Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[Cl:26].[Cl:27]N1C(=O)CCC1=O.CCOCC.O>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[C:24]([Cl:27])[O:23][C:22]=1[Cl:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cc(Cl)oc1Cl
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 5-amino-4-(2-chlorofuran-3-yl)-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.15 g) in tetrahydrofuran (7 ml) was added N-chlorosuccinimide (0.048 g). The mixture was left at room temperature for 24 hours and then heated at 50° C. for 3 hours and then left at room temperature for 96 hours. The reaction mixture was poured into ether (25 ml) and water (25 ml). The organic layer was washed with water (25 ml), then dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (10 g) eluted with hexane:dichloromethane (50:50). Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 193-194° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:9][CH:8]=1)[C:4](O)=[O:5].C1C2C(=CC=CC=2)C=CC=1COC1C=C(C([O:49][N:50]=[CH:51]C(O)=O)CCCC2C=CC=CC=2)C=CC=1.N>>[OH:49][N:50]([CH3:51])[C:4](=[O:5])[CH:3]([O:2][CH3:1])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:9][CH:8]=1
Reactant: COC(C(=O)O)c1ccc(OCc2ccccn2)cc1
Reactant: O=C(O)C=NOC(CCCc1ccccc1)c1cccc(OCc2ccc3ccccc3c2)c1
Agent: N
Product: COC(C(=O)N(C)O)c1ccc(OCc2ccccn2)cc1

Procedure:
The desired material was prepared according to the procedures described in Example 5 substituting 2-methoxy-2-[4-(pyrid-2-ylmethoxy)phenyl]acetic acid for {[1-(3-[2-naphthylmethoxy]phenyl)-4-phenylbutyl]oximino}acetic acid. 1H NMR (DMSO-d6, 300 MHz) δ 3.07 (s, 3H), 3.12 (s, 3H), 5.18 (s, 2H), 5.23 (s, 1H), 7.0 (d, J=7Hz, 2H), 7.3 (d, J=7Hz, 2H), 7.34 (m, 1H), 7.5 (d, J=7Hz, 1H), 7.83 (dt, J=7Hz, 2Hz, 1H), 8.04 (m, 1H), 9.9 (bs, 1H). IR (CDCl3): 3620, 3500, 1640, 1610 cm-1. MS (DCI/NH3) m/e 301 (M+H)+. Analysis calcd for C16H18N2O4 ·0.5 H2O: C, 61.73; H, 6.15; N, 9.04. Found: C, 61.96; H, 5.77; N, 8.86. (In some examples O-acylated products were isolated.)
Reaction SMILES: C(O[C:4](=[O:22])[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[CH3:21])C.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C[Al](C)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4](=[O:22])[C:5]2[C:10]([C:11]([F:12])([F:14])[F:13])=[CH:9][C:8]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:7][C:6]=2[CH3:21])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1C(F)(F)F
Reactant: NCc1ccc(Cl)cc1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCOCC2)cc(C(F)(F)F)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 110 °C
Yield: 80 %

Procedure:
A mixture of 2-methyl-4-morpholin-4-yl-6-(trifluoromethyl)-benzoic acid ethyl ester (0.27 g, 0.85 mmol), 4-chlorobenzylamine (1.21 g, 8.51 mmol) and trimethylaluminium (2M in toluene) (2.98 ml, 5.96 mmol) in toluene (9 ml) is heated at 110° C. for 4 d. After completion of the reaction (monitored by TLC), a 2M aqueous solution of sodium hydroxide is carefully added and the mixture is extracted with ethyl acetate (2×15 ml). The combined organic layers are washed with 2M aqueous solution of sodium hydroxide (10 ml), brine (10 ml) and dried over sodium sulfate. The solvent is evaporated to get the crude product, which is purified by column chromatography (silica gel, 30% ethyl acetate/cyclohexane) to afford N-[(4-chlorophenyl)-methyl]-2-methyl-4-morpholin-4-yl-6-(trifluoromethyl)-benzamide (example 19) (0.28 g, 0.68 mmol, 80%). [M+H]+ 413.1.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].CC(O)=O.[CH2:19]([CH2:23][C:24](=O)[CH3:25])[C:20]([CH3:22])=O>C1CCCCC1.C(Cl)Cl>[C:11]([C:9]1[CH:8]=[CH:7][C:5]([N:6]2[C:24]([CH3:25])=[CH:23][CH:19]=[C:20]2[CH3:22])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(=O)CCC(C)=O
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 48.6 %

