Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].NC(OCC)=O.[C:17](Cl)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[C:17]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: CCOC(N)=O
Product: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
A number of different blocking agents can be used to block the amine group on the glutamic acid. These blocking agents include acyl-type protecting groups, urethan protecting groups, alkyl-type protecting groups, and arylidene-type protecting groups. Alternatively, rather than using blocking agents, the amine group can be protonated to block its functionality. Preferably, blocking of the glutamic acid is achieved by reacting it with carbobenzoxy chloride in an aqueous alkaline solution to form N-carbobenzoxy glutamic acid, which is commonly referred to as Z-glutamic acid. This reaction is inexpensive and provides about a 90% yield of Z-glutamic acid. Alternatively, Z-glutamic acid can be obtained from Aldrich Chemical Company, 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233. Z-glutamic acid has the following structure:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:25][NH:26]C(OC(C)(C)C)=O)[C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[C:21]([O:23][CH3:24])=[O:22])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH2:26][CH2:25][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[C:21]([O:23][CH3:24])=[O:22])=[O:14]
Reactant: COC(=O)[C@H]1CCCCN1C(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1CCCCN1C(=O)[C@H](CN)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a round bottom flask was added (R)-methyl 1-((S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propanoyl)piperidine-2-carboxylate (1.80 gm, 3.88 mmol), DCM (5 mL) and TFA (5 mL). The reaction mixture was stirred at rt for 1 hr. The reaction mixture was then concentrated and dried under vacuum for 3 hr to afford (R)-methyl 1-((S)-3-amino-2-(benzyloxycarbonylamino)propanoyl)piperidine-2-carboxylate trifluoroacetate (1.87 g, 3.92 mmol, 100% yield) as a colorless oil. Anal. Calcd. for C18H25N3O5 m/z 363.4. found: 364.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:27][C:28](O)=[O:29])([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[O:18][C:17]3=[O:31])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:27][CH2:28][OH:29])([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[O:18][C:17]3=[O:31])[CH3:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CC(=O)O)(c2cccs2)OC1=O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCO)(c2cccs2)OC1=O
Yield: 40 %

Procedure:
A solution of 2-((S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-(thiophen-2-yl)-1,3-oxazinan-6-yl)acetic acid (218 mg, 0.5 mmol) in THF anhydrous (10 mL) was added BH3 (3.0 mL) at 0 and then stirred at reflux for 2 h. Then the reaction mixture quenched by water and separated, extracted with EtOAc twice. The organic phases was dried over Na2SO4, filtered and concentrated to afford the residue, which was purified by TLC to give (S)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-6-(2-hydroxyethyl)-6-(thiophen-2-yl)-1,3-oxazinan-2-one (85 mg, 40%). LC-MS Method 3 tR=1.35, min, m/z=426, 448; 1H NMR (CD3OD): 1.50 (m, 3H), 2.15 (m, 2H), 2.30 (m, 1H), 2.40 (m, 1H), 2.60 (m, 1H), 3.15 (m, 1H), 3.45 (m, 1H), 3.70 (m, 1H), 5.60 (m, 1H), 6.90 (m, 1H), 7.00 (m, 1H), 7.10 (m, 4H), 7.35 (m, 3H), 7.55 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[C:11](=[O:36])[N:12]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)=[O:4].[CH3:37][C:38]([CH3:54])([CH3:53])[C:39]([O:41][NH:42][C:43]([CH:45]([CH2:49][CH:50]([CH3:52])[CH3:51])[C:46](O)=[O:47])=[O:44])=[O:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:46](=[O:47])[CH:45]([C:43](=[O:44])[NH:42][O:41][C:39](=[O:40])[C:38]([CH3:53])([CH3:37])[CH3:54])[CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:7][N:6]1[C:11](=[O:36])[N:12]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)=[O:4]
Reactant: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)N1C[C@@H](N)C[C@H]1C(=O)OC
Reactant: CC(C)CC(C(=O)O)C(=O)NOC(=O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)N1C[C@@H](NC(=O)C(CC(C)C)C(=O)NOC(=O)C(C)(C)C)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
(2S,4S)-4-Amino-1-{pentyl-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]carbamoyl}-pyrrolidine-2-carboxylic acid methyl ester (2.0 g, 3.0 mmol) and 2-(2,2-dimethyl-propionyloxycarbamoyl)-4-methylpentanoic acid (1.2 g, 1.4 equiv) were dissolved in DMF (20 mL). DIPEA (2 mL, 3.5 equiv) was added, followed by HATU (1.4 g, 1.2 equiv). The mixture was stirred for 16 hours at room temperature and then partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous phase was re-extracted with EtOAc (100 mL). The combined organics were washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, and evaporated to afford the title compound (2.2 g, 3 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C38H52N8O7, 732.9. found 733.5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10].O>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(Cl)ccn1
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1nccc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
To a solution of 2-amino-4-chloropyridine (5.00 g, 0.0389 mol) in sulfuric acid (40.8 mL) with stirring at 0° C. was added a solution of nitric acid (2.72 g, 0.0389 mol) and sulfuric acid (3.89 g, 0.0389 mol). The mixture was stirred (1 hr) then poured into 200 g ice and 100 ml water. The solid was filtered and collected. The solution was neutralized with 28% NH3 in water to pH ˜5. The solution was extracted with EtOAc (3×300 ml). The solid also was dissolved in EtOAc and neutralized with 28% NH3 in H2O. The organic layers were combined, concentrated with 30 g silica gel, and purified by flash chromatography (20 to 60% EtOAc/hexanes) to afford the title compound (2.40 g, 36%) as a yellow solid.
Reaction SMILES: [O:1]1[C:5]2[C:6](=O)[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1.[OH-].[Na+].P(Cl)(Cl)([Cl:36])=O>>[Cl:36][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2][O:1][C:5]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2ccoc12
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Clc1nccc2ccoc12

