Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]1[C@@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:38][CH2:39][C:40]1[C:41]([OH:48])=[N:42][C:43]([CH3:47])=[CH:44][C:45]=1[CH3:46]>ClCCl>[OH:48][C:41]1[C:40]([CH2:39][NH:38][C:8]([C:6]2[CH:5]=[CH:4][N:3]([C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:2](=[O:1])[CH:7]=2)=[O:10])=[C:45]([CH3:46])[CH:44]=[C:43]([CH3:47])[N:42]=1
Reactant: C[C@H](c1ccccc1)n1ccc(C(=O)O)cc1=O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccn([C@H](C)c3ccccc3)c(=O)c2)c(O)n1
Temperature: 0 °C
Reaction time: 13 h
Yield: 68.1 %

Procedure:
To a solution of (R)-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxylic acid (336 mg, 1.4 mmol), 1-hydroxybenzotriozole (373 mg, 2.8 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (531 mg, 2.8 mmol), triethylamine (1.0 mL) in dichloromethane (30 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (210 mg, 1.4 mmol). The reaction mixture was stirred at 0° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give (R)—N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-2-oxo-1-(1-phenylethyl)-1,2-dihydropyridine-4-carboxamide as a white solid (360 mg, 68%). LRMS (M+H+) m/z: calcd 377.17. found 377. HPLC Purity (214 nm): 100%. 1H NMR (300 MHz, d6-DMSO): δ 11.44 (s, 1H), 8.53 (t, J=4.8 Hz, 1H), 7.66 (d, J=3.3 Hz, 1H), 7.38-7.26 (m, 5H), 6.78 (s, 1H), 6.51 (dd, J=1.8 Hz, J2=6.9 Hz, 1H), 6.13 (q, J=7.2 Hz, 1H), 5.84 (s, 1H), 4.22 (d, J=4.8 Hz, 2H), 2.13 (s, 3H), 2.10 (s, 3H), 1.68 (d, J=7.2 Hz, 3H).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1.[F:12][CH2:13][C:14]1([CH:18]=[O:19])[CH2:17][O:16][CH2:15]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[F:12][CH2:13][C:14]1([CH:18]([C:9]2[O:8][C:7]([CH3:6])=[CH:11][CH:10]=2)[OH:19])[CH2:17][O:16][CH2:15]1
Reactant: O=CC1(CF)COC1
Reactant: Cc1ccco1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C(O)C2(CF)COC2)o1
Temperature: -70 °C
Reaction time: 3 h
Yield: 106.3 %

Procedure:
11.0 ml (27 mmol, 1.5 eq) of a 2.5 M solution of n-butyllithium in hexane were added dropwise to a solution of 2.25 g (27 mmol, 1.5 eq) of 2-methylfuran in 40 ml of tetrahydrofuran cooled to −70° C. The reaction medium was stirred and allowed to return to ambient temperature for 3 hours. The reaction medium was cooled to −70° C. and then 2.16 g (18 mmol, 1 eq) of 3-fluoromethyloxetane-3-carbaldehyde were added. The reaction medium was stirred at ambient temperature for two and a half hours. The reaction medium was treated with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined, washed with a saturated sodium chloride solution and evaporated. 3.83 g of (3-fluoromethyloxetan-3-yl)-(5-methylfuran-2-yl)methanol were obtained in the form of a dark orange oil. Yield=71%. TLC SiO2/CH2Cl2:MeOH (96/4), developing with KMnO4.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([CH2:9][C:10]([OH:12])=O)[N:5]=1)([O-:3])=[O:2].[CH2:13]([C@@H:20]1[NH:25][CH2:24][CH2:23][N:22]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([CH2:40][CH3:41])=[N:31][N:32]3[CH:35]3[CH2:39][CH2:38][CH2:37]C3)=[CH:28][CH:27]=2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([C@H:20]1[CH2:21][N:22]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([CH2:40][CH3:41])=[N:31][N:32]3[CH:35]3[CH2:37][CH2:38][CH2:39]3)=[CH:28][CH:27]=2)[CH2:23][CH2:24][N:25]1[C:10](=[O:12])[CH2:9][C:6]1[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][N:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1n[nH]c([N+](=O)[O-])n1