Procedure:
To a stirring solution of 2-nitro-4-tert-butylaniline (0.5 g, 2.57 mmol) in cyclohexane (10 mL) was added AcOH (00.1 mL) and acetonylacetone (0.299 g, 2.63 mmol) via syringe. The reaction mixture was heated at 120° C. for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temp., diluted with CH2Cl2 (10 mL) and sequentially washed with a 1N HCl solution (15 mL), a 1N NaOH solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting orange-brown solids were purified via column chromatography (60 g SiO2; gradient from 6% EtOAc/94% hexane to 25% EtOAc/75% hexane) to give 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole as an orange-yellow solid (0.34 g, 49%): TLC (15% EtOAc/85% hexane) Rf 0.67; 1H NMR (CDCl3) δ 1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7.62 (dd, 1H), 7.88 (d, J=2.4 Hz, 1H); CI-MS m/z 273 ((M+H)+, 50%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[C:20](Cl)(=O)C.[CH2:24]([N:26]1[C:38]2[CH:37]=[CH:36][C:35]([NH2:39])=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH3:25]>>[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([NH:39][C:35]1[CH:36]=[CH:37][C:38]2[N:26]([CH2:24][CH3:25])[C:27]3[C:32]([C:33]=2[CH:34]=1)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:19])(=[O:7])[CH3:20]
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)Cl
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCON=C1C[C@@H](C(=O)Nc2ccc3c(c2)c2ccccc2n3CC)N(C(C)=O)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, acetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 87% purity by LC/MS. MS(ESI+): m/z=407.2.
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:28]([S:30][C:31]1([CH2:42][CH2:43]O)[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([F:40])[CH:38]=2)[NH:33][C:32]1=[O:41])[CH3:29]>>[CH2:28]([S:30][C:31]1([CH2:42][CH2:43][N:14]2[CH2:15][CH2:16][N:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:13]2)[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([F:40])[CH:38]=2)[NH:33][C:32]1=[O:41])[CH3:29]
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: CCSC1(CCO)C(=O)Nc2ccc(F)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCSC1(CCN2CCN(c3cccc4ccccc34)CC2)C(=O)Nc2ccc(F)cc21

Procedure:
The product is obtained by following the procedure described under 1.3, starting with 31.6 g (0.148 mole) of 1-naphthylpiperazine and 30.5 g (0.074 mole) of 3-(ethylthio)-5-fluoro-3-(2-hydroxyethyl) -1,3-dihydro-2(2H)-indolone tosylate.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:12])[O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[N+:13]([O-])=O.[BH4-].[Na+]>CO.O.Cl[Ni]Cl>[NH2:13][C:3]1[CH:4]=[CH:5][C:6]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[N:7][C:2]=1[Br:1]
Reactant: COC(=O)Nc1ccc([N+](=O)[O-])c(Br)n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)Nc1ccc(N)c(Br)n1
Reaction time: 0.01 h
Yield: 97.5 %