Procedure:
A solution of 6-H-furo[2,3-c]pyridin-7-one (1.0 g) in phosphorous oxychloride (10 ml) was stirred at 110° C. for 30 minutes under dry nitrogen. The mixture was cooled, poured onto ice/water (50 ml) and basified to pH10 with 2N sodium hydroxide solution. The mixture was extracted with ether (3×50 ml), the combined extracts dried over sodium sulfate and filtered. Removal of the solvent in vacuo gave the title compound (1.0 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])COC)(=[O:13])=[O:12])=[C:7]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:18]2[CH:22]=[CH:21][S:20][C:19]=2[C:23]([O:25][CH3:26])=[O:24])(=[O:13])=[O:12])=[C:7]([CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1CCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1CCc1ccccc1
Temperature: 75 °C
Yield: 54.6 %

Procedure:
To a solution of 41 (143.0 mg; 0.32 mmol) in tetrahydrofuran (6 mL) was added aqueous hydrochloric acid (6 mL; 12 mmol; 2N). The reaction mixture was heated at 75° C. for 4 hours, and then additional aqueous hydrochloric acid (3.0 mL; 6N) was added and the reaction mixture further heated at reflux for 4-5 hours. The reaction mixture was allowed to cool to room temperature and then extracted with ethyl acetate (15 mL). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield an orange oil residue which was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 40% v/v over 400 mL gradient elution) to yield the title product as a clear oil (80.0 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>>[OH:31][CH2:30][CH2:29][CH2:28][NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:23])[F:21])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26]
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Reactant: NCCCO
Product: N#Cc1ccc2c(c1)cc(C(=O)NCCCO)n2Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 3-amino-1-propanol in a manner similar to that described in Example 11.
Reaction SMILES: C([NH:3][C@@H:4]1[C:27](=[O:28])[N:6]2[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]3[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=3)[CH2:9][S:10][C@H:5]12)=O.[ClH:29].C(OCC)(=O)C>C(O)=O>[ClH:29].[ClH:29].[NH2:3][C@@H:4]1[C:27](=[O:28])[N:6]2[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]3[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=3)[CH2:9][S:10][C@H:5]12
Reactant: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC=O)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Product: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a cooled solution of 7β-formamido-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl) methyl}ammonio]methyl-3-cephem-4-carboxylate (4.084 g) in formic acid (8.1 ml) was added dropwise conc. hydrochloric acid (2.5 ml). The mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was added dropwise to ethyl acetate (400 ml) and the supernatant was decanted. The residual oil was dissolved in methanol (50 ml) and the solution was poured into ethyl acetate (600 ml). The resulting precipitates were collected by filtration, washed with ethyl acetate and diisopropyl ether and dried in vacuo. The powder was dissolved in cold water (28 ml) and chromatographed on Diaion HP-20 (28 ml) at 5° C., and the elution was carried out with water. To the eluate (30 ml) was added dropwise cold isopropyl alcohol (19 ml) under cooling and the mixture was stirred at 5° C. for an hour. The resultant crystal was collected by filtration washed with a cooled mixture of isopropyl alcohol and water (10:1) and cold isopropyl alcohol, and dried in vacuo to give 7β-amino-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4carboxylate dihydrochloride (728 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1.[O-:23][S:24]([O-:26])=[O:25].[Na+:27].[Na+].CCO>O>[Na+:27].[CH2:16]([O:15][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:24]([O-:26])(=[O:25])=[O:23])[CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCCCCCCc1cccc(OCc2ccccc2)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCCCc1cccc(OCc2ccccc2)c1

