Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=3[CH3:22])[CH2:31][CH2:32]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Cc1cccc(N2CCNCC2)c1C
Product: CCc1cc(NC(=O)N2CCN(c3cccc(C)c3C)CC2)c(OC)nc1C
Yield: 82 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2,3-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7].[Br:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCCCCC>[Br:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1/[CH:4]=[CH:5]/[C:6]([O:8][CH3:9])=[O:7]
Reactant: BrCCCBr
Reactant: COC(=O)C=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: COC(=O)/C=C/c1ccccc1OCCCBr
Yield: 89.4 %

Procedure:
To a solution of methyl 2-hydroxycinnamate (1.31 g; 7.33 mmol) in 50 ml acetone was added 1,3-dibromopropane (1.50 ml; 14.8 mmol) and K2CO3 (4.36 g; 13.4 mmol). The mixture was heated to reflux for 12 h, cooled to r.t, diluted with hexane (50 ml), filtered and finally concentrated to afford the title product (1.96 g; 50% pure), which was used as such in the next step.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH2:6]([C:8]1[C:13]([I:14])=[C:12](O)[CH:11]=[CH:10][N:9]=1)[CH3:7].CCN(CC)CC>CC#N>[Cl:3][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:6][CH3:7])[C:13]=1[I:14]
Reactant: CCc1nccc(O)c1I
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1nccc(Cl)c1I
Temperature: 60 °C

Procedure:
A solution of 165.1 g (1.08 mol) POCl3 in 100 mL CH3CN is added dropwise to a solution of 27.1 g (108 mmol) 2-ethyl-3-iodo-pyridin-4-ol in 150 mL CH3CN at RT. Then Et3N (21.9 g, 216 mmol) is added slowly over 20 min before the reaction mixture is heated to 60° C. for 3 h. The reaction mixture is evaporated in vaccuo to afford an oil. This crude oil is poured into the crushed ice, and the aqueous phase is extracted with petroleum ether/EtOAc (3×, 200 mL; 10:1). The organic phase is collected, dried over anhydrous Na2SO4. The solvent is removed in vacuo to afford desired product. Yield: 22.0 g (76%).
Reaction SMILES: [CH:1]([C:4]1[C:9](S(C2C=CC(C)=CC=2)(=O)=O)=[CH:8][C:7]([C:20]2[N:21]=[CH:22][S:23][CH:24]=2)=[C:6]([O:25][CH3:26])[CH:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=[O:28].[K+].[K+]>CO>[CH:1]([C:4]1[CH:5]=[C:6]([O:25][CH3:26])[C:7]([C:20]2[N:21]=[CH:22][S:23][CH:24]=2)=[CH:8][C:9]=1[OH:28])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1-c1cscn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(C(C)C)c(O)cc1-c1cscn1

Procedure:
A mixture of 4-[4-Isopropyl-2-methoxy-5-(toluene4-sulfonyl)-phenyl]-thiazole (1.0 g, 2.27 mmol) and K2CO3 (1.6 g, 11.34 mmol) in anhydrous MeOH (10 ml) was refluxed for 8 hrs. Solvent was removed in vacuo and the residue was partitioned between methylene chloride and water. The combined organic extract was dried over Na2SO4, filtered, and concentrated to give 2-Isopropyl-4-methoxy-5-thiazol-4-yl-phenol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([CH3:25])([CH3:24])[C:21](O)=[O:22])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:35]1[C:39]2C=CC=CC=2N=N1.CN1CC[O:48][CH2:47]C1.CNOC.Cl.CN(C)CCCN=C=NCC>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:21](=[O:22])[NH:35][CH2:39][O:48][CH3:47])([CH3:25])[CH3:24])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[CH:31]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2CCNC(=O)OC(C)(C)C)c1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CNOC
Agent: Cl
Product: COCNC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 2-[3-(2-tert-butoxycarbonylamino-ethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid (1.23 g in 15 mL N,N-dimethylformamide) at 0° C. was added 608 mg of 1-hydroxybenzotriazole (HOBt), 0.48 mL 4-methylmorpholine and 352 mg of N,O-dimethylhydroxylamine hydrochlorideand the mixture stirred at low temperature. After 15 minutes, 826 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) were added and the mixture warmed to room temperature. The reaction was quenched after 3.5 days by concentration in vacuo, resuspending in ethyl acetate and washing sequentially with water, 0.3N sodium bisulfate, water, saturated sodium bicarbonate and brine. The organic portion was dried over sodium sulfate and the concentrate purified by flash chromatography on silica gel (hexane:ethyl acetate, 3:1) to give the title compound (905 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([I:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4](Cl)=[N:5][C:6]1[C:11]([F:12])=[CH:10][N:9]=[CH:8][C:7]=1F.NC(N)=[S:23].N1C=CC=CC=1.CCN(CC)CC>C(O)(C)C>[Cl:1][C:2]1[CH:18]=[C:17]([I:19])[CH:16]=[C:15]([Cl:20])[C:3]=1[C:4]1[S:23][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([F:12])[C:6]=2[N:5]=1
Reactant: Fc1cncc(F)c1N=C(Cl)c1c(Cl)cc(I)cc1Cl
Reactant: NC(N)=S
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Fc1cncc2sc(-c3c(Cl)cc(I)cc3Cl)nc12
Temperature: 70 °C
Yield: 65.7 %

