Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.O[C@H:26]1[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:12]1([C:9]([CH2:10][CH3:11])=[C:8]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[C:5]2[CH:6]=[CH:7][C:2]([O:1][C@@H:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[CH:3][CH:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(O)cc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=C(c1ccc(O)cc1)c1ccc(O[C@@H]2CCNC2)cc1)c1ccccc1
Yield: 19.7 %

Procedure:
Following the same procedure as described in example 16, step D & E, 4-(1-(4-hydroxylphenyl)-2-phenylbut-1-enyl)phenol (150 mg, 0.474 mmol) was reacted with (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (107 mg, 0.571 mmol), followed by de-Boc in condition of TFA/CH2Cl2, to give the desired product (36 mg, 20% yield, Z/E=1/1). m/z=386[M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:32])[N:16]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[N:40]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.Cl>O1CCCC1>[CH2:25]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([OH:24])=[C:14]([C:8]2[NH:7][C:6]3[S:5][CH:4]=[C:3]([CH2:2][NH:1][C:46]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:47])[C:11]=3[S:10](=[O:13])(=[O:12])[N:9]=2)[C:15]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(Cc3ccccc3)c1=O)N2)N1CCOCC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 40.4 %

Procedure:
To the solution of the product of Example 345 (0.015 g, 0.032 mmol) in tetrahydrofuran (0.4 mL) was added triethylamine (0.009 mL, 0.064 mmol). The mixture was cooled to 0° C. and 4-morpholinecarbonyl chloride (0.004 mL, 0.035 mmol) was added. The reaction mixture was warmed to 23° C. and stirred for 15 hours. 1 N hydrochloric acid (0.065 mL, 0.064 mmol) was added and the mixture was then concentrated under reduced pressure. The product was washed with diethyl ether and water to give the title compound (7.5 mg, 40%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (500 MHz, DMSO-d6) δ 3.57 (t, 4 H) 4.38 (d, J=4.88 Hz, 2 H) 5.60 (bs, 2 H) 7.11 (m, 2 H) 7.27 (m, 6 H) 7.38 (m, J=7.32, 3.05 Hz, 1 H) 7.49 (m, J=7.32 Hz, 1 H) 7.73 (bs, 1 H) 8.21 (d, J=7.32 Hz, 1 H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=1[Cl:15])(=[O:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[C:12]([C:33]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:28])[CH:34]=2)[CH:11]=[CH:10][C:9]=1[Cl:15])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(Br)ccc1Cl
Reactant: Cc1cc(B(O)O)ccn1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cc(-c2ccnc(C)c2)ccc1Cl

Procedure:
By carrying out the operation analogously to example 3, starting from 5-bromo-2-chlorophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation X, and 2-methyl-4-pyridineboronic acid, the expected product is obtained and is reacted further without additional purification in order to obtain the nonacetylated xyloside.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([OH:38])=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:59]([O:63][C:64]([N:66]1[CH2:71][CH2:70][CH:69]([CH2:72]O)[CH2:68][CH2:67]1)=[O:65])([CH3:62])([CH3:61])[CH3:60]>C(Cl)Cl>[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH2:72][CH:69]4[CH2:70][CH2:71][N:66]([C:64]([O:63][C:59]([CH3:60])([CH3:62])[CH3:61])=[O:65])[CH2:67][CH2:68]4)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:39])[NH:20]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Diisopropyl azodicarboxylate (139 μl, 0.71 mmol) was added to a mixture of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 7), triphenylphosphine (186 mg, 0.71 mmol) and 1-(tert-butoxycarbonyl)-4-hydroxymethylpiperidine, (also known as tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate), (152 mg, 0.71 mmol) in methylene chloride (3 ml), cooled in an ice/water bath. The mixture was allowed to warm to ambient temperature and was stirred overnight. The mixture was concentrated under reduced pressure and the residue purified by column chromatography, eluting with 1% methanol/methylene chloride and 0.1% triethylamine to give tert-butyl 4-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)methyl]piperidine-1-carboxylate (293 mg containing 13.5 mol % triphenylphospine oxide, 86%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([N:19]([CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)[CH3:20])=[O:18])=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([NH:8][C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([N:19]([CH3:20])[CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH3:31])[CH:23]=2)=[O:18])=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1ccc(N)nc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(/C=C/C(=O)N(C)Cc2cn(C)c3ccccc23)cn1
Reaction time: 48 h
Yield: 44.5 %