Procedure:
To a solution of methyl 6-bromo-5-nitropyridin-2-ylcarbamate (700 mg, 2.5 mmol) in CH3OH (20 mL) was added NiCl2 (1.2 g, 5.1 mmol) and NaBH4 (300 mg, 7.6 mmol) successively at 0° C. The mixture was stirred for 20 seconds. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give methyl 5-amino-6-bromopyridin-2-ylcarbamate (600 mg, 96%). 1H NMR (400 MHz, CDCl3) □ 7.75 (d, J=8.4 Hz, 1H), 7.13 (brs, 1H), 7.09 (d, J=8.8 Hz, 1H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1.[CH2:24]([CH2:26][NH2:27])[OH:25].O>CN(C=O)C>[OH:25][CH2:24][CH2:26][NH:27][C:21]([C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:23]
Reactant: NCCO
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCO)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (200 mg, 0.64 mmol) in DMF (8 mL) was added 1,1-carbonyl-diimidazole (135 mg, 0.83 mmol) and the mixture was stirred for 4 h at room temperature. Ethanolamine (0.27 mL, 4.50 mmol) was added and stirring was continued for 1 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate (90 mL). The combined organic layers were washed with water (60 mL) and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 30:70) afforded the title compound (215 mg, 94%) as a white foam. MS: m/e=355.2 [M+H]+.
Reaction SMILES: [CH2:1]([C@:3]1([CH2:20][C:21](O)=[O:22])[C@@H:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)[CH3:2].CN1CCOCC1.ClC(OCC)=O.[CH2:37]([NH2:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O1CCCC1.C1C=CC=CC=1>[CH2:37]([NH:44][C:21](=[O:22])[CH2:20][C@@:3]1([CH2:1][CH3:2])[C@@H:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCc1ccccc1
Reactant: CC[C@@]1(CC(=O)O)CCCN2CCc3c([nH]c4ccccc34)[C@@H]21
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CC[C@@]1(CC(=O)NCc2ccccc2)CCCN2CCc3c([nH]c4ccccc34)[C@@H]21
Temperature: -5 °C
Yield: 44 %

Procedure:
3.12 g. (0.01 mole) of (-)-(1S,12bS)-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indol[2,3-a]quinolizin-1-yl-acetic acid are added to a solution containing 2.04 g. (0.02 moles) of N-methylmorpholine (redistilled from sodium) in 20 ml. of dry tetrahydrofuran while stirring under nitrogen, then the solution is cooled to -5° C. and 1.10 g. (0.01 mole) of ethyl chloroformate are rapidly dropped in while stirring vigorously and keeping the inner temperature at or lower than 0° C. The mixture is stirred at 0° C. for 30 minutes, then a mixture containing 1.18 g. (0.011 moles) of benzylamine in 10 ml of dry tetrahydrofuran is dropwise added at a temperature between -5° C. and 0° C. during 10 minutes. The mixture is stirred at 0° C. for 30 minutes and then during an additional stirring for 4 hours the temperature of the mixture is allowed to warm to room temperature. The mixture is evaporated on a rotating evaporator. After shaking thoroughly the residue with 50 ml. of dichloromethane and 20 ml. of water, the phases are separated. The dichloromethane solution is washed with 20 ml. of 5% sodium carbonate solution and then three times with 20 ml of water each, dried over anhydrous magnesium sulphate and evaporated. The residue which is the crude product, is purified by column chromatography on silica gel by using toluene containing 10% of diethylamine as eluant to give 1.89 g. (44% yield) of the title product which can further be purified by recrystallization from benzene, m.p. 179°-180° C.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[CH:4][C:5]([F:16])=[C:6]([C@:8]2([CH3:15])[CH2:13][CH2:12][S:11][C:10]([NH2:14])=[N:9]2)[CH:7]=1.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1.[C:27](=[O:30])([O-])[O-:28].[Cs+].[Cs+]>COCCOC.O.C(O)C.O.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>[C:6]([O:28][C:27](=[O:30])[NH:14][C:10]1[S:11][CH2:12][CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([C:22]3[CH:23]=[N:18][CH:19]=[N:20][CH:21]=3)[C:3]([F:17])=[CH:4][C:5]=2[F:16])([CH3:15])[N:9]=1)([CH3:8])([CH3:7])[CH3:5]
Reactant: C[C@@]1(c2cc(Br)c(F)cc2F)CCSC(N)=N1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(-c3cncnc3)c(F)cc2F)CCS1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67 %

