Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[NH:13])SC)=[CH:5][CH:4]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[NH:13])=[CH:5][CH:4]=1
Reactant: CSC(=N)Nc1ccc(Cl)cc1
Reactant: NCCCN1CCCC1
Agent: I
Solvent: CCO
Product: N=C(NCCCN1CCCC1)Nc1ccc(Cl)cc1
Yield: 69.4 %

Procedure:
A solution of the product of step b (986 mg, 3.00 mmol) and N-(3-aminopropyl)-pyrrolidine (0.948 ml, 7.50 mmol) in ethanol (10 ml) was heated at reflux for 16 h. The solvent was removed at reduced pressure and the residue suspended in aqueous ammonia (880, 25 ml). The solid was removed by filtration and the filter-cake washed sequentially with water (50 ml) and diethyl ether (50 ml) to give the title compound as a white solid (585 mg, 69%). 1H NMR (DMSO-6) 7.18-7.12 (2H, m), 6.76-6.66 (2H, m), 5.8-4.8 (3H, br s), 3.12 (2H, t, 6.9), 2.43-2.36 (6H, m), 1.69-1.56 (6H, m). Microanalysis found C 60.01 H 7.62 N 19.74. C14H21ClN4 requires C 59.88 H 7.54 N 19.95.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([CH3:11])=[CH:6][C:7]=1[N+]([O-])=O.[BrH:15]>>[Br:15][C:7]1[CH:6]=[C:5]([CH3:11])[N:4]=[C:3]([C:12]([OH:14])=[O:13])[C:2]=1[CH3:1]
Reactant: Br
Reactant: Cc1cc([N+](=O)[O-])c(C)c(C(=O)O)n1
Product: Cc1cc(Br)c(C)c(C(=O)O)n1

Procedure:
The title compound, was prepared by treatment of 3,6-Dimethyl-4-nitro-pyridine-2-carboxylic acid with 49% hydrobrornic acid at 101° C. in accordance with the general method of example 1, step 3 to yield the title compound as an amorphous yellow solid, which is directly used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40.5 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (8.9 g, 59.7 mmol) and triethylamine (11 mL, 78.9 mmol) in 90 mL of DCM at 0° C., was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.89 g, 24.4 mmol). The mixture was stirred at room temperature for 3 days, concentrated under vacuum and purified by flash chromatography (eluent: 0 to 50% EtOAc in hexane with 0.1% triethylamine) to afford 3.09 g (40%) of 17a.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH2:15][CH2:16][OH:17].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:17][CH2:16][CH2:15][CH2:14][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: NCCCO
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(NCCCO)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzonitrile (1.0 g; 6.02 mmol), 0.502 ml (6.62 mmol) of 3-amino-propan-1-ol and 1.15 ml (6.62 mmol) of diisopropylethylamine in 5 ml THF is stirred at rt for 1 hr (temperature raises somewhat at the beginning). After concentration in vacuo the residue is dissolved in 50 ml of ethyl acetate, washed with 50 ml of 4% aqueous sodium hydrogen carbonate and brine, dried and concentrated. 1.32 g of pure title compound as a solid are thus obtained (99% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].ClC1C([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)=CC=CC=1N>>[Cl:9][C:7]1[CH:6]=[C:4]([CH:3]=[C:2]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)[CH:8]=1)[NH2:5]
Reactant: CC1(C)OB(c2cccc(N)c2Cl)OC1(C)C
Reactant: Nc1cc(Cl)cc(Br)c1
Product: CC1(C)OB(c2cc(N)cc(Cl)c2)OC1(C)C
Yield: 48 %