Procedure:
Acetic anhydride (0.12 mL, 1.24 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)-N-(1-methyl-1H-indol-3-ylmethyl)-N-methylacrylamide (0.10 g, 0.31 mmole) and sodium bicarbonate (0.13 g, 1.55 mmole) in THF (20 mL) at RT, and the reaction was heated at reflux under nitrogen. After 48 hr, the reaction was concentrated in vacuo and the residue was diluted with water and extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (ethyl acetate) gave the title compound (50 mg, 45%) as a white solid: MS (ES) m/e 363 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C@H:6]1[C@@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23](OC(C)(C)C)=O)[CH2:7]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Na+].[Na+].BrC1[S:38][C:39]2[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=2[N:41]=1>>[CH2:1]([NH:5][C@H:6]1[C@@H:11]([NH:12][C:13]([C:15]2[NH:16][C:17]([CH2:21][CH3:22])=[C:18]([Cl:20])[N:19]=2)=[O:14])[CH2:10][CH2:9][N:8]([C:23]2[S:38][C:39]3[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)[CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Reactant: CCCCN[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCCN[C@@H]1CN(c2nc3cccc(C(=O)OCC)c3s2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 65 %

Procedure:
The same operation as in Example (1h) was performed using tert-butyl cis(±)-3-(butylamino)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained by the method described in Example (77d) (12.3 mg, 0.029 mmol), sodium carbonate (45 mg, 0.42 mmol) and ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (10.4 mg, 0.036 mmol), to obtain 10.0 mg of the title compound (65%).
Reaction SMILES: [C:1]([NH:11][CH:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])=[O:25]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][CH:12]([C:14](=[O:16])[NH:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24](=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 0.67 h

Procedure:
50 g of carbobenzoxy-DL-alanine are dissolved in 400 ml of absolute tetrahydrofuran, treated dropwise while cooling with ice with 30 g of thionyl chloride and stirred for 40 minutes, a suspension of 50 g of 2-amino-5-nitro-2'-fluorobenzophenone in 200 ml of absolute tetrahydrofuran then being rapidly added dropwise. Subsequently, the mixture is stirred at room temperature for 18 hours, the solution is concentrated and the residue is treated with ice and 10% sodium bicarbonate solution. The mixture is extracted with methylene chloride, the organic solution is dried with sodium sulphate, filtered and concentrated. The residue is crystallised from ethanol and yields rac-benzyl-{1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]ethyl}carbamate which is further processed directly as the crude product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:11][C:5]1[CH:4]=[CH:3][C:2]([C:43]#[C:42][Si:39]([CH3:41])([CH3:40])[CH3:38])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: Cc1ccc(Br)cc1C(N)=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C#C[Si](C)(C)C)cc1C(N)=O
Temperature: 120 °C

Procedure:
To a mixture of 5-bromo-2-methylbenzamide (I69) (0.292 g, 1.36 mmol), PdCl2(PPh3)2 (0.049 g, 0.070 mmol), triphenylphosphine (0.054 g, 0.21 mmol) and copper iodide (0.036 g, 0.19 mmol) in DMF (3 mL) was added triethylamine (0.570 mL, 4.09 mmol) and trimethylsilylacetylene (0.210 mL, 1.49 mmol) and the resulting mixture heated under microwave irradiation at 120° C. for 25 minutes. The resulting mixture was concentrated under reduced pressure and purified using silica gel column chromatography (0-20% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I70) (0.190 g, 60%); 1H NMR (400 MHz, d6-DMSO) δ 7.80 (s, 1H), 7.40 (m, 3H), 7.24 (d, J=7.9 Hz, 1H), 2.36 (s, 3H), 0.22 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]=1>C(O)C.[H][H].[Pt]>[OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)=NCC2
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Yield: 95 %