Procedure:
Following the procedure described for 11.1 using 10.2 (0.4 g, 1.1 mmol), Na2SO3 (0.19 g, 1.5 mmol) and EtOH (8 mL)/H2O (4 ml) mixture, the crude 11.2 was obtained and used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[CH3:31][C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: Cc1cccc(B(O)O)c1C
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cccc(-c2ccccc2SCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1C
Yield: 16 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.123 mmol) in DME (4 ml)/2M Na2CO3 (0.645 ml, 1.29 mmoles) was treated with 2,3-dimethylphenylboronic acid (36.9 mg, 0.246 mmol) and Pd[PPh3]4 (70.2 mg, 0.061 mmol) for 65 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient. Further purification by RP HPLC afforded the product (8.5 mg, 16.4%). MS m/e 433.24 (M+H+)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:19]([CH3:28])[C:20](=[O:27])[N:21]([CH3:26])[C:22](=[O:25])[C:23]=1[CH3:24]>>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:19]([CH3:28])[C:20](=[O:27])[N:21]([CH3:26])[C:22](=[O:25])[C:23]=1[CH3:24])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Cc1c(NCCCCN)n(C)c(=O)n(C)c1=O
Product: Cc1c(NCCCCNCC(O)COc2ccccc2)n(C)c(=O)n(C)c1=O
Reaction time: 48 h

Procedure:
4.5 g. Phenyl glycidyl ether and 12.0 g. 4-(4-aminobutylamino)-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione are mixed and left to stand for 48 hours at ambient temperature. The reaction mixture is then separated chromatographically and salt formation is carried out in the manner described in Example 29. There are obtained 2.6 g. (19% of theory) of the desired product in the form of colorless crystals; m.p. 148°-150° C., with bubble formation.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH3:13][NH:14][O:15][CH3:16].[Br:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)[CH:21]=[CH:20][C:19]=1[CH2:29][C:30]([OH:32])=O.C1C=CC2N(O)N=NC=2C=1>C(#N)C.C(N(CC)CC)C>[Br:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH:26]2[CH2:27][CH2:28]2)[CH:21]=[CH:20][C:19]=1[CH2:29][C:30]([N:14]([O:15][CH3:16])[CH3:13])=[O:32]
Reactant: O=C(O)Cc1ccc(OCC2CC2)cc1Br
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CON(C)C(=O)Cc1ccc(OCC2CC2)cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.6 %

Procedure:
WSC (4.89 g) was added to a solution of N,O-dimethylhydroxyamine hydrochloride (2.49 g), [2-bromo-4-(cyclopropylmethoxy)phenyl]acetic acid (4.85 g), HOBt (3.91 g) and triethylamine (3.56 mL) in acetonitrile (100 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with 1M hydrochloric acid, water, saturated sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, passed through an NH silica gel pad, and the solvent was evaporated under reduced pressure to give the title compound (4.78 g). MS (ESI+): [M+H]+ 328.0.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11](#[N:15])[CH2:12][C:13]#[N:14].C(O)C.[BH4-].[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH2:4][CH:12]([C:11]#[N:15])[C:13]#[N:14]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: N#CCC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC(C#N)Cc1ccc(Br)cc1F
Yield: 95.7 %