Procedure:
This material was prepared from 3-bromo-5-chloroaniline following a similar procedure used for SM-9, step 3. The crude product was purified by flash chromatography (RediSep Cyano®, Teledyne ISCO, 0-50% EtOAc in hexanes) to afford 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (48%) as a pale orange solid: LCMS(m/z) 172.1 (MH+), tR=0.33 minute.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:23])[S:4]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[C:10](Cl)=[O:11])(=[O:6])=[O:5].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>O1CCCC1>[CH2:24]([N:26]([CH2:27][CH3:28])[C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:15]([N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[C:7]([S:4](=[O:6])(=[O:5])[N:3]([CH3:23])[CH3:2])[CH:8]=1)[CH3:25]
Reactant: CCNCC
Reactant: CN1CCN(c2ccc(C(=O)Cl)cc2S(=O)(=O)N(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(N2CCN(C)CC2)c(S(=O)(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
40 Grams of 3-dimethylsulfamoyl-4-(4-methylpiperazine-1-yl)-benzoylchloride-hydrochloride (0.1 mole) were introduced portionwise, while stirring at room temperature, into a solution of 20 g of diethylamine in 0.4 l of tetrahydrofurane. After the addition had been completed, the mixture was stirred for another 30 minutes at room temperature, and subsequently the tetrahydrofurane was completely eliminated in vacuo. The evaporation residue crystallized when triturated with 0.2 l of water, and, after having been suction-filtered and dried, it was recrystallized from butylacetate.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][CH3:10])=[N:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[CH2:23]([N:25](CC)CC)[CH3:24].C(Cl)(=O)C>C1C=CC=CC=1>[CH2:9]([N:8]1[C:7]2=[N:6][C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=[C:2]2[N:25]=[C:23]1[CH3:24])[CH3:10]
Reactant: CCNc1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Reactant: CCN(CC)CC
Solvent: CC(=O)Cl
Solvent: c1ccccc1
Product: CCn1c(C)nc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 15 °C

Procedure:
2-Chloro-3-ethylamino-5,6-diphenylpyrazine, (3.10 g, 0.01 moles) is dissolved in benzene (50 ml) and then triethylamine (1.29 g, 0.013 moles) and acetyl chloride (1.00 g, 0.013 moles) are added. The solution is refluxed 41/2 hours, cooled to 15°C and filtered. The filtrate is diluted with ethanol (3ml), warmed briefly at 50°C and then all volatile materials evaporated. The resultant brown oil is treated with liquid ammonia (17 g) in ethanol (60 ml) in a bomb at 165°C for 12 hours. The solution is diluted with water (200 ml), cooled and the yellow precipitate filtered off. The solid is triturated with boiling 50% aqueous methanol, filtered, and the filtrate chilled. The product is collected by filtration. Yield 0.45 g (14%). It is recrystallized from benzene-heptane, m.p. 178.5°-180°C.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].[CH2:9]1[O:11][CH2:10]1.[OH-].[K+]>O>[CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:4])[O:5][CH2:9][CH2:10][OH:11])[CH3:2]
Reactant: CCP(=O)(O)CCO
Reactant: C1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCP(=O)(CCO)OCCO
Yield: 95 %

Procedure:
A 500 ml five-neck flask equipped with gas inlet tube, thermometer, high-performance stirrer and reflux condenser with gas incineration is charged with 138 g (1 mol) of ethyl(2-hydroxyethyl)phosphinic acid (produced as in Example 8) and ethylene oxide is passed in. A reaction temperature of 70° C. is set, followed by further reaction for 1 h. The ethylene oxide takeup is 64.8 g. The acid number of the product is less than 1 mg KOH/g. 173 g (95% of theory) of 2-hydroxyethyl ethyl(2-hydroxyethyl)phosphinate as colorless, water-clear liquid were obtained.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.O.Cl>C(O)(C)C>[CH2:1]1[CH2:2][CH2:3][CH:4]([C@@H:7]([NH2:11])[C:8]([OH:10])=[O:9])[CH2:5][CH2:6]1
Reactant: N[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: N[C@@H](C(=O)O)C1CCCCC1
Temperature: 55 °C
Reaction time: 7 h