Procedure:
0.01 mole (2.65 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-3,4-dihydroisoquinoline is dissolved in 50 ml of ethanol, and the mixture is reduced in hydrogen atmosphere, in the presence of a 10% platinum-on-activated carbon catalyst, under normal conditions. After uptake of the calculated amount of hydrogen (1 to 2 hours), the catalyst is filtered off and the filtrate is evaporated to yield the aimed compound in crystalline form.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:11][CH:12]=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:47])[CH:27]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:16]=[C:13](/[CH:14]=[CH:27]/[C:26]([O:25][CH3:24])=[O:47])[CH:12]=[N:11][C:10]=1[NH:17][C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1csc(Nc2ncc(C=O)cc2OCc2ccccc2)n1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
A 25 mL round-bottomed flask was charged with 5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)nicotinaldehyde (500 mg, 1.54 mmol) and THF (10 mL). Methyl(triphenylphosphoranylidene)acetate (668 mg, 2.00 mmol) was added and the reaction was stirred at room temperature for 1 hour. An additional 668 mg of methyl(triphenylphosphoranylidene)acetate was added and the reaction was stirred overnight. The solids were filtered off and the filtrate was purified on a silica gel column (1:1 EtOAc:Hexanes) to afford (E)-methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-yl)acrylate (450 mg, 76.8% yield) as a yellow foam. 1H NMR (CDCl3) 8.69 (s, 1H), 8.07 (d, 1H), 7.65 (d, 1H), 7.42 (m, 5H), 7.25 (m, 1H), 6.45 (m, 1H), 6.30 (d, 1H), 5.15 (s, 2H), 3.81 (s, 3H), 2.33 (s, 3H). Mass spectrum (apci) m/z=382.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:12]=[N:13][N:14]([CH3:16])[N:15]=3)[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:12]=[N:13][N:14]([CH3:16])[N:15]=3)[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2ccc(-c3nnn(C)n3)cc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nnc(-c2ccc3scc(CBr)c3c2)n1
Yield: 74.1 %

Procedure:
To a refluxing mixture of 3-methyl-5-(2-methyltetrazol-5-yl) benzo[b]thiophene (0.162 g, 0.703 mmol) and benzoyl peroxide (10.6 mg) in carbon tetrachloride (10 ml) irradiated with two desk lamps (2×60 W) was added N-bromosuccinimide (0.126 g, 0.707 mmol) in small portions. After the addition was complete the mixture was heated at reflux for a further 90 min, then filtered and the filtrate was evaporated in vacuo to leave an oil/solid mixture. Chromatography on flash silica, eluting with dichloromethane gave 0.161 g of crude 3-bromomethyl-5-(2-methyltetrazol-5-yl) benzo[b]thiophene as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].[C:22]([C:26]1[CH:41]=[CH:40][C:29]([CH2:30][NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:22]([C:26]1[CH:41]=[CH:40][C:29]([CH2:30][N:31]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[C:12](=[O:14])[CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CC(C)(C)c1ccc(CNCc2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(Cl)cc2)Cc2ccc(C(C)(C)C)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g, 3.00 mmol) in methylene chloride (30 mL) were added N-(4-tert-butylbenzyl)-N-(4-chlorobenzyl)amine (1.04 g, 3.60 mmol), N,N-diisopropylethylamine (1.20 mL, 6.9 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.01 g, 3.15 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (220 mL) and the organic phase was washed with 2 M HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Twice repeated purification on prepacked columns of silica gel (Isolute® SPE Column, 50 g/150 mL) with methanol (0-2% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 0.459 g (27%) of a whitish oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:14]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][C:11]([NH2:12])=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1.[CH3:25]I>CN(C)C=O.[Ag]=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:14]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][C:11]([NH:12][CH3:25])=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1
Reactant: CI
Reactant: COCCOCOc1cc(N)c([N+](=O)[O-])cc1OCOCCOC
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CNc1cc(OCOCCOC)c(OCOCCOC)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
1.57 g (4.54 mmol) of 4,5-di(2-methoxyethoxymethoxy)-2-nitroaniline obtained in step (C) of Reference Example 34 was dissolved in 16 ml of N,N-dimethylformamide, and 2 g (8.63 mmol) of silver oxide and 10 ml (160 mmol) of methyl iodide were added thereto. The mixture was stirred at room temperature for one hour. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate/hexane=1/1). The eluted fraction containing the desired compound was concentrated to obtain 0.85 g of crude 4,5-di(2-methoxyethoxymethoxy)-N-methyl-2-nitroaniline. (B) 0.85 g of the crude product obtained in the above reaction (A) was dissolved in 16 ml of ethanol, and 0.4 g of a 10% palladium carbon catalyst was added thereto. The catalytic hydrogenation was conducted at 80° C. for two hours. The catalyst was removed by filtration, and then to the filtrate, 1 g (6.25 mmol) of potassium O-ethyl dithiocarbonate was added. The mixture was refluxed at a boiling point for two hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water. The solution was adjusted to pH5.0 with acetic acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel C-300, ethyl acetate/hexane=3/1) to obtain 67 mg of the above-identified compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:36])[CH2:22][CH2:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])[O:16][C:15]2=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C1C=C(Cl)C=C(C(OO)=[O:46])C=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@@H:17]([CH2:19][NH+:20]([O-:46])[C:21](=[O:36])[CH2:22][CH2:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])[O:16][C:15]2=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=C(CCC(=O)c1ccc2ccccc2c1)NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(CCC(=O)[NH+]([O-])C[C@@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.9 %