Reactant: CCc1nn(C2CCCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Product: CCc1nn(C2CCC2)c2cc(N3CCN(C(=O)Cc4n[nH]c([N+](=O)[O-])n4)[C@@H](Cc4ccccc4)C3)ccc12

Procedure:
Prepared by the method outlined for Example 189 using (5-Nitro-1H-[1,2,4]triazol-3-yl)-acetic acid and ester 6-(S)-3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole (Example 56, Compound 144) as starting materials. Product as an oil. LC/MS (Method B) 2.56 min, [M+1]+ 529. Potency class ND.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([Cl:24])=[CH:12][C:11]=1[C:25](=[O:27])[CH3:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:28]([O:30][C:31](=[O:37])[C:32](OCC)=[O:33])[CH3:29]>C(O)(=O)C>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([Cl:24])=[CH:12][C:11]=1[C:25](=[O:27])[CH:26]=[C:32]([OH:33])[C:31]([O:30][CH2:28][CH3:29])=[O:37])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)C(O)=CC(=O)c1cc(Cl)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.17 h
Yield: 97.3 %

Procedure:
Sodium metal (1.35 g, 58 mmol) was cut into small pieces, rinsed with hexane to remove mineral oil, and added portion wise to anhydrous EtOH (100 ml) under a nitrogen atmosphere over a period of 20 min. The reaction mixture was stirred for a further 10 min until all sodium had reacted. 1-[2,4-bis(benzyloxy)-5-chlorophenyl]ethanone (10 g, 27.3 mmol) was added portion wise over 5 min, and the resulting suspension was then stirred for further 5 min at RT. Diethyloxalate (6 ml, 43 mmol) was added, resulting in a thick yellow coloured precipitate. The reaction mixture was heated to reflux for 4 h, affording a dark homogeneous solution, which, upon cooling, produced a solid mass to which acetic acid (6 ml) was added. The mixture was triturated to afford a yellow solid, which was filtered, washed sequentially with water, EtOH, and Et2O, and then dried under vacuo to afford the title compound ethyl 4-(2,4-bis(benzyloxy)-5-chlorophenyl)-2-hydroxy-4-oxobut-2-enoate (12.4 g, 98%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]([F:33])([F:32])[C:25]1[O:29][N:28]=[C:27]([CH2:30][NH2:31])[CH:26]=1>>[F:33][C:24]([F:23])([F:32])[C:25]1[O:29][N:28]=[C:27]([CH2:30][NH:31][C:14]([C:12]2[CH:11]=[CH:10][C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:13]=2)=[O:16])[CH:26]=1
Reactant: NCc1cc(C(F)(F)F)on1
Reactant: O=C(O)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Product: O=C(NCc1cc(C(F)(F)F)on1)c1ccc(OCC2CC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 41 using 6-(4-Chloro-phenyl)-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (example AW) and 5-trifluoromethyl-isoxazol-3-methanamine hydrochloride (example BF) as starting materials, LC-MS (UV peak area/ESI) 97.8%, 452.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[N:23][CH:24]=1)[O:21][CH2:20][CH2:19][O:18][C:17](=[O:25])[C:16]1=[C:26]3[N:27]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:21])[N:23]([CH:24]=1)[CH2:20][CH2:19][O:18][C:17](=[O:25])[C:16]1=[C:26]3[N:27]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C1OCCOc2ncc(F)cc2[C@H]2CCCN2c2ccn3ncc1c3n2
Solvent: CC#N
Solvent: O
Product: O=C1OCCn2cc(F)cc(c2=O)[C@H]2CCCN2c2ccn3ncc1c3n2
Yield: 9 %

Procedure:
Obtained as a by-product of Example 14, Step C, and isolated as a white solid (5 mg, 9% yield) by reverse phase column chromatography (Biotage SP4 system C-18 25+M column, 5 to 60% acetonitrile/water) of the crude material of Example 14, Step C. MS (apci) m/z=370.2 (M+H).
