Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C(Cl)Cl>[O:21]1[CH2:22][CH2:23][N:18]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[CH2:19][CH2:20]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a stirred suspension of 4-(bromomethyl)benzonitrile (4.00 g, 20 mmol) in DCM (50 ml), at room temperature, triethylamine (4.12 g, 41 mmol) and morpholine (2.67 g, 31 mmol) were added. The reaction mixture was stirred overnight at room temperature. The solution was then diluted with DCM (100 ml) and washed with NaHCO3 saturated aqueous solution (50 ml), the organic phase was separated, dried over magnesium sulphate and solvents evaporated under reduced pressure. The product was purified by column chromatography using a 80 g silica gel cartridge and the following gradient: Solvent A: DCM, Solvent B: MeOH, 1 min hold at 100% A followed by 12 min ramp to 2.5% B and then 5 min hold at 2.5% B. The desired fractions were combined and concentrated to dryness under reduced pressure to obtain the desired product as a white solid (3 g, 14.8 mmol, Yield 72%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>CO.ClCCl.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ccc(N)cc2)CC1
Yield: 63.6 %

Procedure:
1-Methyl-4-(4-nitro-phenyl)-piperazine (200 mg) was hydrogenated over 10% Pd—C (20 mg) in methanol (20 ml) at atmospheric pressure until no further gas uptake was observed. The reaction mixture was then filtered over celite and concentrated to give a crude solid. Column chromatography over silica gel using 4% methanol in dichloromethane gave 4-(4-methyl-piperazin-1-yl)-phenylamine (110 mg, 64%) as solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1CCC(N=C=NC2CCCCC2)CC1.C(Cl)Cl.[C:29](O)([CH3:32])([CH3:31])[CH3:30]>CN(C1C=CN=CC=1)C>[C:29]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1])([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(O)c1ccccc1Br
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
2-Bromobenzoic acid (203.2 g, 1011 mmol) was added to a solution of 1.0 M DCC in DCM (1011 mL, 1011 mmol) and cooled at 0° C. DMAP (11.36 g, 93.0 mmol) and t-butyl alcohol (106.3 mL, 1112 mmol) were added and the mixture was stirred at room temperature for 10 minutes, then warmed to room temperature and stirred overnight. The mixture was then filtered, washed with saturated NaHCO3 (200 mL), saturated aqueous NaCl, dried over MgSO4, filtered and concentrated under reduced pressure to yield compound A as a clear oil (168.4 g).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:8])=[O:16])=[CH:13][CH:12]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=Cc1ccccc1
Product: COc1ccc(C(=O)C(O)c2ccccc2)cc1