Procedure:
A suspension of 2,6-dichloro-N-(3,5-difluoropyridin-4-yl)-4-iodobenzimidoyl chloride (8.8 g, 19.7 mmol), thiourea (6.0 g, 78.8 mol) and pyridine (5.4 mL, 66.9 mmol) in isopropanol (80 mL), under a nitrogen atmosphere, was heated under reflux for 6 hours. After this time, the reaction mixture was cooled to 70° C. and Et3N (16.4 mL, 118.1 mmol) was added over 5 minutes and then the resultant mixture was heated under reflux for a further 18 hours. Upon cooling to room temperature, the precipitate obtained was collected by filtration and the filtrate was then partitioned between water and EtOAc. The aqueous phase was further extracted with EtOAc (×2) and the combined organic layers were dried (MgSO4), filtered and concentrated to dryness to afford the title compound as an off-white solid (5.5 g, 66% yield). LCMS (Method D): RT=4.22 min, m/z: 426 [M+H+].
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH3:25])[C:23]=1Br)=[O:18])[CH3:15].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(N(C)C)=O>[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH3:25])[C:23]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18])[CH3:15]
Reactant: CCOC(=O)c1cnn(C)c1Br
Reactant: Oc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnn(C)c1Oc1ccccc1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
Phenol (30.29 g; 321.80 mmol) was dissolved in DMA and K2CO3 (88.95 g; 643.60 mmol) was added portion wise. It was stirred for 10 minutes, then 5-Bromo-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (50.0 g; 214.53 mmol) was dropped to the reaction mixture and heated up to 140° C. for 16 hours. A 10% citric acid solution was added and extracted with DCM. The organic layer was washed with sodium bicarbonate and brine, then dried and purified through column chromatography.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CN=C1>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CN(C(=O)OCc2ccccc2)C1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
Subsequently, to a solution of 1-benzyloxycarbonyl-3-hydroxyazetidine (1.91 g, 9.22 mmol) in dimethylformamide (96 ml) were added t-butyldiphenylsilyl chloride (2.88 ml, 11.1 mmol) and imidazole (756 mg, 11.1 mmol) in an ice bath. The resulting mixture was stirred in the ice bath for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1) as the eluant to afford 1-benzyloxycarbonyl-3-t-butyldiphenylsilyloxyazetidine (4.04 g, yield 98%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:17].[OH-].[Ca+2].[OH-]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:11])([CH3:9])[CH3:10])=[N+:6]([O-:17])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(O)c1ccc(Br)cn1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(O)c1ccc(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from Step 1 in methylene chloride (5 ml/mmol) at room temperature was added m-chloroperoxybenzoic acid 70% (1.1 eq) and the resulting mixture was stirred at room temperature for 18 hours. An excess of calcium hydroxide was added and after 5 minutes the mixture was filtered through a bed of celite. The crude product from evaporation of the filtrate was chromatographed on silica gel eluting with 80% ethyl acetate in hexane and the 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine N-oxide compound was obtained as a white solid.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[Cl:9][C:10]1[CH:29]=[CH:28][C:13]2[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:23]([CH2:25][C:26]#[CH:27])[NH2:24])=[N:15][O:16][C:12]=2[CH:11]=1>CO>[ClH:9].[O:16]1[C:12]2[CH:11]=[CH:10][CH:29]=[CH:28][C:13]=2[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C@@H:23]([CH2:25][CH:26]=[CH2:27])[NH2:24])=[N:15]1
Reactant: C#CCC(N)c1ccccc1-c1noc2cc(Cl)ccc12
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: C=CC[C@@H](N)c1ccccc1-c1noc2ccccc12
Product: Cl