Procedure:
To a 100° C. solution of (S)-4-(5-bromo-2,4-difluorophenyl)-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine (12.6 g, 29.9 mmol, 1 equiv) in 1,2-dimethoxyethane:water:ethanol (15:7:5, 300 mL) is added a pyrimidine-5-boronic acid (25 g, 203 mmoles, 6.8 equiv) followed by cesium carbonate (58 g, 180 mmoles, 6 equiv) and bis(triphenylphosphine)palladium(II) chloride (4.2 g, 6.0 moles, 0.2 equiv). After 40 minutes, the reaction is cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with a step gradient of hexanes:ethyl acetate (7:3) to hexanes:ethyl acetate (1:1) to give the title compound (67% yield): MS (m/z): 421 (M+1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[C:24]4[CH2:25][CH2:26][CH2:27][C:23]=4[N:22]=[C:21]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[N:20]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6]>O.CO>[CH:28]1([C:21]2[N:20]=[C:19]([NH:18][C:15]3[CH:14]=[CH:13][C:12]([C:7]4([C:5]([OH:6])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8]4)=[CH:17][CH:16]=3)[C:24]3[CH2:25][CH2:26][CH2:27][C:23]=3[N:22]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(=O)C1(c2ccc(Nc3nc(C4CCCC4)nc4c3CCC4)cc2)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2ccc(Nc3nc(C4CCCC4)nc4c3CCC4)cc2)CCCC1
Temperature: 90 °C
Yield: 93.6 %

Procedure:
A solution of sodium hydroxide (4.14 g, 100 mmol) in water (100 mL) was added to a solution of 1-[4-(2-cyclopentyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]-cyclopentanecarboxylic acid methyl ester (7.0 g, 17.2 mmol) in MeOH (100 mL) and the mixture was heated at 90° C. for 8 hours. After evaporation of MeOH under reduced pressure, the mixture was cooled to a temperature in the range of 15° C. to 40° C., and acidified with hydrochloric acid to adjust pH to 3-4. The precipitate formed after standing at a temperature in the range of 15° C. to 40° C. was filtered and washed several times with water, and dried under vacuum. The solid was recrystallized from MeOH to afford the title compound as a white powder (6.3 g, 94% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[C@@H:17]([OH:18])[C:16](=[O:19])[N:15]([CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH3:23])[C:14]3[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:13]=3[S:12]2)=[CH:7][CH:6]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1C=CC=CC=1.CN(C)C=O.O>[ClH:35].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[C@@H:17]([O:18][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:16](=[O:19])[N:15]([CH2:20][CH2:21][NH:22][CH3:23])[C:14]3[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:13]=3[S:12]2)=[CH:9][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C(=O)OC(C)(C)C)C(=O)[C@@H]2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CNCCN1C(=O)[C@H](OCc2ccccc2)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 150 %