Reaction SMILES: C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.C(P(CCCC)CCCC)CCC.[Cl:30][C:31]1[C:39]([F:40])=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][CH2:34][N:35]2[C@@H:41]([CH2:60][CH2:61]O)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([S:51](=[O:59])(=[O:58])[NH:52][C:53]2[S:54][CH:55]=[CH:56][N:57]=2)=[CH:47][N:46]=1)=[O:43].O>C1COCC1>[Cl:30][C:31]1[C:39]([F:40])=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][CH2:34][N:35]2[C@H:41]1[CH2:60][CH2:61][N:44]([C:45]2[N:46]=[CH:47][C:48]([S:51]([NH:52][C:53]3[S:54][CH:55]=[CH:56][N:57]=3)(=[O:59])=[O:58])=[CH:49][CH:50]=2)[C:42]1=[O:43]
Reactant: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cn1)[C@H](CCO)N1CCc2c1ccc(F)c2Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C1[C@@H](N2CCc3c2ccc(F)c3Cl)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cn1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Prepared using General Procedure 3. To a stirring solution of di-tert-butyl-azodicarboxylate (44 mg, 0.05 mmol) and THF (0.5 mL), under N2, at 0° C., was added tributylphosphine (48 mg, 0.19 mmol), dropwise over 5 minutes. The colourless solution was stirred at 0° C. for 30 minutes. A solution of (S)-2-(4-chloro-5-fluoroindolin-1-yl)-4-hydroxy-N-(5-(N-thiazol-2-ylsulfamoyl)pyridine-2-yl)butanamide (24 mg, 0.05 mmol) in THF (0.5 mL) was added dropwise over 5 minutes. The solution was stirred at ambient temperature for 2 hours. To this solution was added H2O (40 uL) and the solution was evaporated to dryness. The residue was purified via reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave (S)-6-(3-(4-chloro-5-fluoroindolin-1-yl)-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)pyridine-3-sulfonamide. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=494.1; tR=1.69 min. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.43 (d, J=8.8 Hz, 1H), 8.20 (dd, J=8.9, 2.5 Hz, 1H), 7.30 (d, J=4.6 Hz, 1H), 7.01 (t, J=9.2 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 6.48 (dd, J=8.7, 3.6 Hz, 1H), 4.89 (q, J=6.6 Hz, 1H), 4.18 (t, J=9.7 Hz, 1H), 3.84-3.77 (m, 1H), 3.65-3.59 (m, 1H), 3.39-3.37 (m, 1H), 3.05-2.98 (m, 2H), 2.38-2.31 (m, 1H), 2.21-2.10 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][NH2:33].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([O:20][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([C:17](=[O:19])[NH:33][CH2:32][CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[F:24])([CH3:15])[CH3:16])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23])[CH3:22]
Reactant: NCCc1ccccc1F
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2ccccc2F)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(2-fluoro-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C23H28FNO5 [M−H]−: 416.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:16](OCC)=[O:17].Cl>CN(C)C=O>[CH:16]([CH:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:17]
Reactant: CCOC=O
Reactant: CCOC(=O)CCC1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
76.0 g of ethyl 3-cyclohexylpropionate are initially introduced into 200 ml of dimethylformamide at 0° to 5° C., and 24.6 g of sodium hydride (80% strength in oil) are added. After dropwise addition of 235 ml of ethyl formate, the mixture is stirred at 25° C. for 24 hours. The batch is stirred into 1.6 l of 10% strength HCl, extracted with 800 ml of methylene chloride and distilled. 34.2 g (41%) of ethyl 2-formyl-3-cyclohexylpropionate of boiling point 91°-95° C./1.25 mm are obtained.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][NH2:9].C[O-].[Na+].C(O[C:16](=[C:18]([C:21]#[N:22])[C:19]#[N:20])[CH3:17])C>C(O)C>[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[N:8]1[C:21]([NH2:22])=[C:18]([C:19]#[N:20])[C:16]([CH3:17])=[N:9]1
Reactant: CCOC(C)=C(C#N)C#N
Reactant: CC1CCCC1NN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C2CCCC2C)c(N)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
To a solution of 2-methylcyclopentylhydrazine hydrochloride (7.4 g, 48.8 mmol) in ethanol (100 ml) was added sodium methoxide (2.6 g, 48.8 mmol). The resulting white suspension was stirred for 10 minutes at room temperature and then (1-ethoxyethylidene)malononitrile (6.7 g, 48.8 mmol) was added. The reaction mixture was heated to reflux and was stirred for 5 hours. The solvent was removed in vacuo and the residue was partitioned between chloroform and water. The organic layer was separated and the aqueous layer was extracted with chloroform three times. The combined organic layers were washed with brine, then dried over anhydrous MgSO4. The solution was passed through a plug of silica gel and the solvent