Procedure:
Using 1.02 g of 2-fluoro-4-bromobenzaldehyde, 0.33 g of malononitrile, 8 ml of ethanol, 1.5 ml of water and 57 mg of sodium borohydride, and according to the process described in the Reference Production Example 19, there was obtained 1.21 g of (2-fluoro-4-bromobenzyl)malononitrile (the intermediate (29)).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52]CC1C=CC=CC=1)[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=2[F:45])[CH2:34][CH2:33]1)=[O:17])C1C=CC=CC=1>[Pd].O1CCCC1>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][OH:52])[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C@H:32]1[CH2:33][CH2:34][C@H:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=2[F:45])[CH2:36][CH2:37]1)=[O:17]
Reactant: O=C(OCCCCCCCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(OCCCCCCCCCCCCC[C@H]1CC[C@H](c2cccc(F)c2F)CC1)C(CCCCCCO)CCCCCCO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
First, 5.3 g of 13-[trans-4-(2,3-difluorophenyl)cyclohexyl]tridecyl 2,2-bis(6-benzyloxyhexyl)acetate, 1.7 g of 10% Pd-C, and 100 ml of tetrahydrofuran were placed in a 300 ml autoclave. The mixture was stirred at room temperature for 2 days under a hydrogen pressure of 10 kg/cm2. A catalyst was filtered away and a filtrate was concentrated. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=7/3) to obtain 4.1 g of 13-[trans-4-(2,3-difluorophenyl)cyclohexyl]tridecyl 2,2-bis(6-hydroxyhexyl)acetate (Y: 98%). The compound thus obtained had a purity of 99% by HPLC.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[OH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=2[O:31][CH2:32][CH:33]2[CH2:35][O:34]2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1>CO.O1CCCC1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=2[O:31][CH2:32][CH:33]([OH:34])[CH2:35][N:12]2[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: COc1cc(CCCCc2ccccc2OCC2CO2)cc(OC)c1
Reactant: OC1CCNCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CCCCc2ccccc2OCC(O)CN2CCC(O)CC2)cc(OC)c1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
561 mg of potassium t-butoxide were added, whilst ice-cooling, to a solution of 688 mg of 4-hydroxypiperidine hydrochloride in methanol, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, the residue was mixed with tetrahydrofuran, and insoluble materials were filtered off. The filtrate was concentrated by evaporation under reduced pressure, to give a colorless oil, which was dissolved in 20 ml of tetrahydrofuran. 1.02 g of 2-{2-[4-(3,5-dimethoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in Example 11(a)] were added to the resulting solution, and the mixture was stirred at 60° C. for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of methylene chloride and methanol as the eluent, to give 1.26 g (yield 95%) of the title compound as a colorless oil.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].C(C(C([O-])=O)C([O-])=O)C.[K+].[K+].C(N1C=CN=C1)(N1C=CN=C1)=O.[Si:27]([O:34][C:35]1[CH:36]=[C:37](C(O)=O)[C:38]2[NH:42][C:41]([CH2:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[N:40][C:39]=2[CH:51]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[Mg+2].[C:56]([O:62][CH2:63][CH3:64])(=[O:61])[CH2:57][C:58]([O-])=[O:59].C(OC(=O)CC([O-])=O)C.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1.C(#N)C.C(N(CC)CC)C>[Si:27]([O:34][C:35]1[CH:36]=[C:37]([C:58](=[O:59])[CH2:57][C:56]([O:62][CH2:63][CH3:64])=[O:61])[C:38]2[NH:42][C:41]([CH2:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[N:40][C:39]=2[CH:51]=1)([C:30]([CH3:32])([CH3:33])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C(=O)O)c2[nH]c(CCc3ccccc3)nc2c1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CCC(C(=O)[O-])C(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cc(O[Si](C)(C)C(C)(C)C)cc2nc(CCc3ccccc3)[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Triethylamine (2.65 mL) and magnesium chloride (2.16 g) were added to dry acetonitrile (37.5 mL) suspension of potassium ethylmalonate (3.23 g), and the mixture was vigorously stirred at room temperature for 16 hours under in an atmosphere of argon. Next, a catalytically effective amount of N,N-dimethylaminopyridine and 1,1′-carbonyldiimidazole (1.35 g) were added to anhydrous tetrahydrofuran (30 mL) solution of 6-t-butyldimethylsilyloxy-2-(2-phenylethyl)benzimidazole-4-carboxylic acid (3.0 g) obtained in Reference Example 23, and the mixture was stirred for 1 hour under an atmosphere of argon. This was diluted to the previously prepared suspension of ethyl malonate magnesium salt while cooling in an ice bath, and the mixture was stirred at room temperature for 2 hours. This was diluted with ice water (50 mL) and, while cooling in an ice bath, adjusted to pH 1 with 4 N hydrochloric acid. While cooling in an ice bath, this was adjusted to pH 8 to 9 with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) and the desired fraction was concentrated to obtain the title compound as colorless oil (3.44 g).