Procedure:
Compounds of the invention having the formula ##STR26## can be prepared as follows. Benzaldehyde and 4-methoxybenzaldehyde are reacted to yield 4-methoxybenzoin, which is converted to the hemisuccinate by reaction with succinic anhydride. The latter is reacted with urea and acetic acid to yield the intermediate 4-(4-methoxyphenyl)-5-phenyl-2-oxazole-propionic acid. ##STR27## The latter intermediate is demethylated with hydrogen bromide and esterified with methanol to yield the corresponding hydroxy methyl ester intermediate, which is then reacted with an appropriate haloalkyl-A compound, where A is as defined hereinbefore and hal is halo, to yield the desired final product as the methyl ester. ##STR28## The ester can be hydrolyzed by conventional methods to yield the desired final product in its free carboxylic acid form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[OH:15])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:16]I.[OH-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CI
Reactant: CCOC(=O)COc1ccc(O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
Ethyl 4 hydroxyphenoxyacetate(l.5 g, 7.6 mmol) was reacted with SO2Cl2 (1.5 mL) to give ethyl 3-chloro-4-hydroxyphenoxyacetate (700 mg, ~80% pure) as a white powder. To a solution of ethyl 3-chloro-4-hydroxyphenoxyacetate (700 mg, 3.0 mmol) and MeI(0.280 mL, 4.5 mmol) in DMF(5 mL) at 0° C. was added 10M aq.NaOH(0.320 mL, 3.2 mmol). The mixture was stirred at r.t. for 12 h, then diluted with H2O and extracted with EtOAc to give ethyl 3-chloro-4 methoxyphenoxy-acetate (700 mg).
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[OH:7][C:2]([CH3:6])([CH3:1])[CH2:3][CH2:4][O:5][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(O)CCO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
10.0 ml (93.7 mmol) of 3-methylbutane-1,3-diol and 7.60 ml (94.9 mmol) pyridine are dissolved in 100 ml DCM. The mixture is cooled in an ice bath. 15.0 g (78.7 mmol) of 4-methylbenzenesulfonyl chloride are added portionwise. The reaction mixture is stirred at r.t. for 16 h. The reaction mixture is poured into 100 ml of 1N aq. HCl and stirred for 10 min. Then the layers are separated. The aq. layer is extracted with DCM. The combined organic layers are washed with brine and dried. The solvent is evaporated and the residue is chromatographed on silica gel (PE/EtOAc) to give the title compound. Yield: 15.3 g; Mass spectrum (ESI+): m/z=276 [M+NH4]+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:18]#[N:19])(C)C.C(Cl)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:18]#[N:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: N#Cc1cc(-c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-phenylpyridine N-oxide (5 g) in DCM (50 mL) was added at RT trimethylsilylcyanide (11 mL), followed by acetyl chloride (3.1 mL) over 10 min. The reaction mixture was stirred overnight at RT. A solution of aq. 10% Na2CO3 was added and the mixture was extracted with EA. The combined org. phases were washed with brine, dried (Na2SO4) and evaporated off. Filtration over a plug of silica gel (Hept/EA 1/1) gave the desired compound (450 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:10][C:11](=O)[CH3:12].C([O-])([O-])=O.[K+].[K+]>CO.O>[Cl:8][C:7]1[C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Nc1nccnc1Cl
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cn2ccnc(Cl)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
A solution of 2-amino-3-chloropyrazine (10 g, 77.5 mmol), chloroacetone (30 mL, 387 mmol) in MeOH (25 mL) is refluxed overnight at 88° C. It is then stirred for 1 h at 0° C. and any solid that forms, is filtered off and washed twice with MeOH (5 mL). The mother liq. are evaporated, diluted with EtOAc, and washed with HCl 2N, water and brine. The water and HCl mother liq. are evaporated to give a yellow solid that is neutralized with a saturated solution of K2CO3 in water, extracted with DCM, dried with MgSO4 anh. filtered and concentrated. The crude material is purified by column chromatography using a gradient of (DCM/MeOH: 1/0 to 99/1) to give 8-Chloro-2-methyl-imidazo[1,2-a]pyrazine as an orange solid (1.02 g, 7.7%).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13]I>CS(C)=O.O>[CH3:13][N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of sodium hydroxide (0.4 g.,10 mmol.) in DMSO (20 mL.) was heated to 80°-85° C. for 6 hours to dissolve most of the solids then allowed to cool to room temperature. To the stirred mixture was added 5-bromoindole (2.0 g., 10 mmol.) followed in 1 hour by methyliodide (0.62 mL., 10 mmol.). After stirring for an additional 3 hours the reaction was shown by TLC analysis to be complete. The reaction mixture was diluted with water then extracted with ether. The extracts were washed 2× with water, dried with Na2SO4, and concentrated in vacuo to give 2.08 g. of 1-methyl-5-bromoindole as a yellow oil which crystallized on standing.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1.O>CN(C)C=O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:19][CH:18]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(Br)cc1)C(=O)OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
A mixture of dimethyl malonate (42.6 g, 322.73 mmol, 4.00 equiv) and potassium carbonate (22.3 g, 161.59 mmol, 2.00 equiv) in N,N-dimethylformamide (200 mL) was stirred for 30 min at 50° C. A solution of 1-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00 equiv) in N,N-dimethylformamide (80 mL) was then added dropwise with stirring to the reaction mixture. The resulting solution was stirred at 50° C. for 2 h. Water (100 mL) was added and the mixture was extracted with 1×400 mL of ethyl acetate. The organic layer was washed with 2×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 22 g (91%) of dimethyl 2-(4-bromobenzyl)malonate as a white solid. LC-MS: (ES, m/z): 301 [M+H]+, 126, 120.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(COC2CCCCO2)cc1
Yield: 92.8 %

Procedure:
A solution of 5.9 g (38.7 mmol) of 4-nitrobenzyl alcohol, 17.6 ml(193.5 mmol) of 3,4-dihydro-2H-pyran and 500 mg (2.6 mmol) of p-toluene sulfonic acid monohydrate in 200 ml of dichloromethane was stirred at room temperature for 4 hours. The reaction mixture was evaporated and the residue purified by flash chromatography on silica gel, using 1:4 ethyl acetate/hexane as eluent. Product containing fractions were combined and evaporated to give 8.52 g (93%) of 2-(4-nitrobenzyloxy)-tetrahydropyran as a pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH3:10])[CH:4]=1)#[N:2].Cl.CCOCC>CO.[Pd]>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([CH2:1][NH2:2])[CH:8]=[CH:7][N:6]=1
Reactant: COc1cc(C#N)ccn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1cc(CN)ccn1
Reaction time: 8 h