Procedure:
100 g (661.5 mmol) D-phenylglycine are dissolved or suspended in 890 ml deionised water, 290 ml isopropanol and 66.7 ml (802 mmol) 37% hydrochloric acid. After addition of 10 g of the Pt/Rh catalyst, 4% Pt+1% Rh on activated carbon (water content approx. 50%, corresponding to approx. 5 wt. % catalyst relative to D-phenylglycine used), the reaction mixture is introduced into a 2 l hydrogenation autoclave. After being rendered inert with nitrogen three times, it is rinsed with hydrogen twice, then a hydrogen overpressure of 8-10 bar is established and the reaction solution heated to 50-60° C. After approximately 6 to 8 hours, hydrogen uptake is completed (theoretical amount of H2 44.4 l). The hydrogenator is depressurised and once again rendered inert with nitrogen three times. The still hot reaction solution is extracted with a nutsch filter and the catalyst is washed with 200 ml deionised water. The filtrate is first adjusted at 40-60° C. to a pH of 2-2.5 with 50% sodium hydroxide solution, during which process the first crystals form. It is then stirred for a further 15-30 minutes at this pH and then adjusted to a pH of 5-6 with 50% sodium hydroxide solution. The reaction mixture is cooled in an ice bath to a temperature of 0-10° C., the product is extracted with a nutsch filter, washed with 300 ml deionised water and dried in a drying oven in vacuo at 50-70° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH:14]([F:16])[F:15])[C:10]#[N:11].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[OH:25].C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:12][O:13][CH:14]([F:16])[F:15])[C:10]#[N:11]
Reactant: N#CC(=NOC(F)F)c1ccccc1CBr
Reactant: Cc1ccc(C)c(O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NOC(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 7.0 g of 2-(2-bromomethylphenyl)-2-difluoromethoxyimino-acetonitrile, 5.4 g of 2,5-dimethylphenol, 16.1 g of pulverized potash and 0.38 g of 18-crown-6 in 35 ml of acetonitrile is stirred at room temperature for 24 hours. For working up, water is added and exhaustive extraction with ethyl acetate is carried out. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography on silica gel with hexane/ethyl acetate (9:1) yields 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-difluoromethoxyiminoacetonitrile in the form of a sticky crystalline mass which, when treated with hexane, yields a fine crystal powder of m.p. 104°-108° C.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.CN(C)P(=O)(N(C)C)N(C)C.C([C:29]([O:31][CH2:32][CH3:33])=[O:30])#N>O1CCCC1>[O:15]=[C:12]1[CH2:13][CH2:14][O:9][CH2:10][CH:11]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: O=C1CCOCC1
Reactant: CCOC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C1COCCC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide (1.14 mol/l solution in n-hexane/tetrahydrofuran, 2.5 ml) was added dropwise to a solution of tetrahydro-4H-pyran-4-one (260 mg) in tetrahydrofuran (13 ml) at −78° C., and the mixture was stirred for one hour while warming to 0° C. The reaction solution was cooled to −78° C. again, hexamethylphosphoric triamide (452 μl) was added and subsequently ethyl cyanoformate (280 μl) was added at the same temperature. The mixture was stirred over one hour while warming to 0° C. The reaction solution was separated by adding distilled water and ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (210 mg).
Reaction SMILES: [N+](=[CH2:3])=[N-].[NH2:4][C@H:5]([C:18]([OH:20])=[O:19])[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>CCOCC.C(O)C>[NH2:4][C@H:5]([C:18]([O:20][CH3:3])=[O:19])[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCC#CC[C@H](N)C(=O)O
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)[C@@H](N)CC#CCNC(=O)OC(C)(C)C