was removed in vacuo. The residue was washed with ether to afford 5.6 g (56%) of 1-(2-methylcyclopentyl)-3-methyl-5-amino-1H-pyrazole-4-carbonitrile as a white powder, m.p. 158°-159° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:42])([F:41])[C:10]1[CH:11]=[C:12]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:13][NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:29]=[C:30]([Br:33])[CH:31]=[CH:32][C:16]1=2.N1C=CC=CC=1>ClCCl>[C:1]([N:14]([CH2:13][C:12]1[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=[C:10]([C:9]([F:8])([F:41])[F:42])[CH:11]=1)[CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:29]=[C:30]([Br:33])[CH:31]=[CH:32][C:16]1=2)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Br)cc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (1.49 g, 6.13 mmol) followed by titanium isopropoxide (1.60 mL, 5.47 mmol) to a solution of tert-butyl 8-bromo-5-oxo-2,3,4,5-tetrahydro benzo[b]azepine-1-carboxylate (1.49 g, 4.38 mmol) in tetrahydrofuran (17.5 mL) at room temperature under nitrogen and stir the solution for 14 h. Dilute the reaction with methanol (35 mL) and slowly add sodium borohydride (0.248 g, 6.57 mmol) to the reaction and stir at room temperature for 3 h. Add 2 N NaOH (20 mL) and water (20 mL) to the reaction and stir for 0.5 h. Filter the mixture and wash the solids with ethyl acetate (3×75 mL). Separate the filtrate and wash the organic layer with brine (25 mL), then dry the solution over sodium sulfate, filter and remove the solvent under reduced pressure to afford tert-butyl 5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate as a white solid. Add acetic anhydride (6.0 mL, 64.0 mmol) dropwise to a suspension of tert-butyl 5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.42 g, 4.26 mmol) and pyridine (5.2 mL, 64.0 mmol) in dichloromethane (17 mL) under nitrogen cooled to 0° C. After the addition is complete, remove the cooling bath and warm the reaction to room temperature and stir for 12 h. Dilute the mixture with dichloromethane (25 mL) and wash with 2 M potassium hydrogen sulfate and saturated aqueous sodium bicarbonate (25 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to afford the title compound as a white solid.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH2:2]1.[O-:26][CH2:27]C.[Na+]>C(O)C>[CH3:27][O:26][CH2:2][C:3]1([OH:1])[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]3=[O:25])=[CH:13][CH:14]=2)[CH2:7][CH2:8]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)cc2)C(=O)O1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COCC1(O)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)CC1
Yield: 50 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol) with sodium ethoxide (1.6 mmol) in ethanol (10 ml) at a temperature 60° C. for 6 hours and by purifying the compound by silica gel column chromatography in 50% yield.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:44])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:24])[OH:23])[C@H:18]1[C:25]([O:27][C@H:28]([C:42]#[N:43])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1)=[O:26].[C:45]([CH:47](O)[C:48](Cl)([Cl:50])[Cl:49])#[N:46]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:44])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:23])[O:24][C:47]([C:45]#[N:46])=[C:48]([Cl:50])[Cl:49])[C@H:18]1[C:25]([O:27][C@H:28]([C:42]#[N:43])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1)=[O:26]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: N#CC(O)C(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC(C#N)=C(Cl)Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
140 mg of 4-dimethlaminopyridine and then 1.76 g of dicyclohexylcarbodiimide were added at 0° C. to a mixture of 3.36 g (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate, 1.7 g of chloral cyanohydrin and 16 ml of methylene chloride and the mixture was stirred at 20° C. for 21/2 hours and was then evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with an 85-15 cyclohexane-ethyl acetate mixture to obtain 1.65 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-(2,2-dichloro-1-cyanovinyloxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+40° (c=0.3% in chloroform).
Reaction SMILES: [CH3:1][C:2]([CH:4]=O)=O.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]>>[CH3:1][C:2]1[CH:4]=[N:13][C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1
Reactant: Nc1ccccc1N
Reactant: CC(=O)C=O
Product: Cc1cnc2ccccc2n1

Procedure:
Methylglyoxal was estimated by derivatization of methylglyoxal with 1,2-diaminobenzene to produce 2-methylquinoxaline according to the method of Cordeiro and Freire (1996) with some modifications.