Procedure:
4-Cyano-2-methoxypyridine (1.7 g) was dissolved in MeOH (50 ml) and conc. HCl (4.96 ml) was added. Pd/C (10%) was added and H2 was added and let stand overnight. The solids were filtered through Celite® and the cake was washed with MeOH (˜250 ml). Concentration in vacuo produced an oil which was dissolved in MeOH (˜20 ml). Et2O (200 ml) was added and stirred for 1 h. The resulting precipitate was filtered and washed with Et2O to afford (2-methoxypyridin-4-yl)methylamine (HCl salt) as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@@H:9]([OH:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].I[CH3:14]>C(#N)C.[Ag]=O>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][C@@H:9]([O:11][CH3:14])[CH3:10])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@H](O)CNC(=O)OC(C)(C)C
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: CO[C@@H](C)CNC(=O)OC(C)(C)C
Yield: 31.4 %

Procedure:
((S)-2-Hydroxy-propyl)-carbamic acid tert-butyl ester (0.25 g, 1.43 mmol) was dissolved in acetonitrile (14 ml) and iodomethane (1.78 ml, 28.5 mmol), and then silver oxide (0.53 g, 2.28 mmol; prepared as in Org. Syn. Coll. Vol. VII, p. 386) were added. The reaction flask was covered to protect from light and the reaction was heated at reflux for 24 h. Additional iodomethane (1.8 ml) and silver oxide (0.26 g) were added and heating was continued until the reaction was judged to be complete by standard reverse phase LC/MS. The reaction mixture was filtered through diatomaceous earth, rinsing with ethyl acetate. After evaporation the residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 85 mg (32%) of ((S)-2-methoxy-propyl)-carbamic acid tert-butyl ester. (M+Na)+=212.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][Cl:15])=[CH:6][C:5]=1[N+:16]([O-])=O.[Cl-].[NH4+].O>[Fe].CO>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][Cl:15])=[CH:6][C:5]=1[NH2:16]
Reactant: COC(=O)c1cc(OC)c(OCCCl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCl)cc1N

Procedure:
A mixture of 68.2 g (235.4 mmol) of 4-(2-chloro-ethoxy)-5-methoxy-2-nitro-benzoic acid methyl ester and 52.6 g (941.8 mmol) of iron was mechanically stirred at reflux in a mixture containing 62.9 g ammonium chloride, 393 ml water, and 1021 ml methanol for 15 hr. The mixture was concentrated and mixed with ethyl acetate. The organic solution was washed with water and saturated sodium bicarbonate. The solution was dried over magnesium sulfate and filtered through a short column of silica gel. The solution was concentrated to 200 ml and diluted with 250 of hot hexane. After standing 47.7 g of the title compound was obtained as a solid: mass spectrum (electrospray, m/e) M+H 259.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8]>O=[Mn]=O.C(Cl)Cl.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: OCc1cnc(Cl)c(Cl)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CCCCCC
Product: O=Cc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (5,6-dichloro-pyridin-3-yl)-methanol (1.78 g, 10 mmol, TCI-US) and MnO2 (17.39 g, 200 mmol, Aldrich) in 1:1 CH2Cl2/hexane (10 ml) was stirred at room temperature for 1 h. The catalyst was filtered and washed with 50% EtOAc/hexane. The filtrate was evaporated and the residue dried in vacuo to give the title compound product, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 176 (M+1).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[N:1]1([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
A solution of 1,2,3,4-tetrahydroquinoline (1.06 g, 7.51 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (2.24 g, 11.26 mmol) in 20 mL 1,2-dichloroethane was treated with sodium triacetoxyborohydride (4.77 g, 22.53 mmol) then acetic acid (1.28 mL, 22.53 mmol). The suspension was stirred at room temperature overnight. At this time, a TLC analysis indicated that 1,2,3,4-tetrahydroquinoline is present along with a more polar spot. To the reaction mixture was added tert-butyl 4-oxopiperidine-1-carboxylate (1.12 g, 5.63 mmol) and sodium triacetoxyborohydride (2.39 g, 11.28 mmol). The suspension was stirred at room temperature for 4 days. After this time, the mixture was cooled to 0° C., quenched with 20 mL 1N NaOH and stirred for 20 minutes. The organic layer was separated and the aqueous layer was extracted with 50 mL CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated to give a yellow residue. This residue was purified by the Biotage purification system using a silica gel 40M column. A gradient of 5% ethyl acetate:hexanes to 30% ethyl acetate:hexanes over 10 column volumes was used to give the title compound (0.89 g, 37.4%). 1H-NMR (CDCl3) δ 7.09-7.03 (m, 1H), 6.97-6.94 (m, 1H), 6.65 (d, J=8.4 Hz, 1H), 6.60-6.55 (m, 1H), 4.30-4.19 (m, 2H), 3.80-3.70 (m, 1H), 3.17 (t, J=5.7 Hz, 2H), 2.84-2.71 (m, 2H), 2.73 (t, J=6.3 Hz, 2H), 1.93-1.85 (m, 2H), 1.78-1.63 (m, 4H), 1.48 (s, 9H). MS (ESI): 317.2 (M+1).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C1COCC1>[CH:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cyclohexylamine (8.5 mL, 0.1 mole) was added drop wise to a solution of benzoylchloride (1.17 mL, 10 mmol) in 35 mL of dry THF at 0° C. The reaction was then stirred at room temperature for 3 hours. After that time water was added and the mixture was poured onto crushed ice. A white solid precipitated. It was collected by filtration and rinsed thoroughly with water. The solid was then dried under vacuum (1.63 g, 80%). NMR 1H (ppm, CDCl3): 7.72 (d, J3=6.78 Hz, 2H), 7.48-7.36 (m, 3H), 6.02 (br. d., J3=6.58 Hz, 1H), 4.00-3.89 (m, 1H), 2.03-1.99 (m, 2H), 1.79-1.71 (m, 3H), 1.44-1.37 (m, 2H), 1.25-1.15 (m, 3H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[NH4+].[OH-:10].[OH-].[Na+]>>[C:1]([OH:8])(=[O:7])[C@H:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:10]
Reactant: [OH-]
Reactant: O=C(O)/C=C/C(=O)O
Agent: [NH4+]
Agent: [Na+]
Product: O=C(O)C[C@H](O)C(=O)O