Procedure:
Titrate a solution of diazomethane in ether into a solution of 1-amino-1-(S)-carboxy-5-(t-butoxycarbonyl amino)-3-pentyne (4 g) in ethanol (200 ml) until a yellow color remains. Evaporate the solvent to obtain 1-amino-1-(s)-methoxycarbonyl-5-(t-butoxycarbonylamino)-3pentyne.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH3:17][C@H:18]1[C@@H:23]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:22][CH2:21][NH:20][CH2:19]1>O.CCOCC>[CH2:1]([O:8][C:9]([N:20]1[CH2:21][CH2:22][C@H:23]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C@H:18]([CH3:17])[CH2:19]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H]1CNCC[C@@H]1Nc1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a rapidly stirred mixture of benzylchloroformate (0.39 ml, 2.76 mmol) and sodium bicarbonate (284 mg, 3.6 mmol) in water (4 ml) and ether (4 ml) is added cis-3-methyl-4-(2-fluoro-phenylamino)-piperidine (500 mg, 2.4 mmol) as a solution in ether (2 ml). The mixture is stirred for one hour at ambient temperature, the layers are separated, and the organics washed with 2N NaOH (2×) and brine (1×). The organics are dried over sodium sulfate and concentrated to give cis-1-benzyloxycarbonyl-3-methyl-4-(2-fluorophenylamino)-piperidine as an oil: 740 mg; 90%.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[C:4]([C:6]1[C:11]([N:12]([CH2:27][O:28][CH3:29])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:9]([Cl:30])=[CH:8][N:7]=1)=[O:5].[CH3:35][S:36](Cl)(=[O:38])=[O:37].Cl.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>N1C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([S:13]([N:12]([C:11]2[C:6]([C:4](=[O:5])[C:3]3[CH:31]=[CH:32][CH:33]=[CH:34][C:2]=3[NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[N:7][CH:8]=[C:9]([Cl:30])[CH:10]=2)[CH2:27][O:28][CH3:29])(=[O:15])=[O:14])=[CH:17][C:18]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CS(=O)(=O)Cl
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1N)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: c1ccncc1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1NS(C)(=O)=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred suspension of N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide in pyridine (1 mL) was added methanesulfonyl chloride (26 mg, 0.226 mmol). After 2 h the reaction mixture was poured into 1 M HCl and the aqueous portions were subsequently extracted with EtOAc. The combined extracts were dried and concentrated under reduced pressure. The resulting residue was dissolved in THF (5 mL), treated with TBAF (1 M in THF, 200 μL, 0.200 mmol), and then stirred at room temperature for 3-4 h. The reaction mixture was subsequently poured into 1 M HCl and the aqueous layer was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide 4-chloro-N-[5-chloro-2-(2-methanesulfonylamino-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. MS m/z: 634.0 (M+Na).
Reaction SMILES: O=C[C@@H]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])O)O)O)O.[C:13]([OH:18])(=[O:17])[C@H:14]([CH3:16])[OH:15].C(O)(=O)CC>C(O)(=O)C>[C:11]([OH:12])(=[O:15])[CH2:9][CH2:7][CH3:5].[C:13]([OH:18])(=[O:17])[CH2:14][CH3:16]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: C[C@H](O)C(=O)O
Solvent: CCC(=O)O
Solvent: CC(=O)O
Product: CCCC(=O)O

Procedure:
When glucose is used as the sole substrate, as in the first experiment, the difference between total carbon yield and butyric carbon yield is greater than when a combination of glucose and L-lactic acid is used, because higher amounts of acetic acid and propionic acid are generated during the fermentation. See FIG. 7. In addition, the butyric carbon yield (61%) is much higher than that of free cell fermentation (see Table 1, 36%), because the immobilized cell beads can be used repeatedly for a long period of time, which may cause cell adaptation to endure higher butyrate concentration, thereby resulting in a higher butyric carbon yield. The second experiment using a feedstock containing both glucose and L-lactic acid affords 69% butyric carbon yield (higher than the theoretical yield), while suppressing the generation of acetic acid and propionic acid (the difference between total carbon yield and butyric carbon yield is only 5%). See FIG. 8. Third, when L-lactic acid is used as the sole substrate, butyric acid is produced in an significant amount, although acetic acid and propionic acid are also generated (the difference between total carbon yield and butyric carbon yield is 23%). See FIG. 9. The total carbon yield, 96%, is very close to the theoretical value (100%). In view of the above, the combination of lactic acid and carbohydrate as substrates in fermentation exceeds those results anticipated under conventional fermentation using glucose as the only substrate, and in some instances may be deemed synergistic with the improvement of the butyric carbon yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=O)[CH:16]=2)[O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=2)[O:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)NC1CCOc2ccc(C=O)cc21
Product: CC(C)(C)OC(=O)NC1CCOc2ccc(CN3CCCCC3)cc21

Procedure:
The reductive amination procedure in Example 1, Step H was used to react (6-formyl-chroman-4-yl)-carbamic acid tert-butyl ester (Step E) with piperidine to provide (6-piperidin-1-ylmethyl-chroman-4-yl)-carbamic acid tert-butyl ester. The Boc group was deprotected with TFA in CH2Cl2 to provide the amine salt. The coupling procedure described in the preparation of Example 1, Step F with 3-(naphthalen-2-yl-sulfonylamino)-3-phenylpropionic acid was used to provide the title compound as a mixture of diastereomers (ca. 1:1 by 1H NMR) isolated as the HCl salt. MS (ESI) 584 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH:3]=[CH:4][CH2:5][OH:6].[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[F:1][C:2]([F:8])([F:7])[CH:3]=[CH:4][CH2:5][O:6][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[Br:9]
Reactant: OCC=CC(F)(F)F
Reactant: Oc1ccc(F)cc1Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(OCC=CC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.1 %

