[CH2:16][NH:17][C@H:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:31][C:30]([N:33]([CH3:37])[CH3:34])=[O:42])=[CH:23][CH:24]=3)[CH2:19]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2c(c1)C[C@@H](NC[C@@H](O)c1ccc(OCc3ccccc3)cc1)CC2
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC[C@@H](O)c1ccc(OCc3ccccc3)cc1)CC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred suspension of (1S)-1-(4-benzyloxyphenyl)-2-[((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)amino]-ethanol (1.30 g) and N,N-diisopropylethylamine (2.91 ml) in dichloromethane (16.7 ml) was added trifluoroacetic anhydride (1.41 ml) at -15° C. After reaction for 20 minutes, water was poured into the reaction mixture and the resulting mixture was extracted with dichloromethane. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The resulting residue was dissolved in N,N-dimethylformamide (8.6 ml), and 2-bromo-N,N-dimethylacetamide (571 mg), cesium carbonate (2.52 g) and molecular sieves 4A powder (860 mg) were added to the solution. After reaction at room temperature for 2.5 hours, water and methanol were added to the reaction mixture under ice-cooling and the resulting mixture was stirred at room temperature for 12 hours. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Recrystallization of the residue from diethyl ether gave 2-[(2S)-2-[[(2S)-2-(4-benzyloxyphenyl)-2-hydroxyethyl]amino]-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide (437 mg) having a melting point of 103-106° C.