Procedure:
To a cooled solution (0-5° C.) of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]-4-(2-naphthyl)-4-oxobutanamide (0.950 gm, 0.0019 moles) in dichloromethane (150 ml) was added 60% m-CPBA (0.550 g, 0.0032 moles) and the resulting solution stirred at room temperature for 12 hr. The solvent was evaporated under reduced pressure and the residue chromatographed over silica gel (100-200 mesh, 40 g). The column was eluted with ethyl acetate (200 ml), followed by a mixture of chloroform:methanol (4:1, 600 ml). Concentration the combined fractions gave the title N-oxide (0.891 g, 82%) as a white solid.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:37][NH2:38]>CCCCCC>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:38][CH2:37][C:36]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:34]([O:33][CH3:32])[CH:35]=2)=[N:9][CH:10]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: CCCCCC
Solvent: C1COCCO1
Product: COc1ccc(CNc2cc(C(Sc3ccc(Cl)cc3)c3cc(F)ccc3F)c(Cl)cn2)cc1OC
Temperature: 25 °C
Yield: 49 %

Procedure:
A dioxane (1.5 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridine (218 mg, 0.523 mmol) obtained in Example 54 and 3,4-dimethoxybenzylamine (400 μl) was heated at 120° C. for 3 days in a sealed tube. The reaction mixture was cooled to room temperature and then, concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (140 mg, 0.256 mmol, 49%) as an amorphous substance.
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+]>[Cl-].[Mg+2].[Cl-]>[NH2:9][C@H:2]([C:1]([OH:8])=[O:7])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Mg+2]
Product: N[C@@H](CC(=O)O)C(=O)O
Reaction time: 48 h

Procedure:
The immobilized Serratia marcescens prepared in the above (1) (60 g) was packed in a jacketed column (4 cm×8 cm) and incubated at 37° C. for 48 hours to activate the immobilized cells (aspartase activity: 1,582,000 μmole/hr). After activation, 1M ammonium fumarate solution containing 1mM magnesium chloride (pH 8.5, 1,000 ml) was passed through the column at 37° C. at the flow rate of 150 ml/hr. The effluent was adjusted to pH 2.8 to give L-aspartic acid (127 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:4])=[O:3].[NH2:14][CH2:15][C@@H:16]([OH:33])[CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[Cl:31])[O:24][CH:21]1[CH2:20][CH2:19][N:18]([CH2:17][C@H:16]([OH:33])[CH2:15][NH:14][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:23][CH2:22]1
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1C(=O)NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 0 °C
Yield: 35 %

Procedure:
A mixture of 2-(methylsulphonyl)benzoic acid (0.063 g), (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and N,N-diisopropylethylamine (0.1 ml) in dry dimethylformamide (3 ml) was cooled to 0° C. with stirring. 2-(1H-9-Azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.13 g) was added and the mixture was stirred at 0° C. for 1-2 h. Saturated sodium bicarbonate solution (10 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was separated and washed with brine and dried over sodium sulphate. The mixture was filtered and the solvent was evaporated. The resulting oil was purified by normal phase chromatography using methanol/dichloromethane as eluent, and by reverse phase HPLC using acetonitrile and 0.1% aqueous ammonium acetate as eluent, to give the title compound as a white solid (0.055 g).