Procedure:
0.28 g of sodium hydride (63% oil dispersion) is added to a solution of 1.05 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-tert.butoxycarbonyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in a mixture of 10 ml of benzene and one ml of dimethylformamide. The mixture is stirred at room temperature for 30 minutes. Then, 0.92 g of benzyl bromide is added to the mixture, and said mixture is stirred at room temperature for 20 hours. The mixture is diluted with water, and the aqueous mixture is extracted with benzene. The extract is washed with water, dried and evaporated to remove solvent. Then, 7 ml of formic acid and one ml of water are added to the residue (oil: 1.36 g) thus obtained, and the mixture is stirred at 40° C. for 1.5 hours. The mixture is evaporated under reduced pressure to remove solvent. The residue is dissolved in 10% hydrochloric acid, and the solution is washed with ether. The aqueous layer is alkalized with ammonia and extracted with chloroform. The extract is washed with water, dried and evaporated to remove solvent. The residue is converted to its hydrochloride and recrystallized from ethanol. 0.83 g of (+)-cis-2-(4-methoxyphenyl)-3-benzyloxy-5-[2-(N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.hydrochloride is obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([CH:13]=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([O:17][C:18](=[O:27])[CH2:19][N:20]1[C:24](=[O:25])[CH2:23][NH:22][C:21]1=[S:26])[CH3:16].N1CCCCC1>ClCCl>[CH2:15]([O:17][C:18](=[O:27])[CH2:19][N:20]1[C:24](=[O:25])/[C:23](=[CH:13]/[C:11]2[O:12][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=3)=[CH:9][CH:10]=2)/[NH:22][C:21]1=[S:26])[CH3:16]
Reactant: O=Cc1ccc(-c2cccc(I)c2)o1
Reactant: CCOC(=O)CN1C(=O)CNC1=S
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCOC(=O)CN1C(=O)/C(=C/c2ccc(-c3cccc(I)c3)o2)NC1=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
5-(3-Iodophenyl)furan-2-carbaldehyde (30 mg, 0.1 mmol) synthesized by the same method as in Example 1 and ethyl-2-(5-oxo-2-thioxoimidazolidin-1-yl)acetate (20 mg, 0.1 mmol) were dissolved in dichloromethane (7 mL), piperidine (20 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) overnight. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give compound 2 in a yield of 21 mg (yield 43.6%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([O:16][CH2:15]2)[C:12]([O-])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:17]([O:20][CH:21](C)C)(C)[CH3:18].S(=O)(=O)(O)[OH:25]>O>[OH:16][CH:15]([C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=1)=[CH2:12])[C:21]([O:20][CH2:17][CH3:18])=[O:25]
Reactant: CC(C)OC(C)C
Reactant: CC(C)(C)c1ccc(C2(C(=O)[O-])CO2)cc1
Reactant: O=S(=O)(O)O
Solvent: O
Product: C=C(c1ccc(C(C)(C)C)cc1)C(O)C(=O)OCC

Procedure:
12.4 Grams of the ethyl 3-methyl-3-(4-t-butylphenyl-glycidate was dissolved in 60 ml. of dry isopropyl ether. Into this solution, 0.3 g. of sulfuric acid was dropped with ice-cooling, and the resulting mixture was reacted at room temperature for 1 hour. Thereafter, the reaction liquid was poured into water, and then extracted with ether. The ether layer was washed with water and with a saturated aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. Subsequently, the ether was evaporated under reduced pressure, and the residue was subjected to distillation to obtain 9.7 g. of the end compound, b.p. 115°- 119° C./0.2 mmHg, yield 78.2% (theoretical value).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccncc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 4-pyridyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4-pyrid-4-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH:3]([CH3:5])[CH3:4].Cl.[CH2:9]([O:13][C:14](=[O:29])[C@H:15]([CH3:28])[NH:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH2:19])[CH:10]([CH3:12])[CH3:11].C(N[C@H](C(O)=O)CC1C=CC=CC=1)(OC(C)(C)C)=O.Cl.C(OC(=O)[C@H](C)N)C(C)C>CO.C(Cl)(Cl)Cl>[CH2:9]([O:13][C:14](=[O:29])[C@H:15]([CH3:28])[NH:16][C:17](=[O:27])[C@H:18]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH:19][C:1](=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)CC(=O)O
Reactant: CC(C)COC(=O)[C@H](C)NC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)CC(C)C

Procedure:
Following General Procedure C and using isovaleric acid (Aldrich) and N-(L-phenylalaninyl)-L-alanine iso-butyl ester hydrochloride (prepared from N-BOC-L-phenylalanine (Sigma) and L-alanine iso-butyl ester hydrochloride (prepared as described in Example 83A above) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=135-138° C.). The reaction was monitored by tlc (Rf=0.3 in 3% MeOH/CHCl3) and the product was purified by silica gel chromatography using 3% MeOH/CHCl3 as the eluent.