Procedure:
(+)-2-(6-chloro-1,2-benzisoxazol-3-yl)-a-2-propynyl-benzenemethanamine (E)-butenedioate (2:1 salt), melting at 176-179° C., a (c=0.5 in methanol) +20.7,
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.CCN(CC)CC.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].O>C(Cl)Cl>[C:24]([NH:1][CH2:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)(=[O:27])[CH:25]=[CH2:26]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)NCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
To a stirred mixture of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (1.0 g, 4.38 mmol) in DCM (20 mL) at 0° C., Et3N (1.33 g, 13.14 mmol) was added and the resulting mixture was stirred at 0° C. for 5 min. To this mixture, a solution of acryloyl chloride (0.39 g, 4.38 mmol) in DCM (5 mL) was added dropwise. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water (20 mL) and extracted with DCM (30 mL×3). The combined organic layer was washed with brine (15 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-50% ethyl acetate/dichloroethane) to afford the desired product (0.6 g, 50% yield) as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:25])[CH:16]([CH2:21][CH2:22][CH2:23]I)[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:25])[CH:16]([CH2:21][CH2:22][CH2:23][S:33][C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: Sc1ccc(Cl)cc1
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCI)C(=O)OC)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCSc2ccc(Cl)cc2)C(=O)OC)cc1
Yield: 80.6 %

Procedure:
A solution of 0.958 g (2.0 mmol) of methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-5-iodopentanoate, 0.35 g (2.4 mmol) of 4-chlorobenzenethiol, and 0.323 g of diisopropylethylamine in 50 ml of isopropyl alcohol was stirred at room temperature for 18 hours. Evaporation of solvent gave 0.8 g of methyl 2-[{[4-(2-butynyloxy)-phenyl]sulfonyl}-(methyl)amino]-5-[(4-chlorophenyl)-sulfanyl]-pentanoate as colorless crystals, mp 88-89° C., Electrospray Mass Spec 496.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Reactant: COc1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4ccccc4F)noc3N)CC2)c1
Yield: 76.6 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (558 mg, 1.41 mmol, 77%) was obtained.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=2)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[OH-].[Na+]>C(O)C.C1COCC1.O>[C:1]([C:4]1[C:5]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=2)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][C:16]([CH3:23])([CH3:22])[C:17]([OH:19])=[O:18])=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: CCOC(=O)C(C)(C)NC(=O)N1CCn2nc(-c3ccc(F)c(Cl)c3)c(C(N)=O)c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(NC(=O)N1CCn2nc(-c3ccc(F)c(Cl)c3)c(C(N)=O)c2C1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of Intermediate 213A (500 mg, 1.106 mmol) in ethanol (20 mL) and THF (20 mL) was added a solution of NaOH (89 mg, 2.213 mmol) in water (10 mL) and the reaction mixture was stirred at RT for 8 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude product was dissolved in water and the pH of solution was adjusted to 4 using a 1.5N aqueous solution of HCl which was then stirred for 10 min. The precipitate was filtered, dried and triturated with diethyl ether to afford Intermediate 213B as pale brown solid (400 mg, 85%). MS(ES): m/z=424 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (s, 1H), 7.89-7.84 (m, 1H), 7.73-7.67 (m, 1H), 7.50-7.44 (m, 1H), 7.35 (s, 1H), 7.20 (br. s., 1H), 6.93 (s, 1H), 4.74 (s, 2H), 4.16-4.10 (m, 2H), 3.85 (d, J=5.5 Hz, 2H), 1.38 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22]O>>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: OCc1cccs1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OCc1cccs1

Procedure:
Following General Procedure C above, and using N-(3chlorophenylacetyl alanine (from Example D above) and 2-thiophenemethanol (Aldrich) the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.[C:22]([N:28]=[C:29]=[O:30])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[C:22]([NH:28][C:29](=[O:30])[O:1][CH2:2][C:3]1[N:4]([CH2:20][CH3:21])[C:5]([S:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)=[C:6]([CH:8]([CH3:9])[CH3:10])[N:7]=1)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CCn1c(CO)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)C(=O)N=C=O
Solvent: C1CCOC1
Product: CCn1c(COC(=O)NC(=O)C(C)(C)C)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of the compound 19 (200 mg, 0.580 mmol) in tetrahydrofuran (1 mL) under ice-cooling was added pivaloyl isocyanate (5 eq.), and stirred at the same temperature for 1 hour. After removing condenser, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and phosphate buffer (pH 7.0). The organic layer was separated, washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluate: hexane - ether (2:1)) to give the compound 81 (227 mg, 83%) as crystals. Mp. 157-159° C. Rf 0.31 (1:2 EtOAc-hexane).
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1F)[C:24]#[N:25].F[C:31](F)(F)[C:32](O)=O>ClCCl>[Cl:20][C:21]1[CH:22]=[C:23]([C:24]#[N:25])[CH:26]=[CH:27][C:28]=1[N:18]([CH2:27][CH2:28][CH2:21][CH2:22][CH2:23][CH2:31][CH3:32])[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:19])[S:12][CH:13]=1
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ccc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 7 and 3-chloro-4-fluorobenzonitrile as starting materials and by operations similar to those of Example 265-1 and Example 265-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.
Reaction SMILES: [C:1]([O-])([O-])=[O:2].[Na+].[Na+].[CH:7]([C:9]1[S:13][C:12](B(O)O)=[CH:11][CH:10]=1)=O.IC1[CH:40]=[CH:39][C:21]([CH2:22][N:23]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([C:10]1[CH:11]=[CH:12][S:13][C:9]=1[C:7]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:20][CH:19]=1)=[O:2]
Reactant: CCOC(=O)CCCCCCN(Cc1ccc(I)cc1)S(C)(=O)=O
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCCCN(Cc1ccc(-c2sccc2C=O)cc1)S(C)(=O)=O