Procedure:
Cell mass grown according to example A is suspended in 8 liters of a 240 g/l solution containing fumaric acid (neutralized with NH4OH NaOH in the molar ratio of 2 to 1). After 12 hours of incubation, 237 g of L-malic acid per liter of fermentation liquid is produced.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8]Br)[CH3:2].NC(N)=[S:15].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][SH:15])[CH3:2]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C)(C)CCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(C)CCCS
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 5-bromo-2,2-dimethylpentanoic acid ethyl ester (2.41 g, 10 mmol) in ethyl alcohol (5 mL) was added thiourea (0.77 g, 10 mmol) and the mixture was refluxed for 3 h under a nitrogen atmosphere. A solution of sodium hydroxide (0.62 g, 15 mmol) in deionized water (2.5 mL) was added and stirring was continued for another 2 h at reflux temperature. The mixture was cooled to rt and the ethanol was distilled off under reduced pressure. Diethyl ether (20 mL) was added and the layers were separated. The organic phase was washed with saturated sodium chloride solution (5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give 5-mercapto-2,2-dimethylpentanoic acid ethyl ester (1.41 g, 74%) as a yellow oil. 1H NMR (300 MHz, CDCl3/TMS): d (ppm): 4.12 (q, J=7.0 Hz, 2H), 2.57-2.43 (m, 2H), 1.69-1.45 (t, 4H), 1.25 (t, J=7.0 Hz, 3H), 1.17 (s, 7H). 13C NMR(75 MHz, CDCl3/TMS): d (ppm): 177.55, 41.0, 39.24, 25.07, 24.90, 14.18.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(OC(=O)C)C>[CH3:23][C:22]([NH:20][CH2:19][C@@H:17]1[O:16][C:15](=[O:21])[N:14]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)=[C:2]([F:1])[CH:3]=2)[CH2:18]1)=[O:24]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of (S)—N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (10 gm) and ethylacetate (100 ml), acetic anhydride (10 ml) is slowly added at ambient temperature, then stirred at ambient temperature for 1 hour. The separated solid is filtered and dried under reduced pressure at 50° C. to give 9.5 gm of linezolid form III.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[Br:10]Br>C(O)(=O)C>[Br:10][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: BrBr
Reactant: Nc1c(F)cccc1F
Solvent: CC(=O)O
Product: Nc1c(F)cc(Br)cc1F
Temperature: 10 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
507.5 g of 2,6-difluoroaniline are added to 2500 ml of acetic acid, the mixture is cooled to 10° C., and a solution of 195 ml of bromine in 250 ml of acetic acid is added dropwise at 10-15° C. over the course of 3 hours. The mixture is subsequently stirred at room temperature for a further 1 hour and poured into 5000 ml of ice-water, the precipitated crystals are filtered off with suction and washed a number of times with a total of 3000 ml of ice-water, and the crystals are dried over Al2O3 under reduced pressure, giving 4-bromo-2,6-difluoroaniline, yield 91.7%, GC 99.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1(N)CCCCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: NC1CCCCC1
Solvent: O
Product: O=C(O)CCC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Yield: 61 %

Procedure:
Prepared analogous to Example 25 from 4-(4'-chloro-4-biphenylyl)-4-oxo-butyric acid. Melting point of the cyclohexylamine salt: 185°-186° C. (from water). Yield: 61% of theory.