Procedure:
A solution of 2.10 gm (16.7 mMol) 1-trifluoromethylprop-1-en-3-ol, 3.19 gm (16.7 mMol) 2-bromo-4-fluorophenol, and 4.81 gm (18.4 mMol) triphenylphosphine in 25 mL dichloromethane was cooled to 0° C. and then 2.9 mL (18.4 mMol) diethyl azodicarboxylate were added. The reaction mixture was stirred for 1 hour at room temperature and then the reaction mixture was directly subjected to flash silica gel chromatography, eluting with 20:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 6 gm of crude 1-(1-trifluoromethylprop-1-en-3-yloxy)-2-bromo-4-fluorobenzene.
Reaction SMILES: Br[C:2]1[C:3]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[C:11]([CH3:15])=[N:12][O:13][CH:14]=1)=[O:8].[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:5]2[CH:4]=[C:3]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[C:11]([CH3:15])=[N:12][O:13][CH:14]=2)=[O:8])=[CH:20][CH:21]=1
Reactant: Cc1nocc1NC(=O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccc(F)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: COCCOC
Product: Cc1nocc1NC(=O)c1cc(-c2cnn(C)c2)c(CN2CCOCC2)cc1OCc1ccc(F)cc1
Temperature: 120 °C

Procedure:
To a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-N-(3-methyl-4-isoxazolyl)-4-(4-morpholinylmethyl)benzamide (may be prepared as described in Example 16; 89 mg, 0.18 mmol) in 1,2-dimethoxyethane (3 ml) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (40.4 mg, 0.19 mmol), sodium carbonate (0.35 ml, 0.35 mmol) and Pd(Ph3P)4 (12.23 mg, 10.59 μmol). The mixture was heated at 120° C. in a microwave for 35 minutes, the solvent removed in vacuo and the residue purified by MDAP to yield the title compound as a white solid. 12 mg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([I:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([I:28])=[CH:27][C:20]=2[NH:19][C:18]1=[O:29])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: NC1CCc2ccc(I)cc2NC1=O
Product: CC(C)(CC(=O)NC1CCc2ccc(I)cc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and the amine obtained in Step E by the procedure described in Example 1, Step F. 1H NMR (200MHz, CDCl3): 1.33 (s,6H), 1.42 (s,9H), 1.80(m,1H), 2.24 (m,2H), 2.50 (m,3H), 4.45 (m,1H), 6.98 (d,8Hz,1H), 7.35 (d,2Hz,1H), 7.43 (dd;2,8Hz;1H). FAB-MS: calculated for C20H28IN3O4 501; found 502 (M+H,20%).
Reaction SMILES: C([O:8][CH2:9][C@H:10]([OH:24])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH:21]1([CH2:20][O:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][C@@H:10]([OH:24])[CH2:9][OH:8])[CH2:23][CH2:22]1
Reactant: [H][H]
Reactant: O[C@@H](COCc1ccccc1)COc1ccccc1OCC1CC1
Agent: [Pd]
Solvent: CCO
Product: OC[C@H](O)COc1ccccc1OCC1CC1

Procedure:
A solution of (S)-1-benzyloxy-3-[o-(cyclopropylmethoxy)phenoxy]-2-hydroxypropane (10.97 g) in 100 ml ethanol, to which is added 3.5 g of 10% palladium on carbon, is hydrogenated at 45 lbs. pressure at room temperature until the uptake of hydrogen ceases (about 10 minutes). The catalyst is filtered off, washed with ethanol and the filtrate concentrated under reduced pressure leaving a crystalline residue that is recrystallized from 35 ml of ethanol; (S)-3-[o-(cyclopropylmethoxy)phenoxy]-1,2-propanediol, m.p. 95°-97°, [α]D25 =5.32° (c=0.99, CH3OH) is obtained.