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (91 mg, 0.08 mmol), Na2CO3 (0.87 mL, 1M) and 5-formyl-2-thiopheneboronic Acid (247 mg, 1.58 mmol) were added to a solution of ethyl 7-{[4-iodobenzyl]-methanesulfonyl-amino}-heptanoate (371 mg, 0.79 mmol) in toluene (33 mL) and EtOH (6.5 mL). The reaction mixture was heated at reflux for 3 h. The solution was diluted with EtOAc and the organic solution was washed with water (2× followed by brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified via radial chromatography (25% EtOAc/hexanes to 50% EtOAc/hexanes) to afford the title compound of Step A (75 mg). 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.44-7.60 (m, 5H), 7.21-7.31 (m, 1H), 4.45 (s, 2H), 4.10 (q, 2H), 3.20 (t, 2H), 2.90 (s, 3H), 2.25 (t, 3H), 1.58 (m, 4H), 1.35 (m, 7H); MS 452 (M+).
Reaction SMILES: [CH2:1]([C@H:4]1[O:6][C@@H:5]1[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH3:3].C(=O)([O-])O.[Na+].[C:16](#[N:18])[CH3:17]>>[CH3:17][C:16]1[O:6][C@H:5]([C:7]([O:9][CH3:10])=[O:8])[C@H:4]([CH2:1][CH2:2][CH3:3])[N:18]=1
Reactant: CC#N
Reactant: CCC[C@H]1O[C@@H]1C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC[C@@H]1N=C(C)O[C@@H]1C(=O)OC
Temperature: 5 °C
Reaction time: 6 h
Yield: 76 %

Procedure:
Acetonitrile (15 ml) was added to methyl (2S,3R)-3-propyl-2-oxiranecarboxylate (1.42 g, 9.8 mmol). The mixture was cooled to 5° C., and boron trifluoride diethyl ether complex (1.24 g, 11 mmol) was gradually added dropwise. The mixture was stirred at room temperature for 6 hours, and saturated aqueous solution of sodium hydrogencarbonate (20 ml) was added. The mixture was concentrated, and was extracted with ethyl acetate (30 ml). The organic layer was washed with water (10 ml×2), and the solvent was evaporated away under reduced pressure. The concentrated residue was purified by silica gel column chromatography to obtain the title compound as a colorless oil (1.23 g, yield: 76%).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH3:6]CCCCC.Cl.[CH3:13][C:14]([CH3:34])([CH3:33])[C:15]#[C:16]/[CH:17]=[CH:18]/[CH2:19][N:20]([CH2:22][C:23]1[CH:28]=[C:27](C)[CH:26]=[C:25]([C:30]([CH3:32])=[CH2:31])[CH:24]=1)[CH3:21]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[C:14]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:30]([CH2:32][CH3:6])=[CH2:31])[CH:24]=2)[CH3:21])=[CH:2][CH:1]=1)([CH3:13])([CH3:33])[CH3:34]
Reactant: CCCCCC
Reactant: C=C(C)c1cc(C)cc(CN(C)C/C=C/C#CC(C)(C)C)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: c1ccccc1
Product: C=C(CC)c1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
Methyl triphenylphosphonium bromide (0.18 g; 4.94×10−1 mmol) was added to benzene (7 ml). While the mixture was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.56 M: 0.32 ml; 5.00×10−1 mmol) was added dropwise. The mixture was stirred for 5 minutes, and Compound 19 (0.08 g; 2.47×10−1 mmol) in benzene (5 ml) was added dropwise thereto, followed by heating under reflux for 2 hours. The mixture was brought to room temperature, and the reaction was stopped by pouring the mixture into ice/water, followed by extraction with benzene (100 ml). The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to thereby yield 0.05 g of the target compound as colorless transparent oily matter (yield: 63%).