Reaction SMILES: [CH3:1][O:2][C:3]1[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=[C:6]([O:9][CH3:10])[CH2:7][N:8]=1.C([Li])CCC.Br[CH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2>O1CCCC1>[CH3:10][O:9][C:6]1[C@H:7]([CH2:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)[N:8]=[C:3]([O:2][CH3:1])[C@@H:4]([CH:11]([CH3:13])[CH3:12])[N:5]=1
Reactant: BrCc1ccc2ncccc2c1
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1Cc1ccc2ncccc2c1
Reaction time: 0.5 h

Procedure:
To a cooled solution (−70° C.) of (2R)-3,6-dimethoxy-2-(propan-2-yl)-2,5-dihydropyrazine (25.8 g, 140 mmol, 2 eq.) in tetrahydrofuran (200 mL) was added dropwise n-butyllithium (2.5 M, 64.4 mL, 161 mmol 2.3 eq.) and then stirred for 30 minutes. A solution of #210 (15.4 g, 70 mmol, 1 eq.) in tetrahydrofuran (150 mL) was added dropwise at −65° C. and then the solution was stirred for 2 hours at this temperature. The reaction was quenched by saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (Gradient: 10 to 16% ethyl acetate in petroleum ether) to afford #211 (7.3 g, 32%, over two steps) as yellow solid. LC-MS (Protocol Z): m/z 326.2[M+H+], retention time=0.88 minutes.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][O:5][N:6]=[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[N:16][OH:17].[OH-].[K+]>O>[CH3:4][O:5][N:6]=[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]1=[N:16][O:17][CH2:1][CH2:2][OH:3]
Reactant: C1CO1
Reactant: CON=C1C(=NO)Oc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CON=C1C(=NOCCO)Oc2ccccc21
Temperature: 5 °C
Reaction time: 2.75 h
Yield: 60.5 %

Procedure:
264.3 g (6.0 mol) of ethylene oxide are passed into a solution of 192.2 g (1.0 mol) of benzofuran-2,3-dione 3-(O-methyl oxime) 2-oxime in 2 l of water at 20° C. in the course of 85 minutes. The solution is cooled to 5° C. and 70 g (1.06 mol) of potassium hydroxide lozenges are added, the temperature rising to 10° C. The mixture is stirred for a further 165 minutes without further cooling and the precipitate formed is filtered off with suction, washed with 500 ml of ice-water in portions and dried in a vacuum drying cabinet at 40° C. 143.0 g (61% of theory) of benzofuran-2,3-dione 2-[O-(2hydroxy-ethyl) oxime]-3-(O-methyl oxime) are obtained as a mixture of two stereoisomers.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.[H][H]>[C].[Pd].CC(O)C>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:12])[CH2:3]1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CC1CC(C)(C)c2cccc(N)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Into a reaction vessel were charged 6.00 parts by weight of (3R)-1,1,3-trimethyl-4-aminoindane (optical purity of 96.5% ee), 0.81 parts by weight of 5% palladium-carbon (STD-type, manufactured by N. E. Chemcat Corporation), and 12 parts by weight of 2-propanol, thereby obtaining a mixture. The reaction vessel was sealed and the gas inside the reaction vessel was replaced with nitrogen. While stirring the mixture at room temperature, to the reaction vessel was charged hydrogen until the internal pressure of hydrogen in the reaction vessel reached 0.5 MPa. After 15 minutes, the gas in the reaction vessel was replaced with nitrogen, and the mixture was stirred at an internal temperature of 150° C. and an internal pressure of 0.8 MPa for 7 hours to obtain a reaction mixture. The obtained reaction mixture was cooled and filtered. The obtained solid was washed with 20 parts by weight of 2-propanol. The washing liquid recovered after washing and the filtrate obtained by filtration were combined. The combined mixture was concentrated under reduced pressure to obtain 5.82 parts by weight of 1,1,3-trimethyl-4-aminoindane. The obtained 1,1,3-trimethyl-4-aminoindane had an optical purity of 1.2% ee and a recovery rate of 97.0%.