Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC.C([Li])CCC.[S:36]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37]1>O1CCCC1>[S:36]1[CH:40]=[CH:39][C:38](/[CH:41]=[CH:5]/[CH2:4][CH2:3][OH:2])=[CH:37]1
Reactant: O=Cc1ccsc1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCC/C=C/c1ccsc1
Reaction time: 0.5 h
Yield: 7.5 %

Procedure:
1.0 g of (3-hydroxypropyl)triphenylphosphonium bromide was dissolved in 20 ml of tetrahydrofuran, and under ice cooling, 3.4 ml of a 15% n-butyllithiumhexane solution was added. After the mixture was stirred for 30 minutes, 270 mg of 3-thiophenecarboxaldhyde was added. The mixture was stirred for 30 minutes, and then the solvent was evaporated. The residue was worked up in a customary manner, and purified by silica gel column chromatography [benzene/ethyl acetate=6/1] to give 28 mg (yield 7%) of the captioned compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:13]=[O:14])=[CH:7]2.[C:15](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[C:11]([O:12][CH3:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:13]=[O:14])=[CH:7]2
Reactant: O=Cc1ccc2c(Br)c(O)ccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc2cc(C=O)ccc2c1Br
Yield: 96 %

Procedure:
Step c) A mixture of 5-bromo-6-hydroxy-2-naphthaldehyde (34.0 g, 135.5 mmol), potassium carbonate (18.7 g, 135.5 mmol), dimethyl sulfate (12.8 mL, 135.5 mmol) and acetone (500 mL), was refluxed for 3 hours. The volatiles were removed in vacuo, and the residue was suspended in water. The precipitated solid was filtered and dried, to yield a yellow solid (34.5 g, 96% yield, m.p. 133°-135° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([OH:19])=O)[N:5]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=O)[CH:6]=1.[CH2:20]([NH2:23])[CH2:21][NH2:22]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[O:19])[N:22]3[CH2:21][CH2:20][NH:23][C:8]3([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[CH2:7][N:5]2[CH:6]=1
Reactant: O=C(Cn1cc(Br)cc1C(=O)O)c1ccc(Cl)cc1
Reactant: NCCN
Solvent: CCO
Product: O=C1c2cc(Br)cn2CC2(c3ccc(Cl)cc3)NCCN12
Yield: 68.7 %

Procedure:
To a solution of crude 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid (100 mg, 0.29 mmol) dissolved in a mixture of xylenes (10 mL) and ethanol (3 mL) was added ethane-1,2-diamine (100 μL, 1.5 mmol). The reaction mixture was heated at reflux. After 90 minutes (monitored by LCMS) the mixture was concentrated in vacuo and the resultant residue purified flash chromatography (Biotage SP4, 40 g cartridge, 0-5% MeOH gradient in CH2Cl2) to give 7-bromo-10a-(4-chlorophenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as a light yellow solid (73 mg, yield: 68%). 1H NMR (400 MHz, d6-acetone): δ 2.74-2.82 (m, 1H), 3.30-3.38 (m, 1H), 3.44 (ddd, 1H, J 7.7, 3.4, 1.3 Hz), 3.67-3.75 (m, 1H), 4.39 (d, 1H, J 12.5 Hz), 4.69 (d, 1H, J 12.5 Hz), 6.68 (d, 1H, 1.8 Hz), 6.79 (d, 1H, J 1.7 Hz), 7.32-7.40 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12].[C-:16]#[N:17].[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:12])[C:16]#[N:17]
Reactant: O=CCCCCCOc1cccc(F)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC(O)CCCCCOc1cccc(F)c1
Reaction time: 8 h

Procedure:
A solution of 1 M NaOH (17.8 mL) was added to a refluxing mixture of 3-fluorophenol (2 g, 17.8 mmol) and 5-bromo-1-hexanol (3.23 g, 17.8 mmol) in water (20 mL). After 3 h, the resulting mixture was cooled to room temperature and diluted with diethyl ether. The layers were separated, the organic layer was washed sequentially with 1N NaOH and water, then dried (Na2SO4) and concentrated to yield 6-(3-fluorophenoxy)hexan-1-ol as an oil. A solution of 6-(3-fluorophenoxy)hexan-1-ol (2.9 g, 13.67 mmol) was added dropwise to a mixture of 1,1,1-tris(acetyloxy)1,1-dihydro-1,2-benziodoxol-3-(1H)-one (7.0 g, 16.4 mmol) with ice-bath cooling. The resulting solution was stirred for 2.5 h at room temperature, then poured into a solution of sodium thiosulfate in saturated aqueous sodium bicarbonate. After 0.5 h, the layers were separated and the aqueous layer was extracted with CH2Cl2. The organic phase was dried (Na2SO4) filtered and concentrated to yield 6-(3-fluorophenoxy)hexanal. A solution of 6-(3-fluorophenoxy)hexanal (2.9 g, 13.8 mmol) in ethyl acetate (20 mL) and water (20 mL) containing NaCN (2 g, 41.4 mmol) was stirred vigorously overnight. After 20 h, the phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water, dried (Na2SO4) and concentrated to yield 7-(3-fluorophenoxy)-2-hydroxyheptanenitrile, which was dissolved in methanol (40 mL) and cooled to −78° C. The solution was saturated with HCl (g) and stored at −10° C. for 18 h. The resulting mixture was concentrated, diluted with ethyl acetate (40 mL) and water (40 mL), then stirred overnight. The layers were separated and the organic phase was dried (Na2SO4) and concentrated to yield the corresponding methyl ester which was dissolved in 9:1 dioxane:water (20 mL) and treated with a solution of LiOH (1.4 g, 58 mmol). The resulting solution was stirred for 4 h then acidified to pH˜3 with 1N HCl. The mixture was then extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with water, dried (Na2SO4) and concentrated to yield 7-(3-fluorophenoxy)-2-hydroxyheptanoic acid as a white solid. (MS m/z=257 MH+).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:32])[CH:8]([O:29][CH2:30][CH3:31])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)C.Cl>O.O1CCCC1>[CH2:30]([O:29][CH:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[CH:12][CH:11]=1)[C:7]([OH:32])=[O:6])[CH3:31]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(S(C)(=O)=O)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(OCCc2ccc(S(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Yield: 86 %

Procedure:
Lithium hydroxide hydrate (57 mg; 1.37 mmole) dissolved in water (2 ml) was added to a solution of 2-ethoxy-3-{4-[2-(4-methanesulfonylphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 87) (384 mg; 0.91 mmole) in tetrahydrofuran 6 ml. After stirring at room temperature for 2 hours more lithium hydroxide hydrate (30 mg) dissolved in water (1 ml) was added. The reaction mixture was stirred at room temperature for 4 more hours. The reaction mixture was acidified with hydrochloric acid (2 M) to pH 4. Tetrahydrofuran was evaporated in vacuo, water (5 ml) was added and the product was extracted with ethyl acetate (10 ml). The organic phase was washed with water, dried (sodium sulfate) and the solvent was evaporated in vacuo. Purification by chromatography on silica gel using heptane:ethyl acetate:acetic acid (10:10:1) as eluant gave 0.307 g (yield 86%) of 2-ethoxy-3-{4-[2-(4-methanesulfonylphenyl)ethoxy]phenyl}propanoic acid as a pale yellow oil that crystallizes when vacuum dried.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[NH2:11]>C(Cl)(Cl)Cl>[CH3:18][O:17][C:13]1[CH:12]=[C:10]([NH:11][S:2]([Cl:1])(=[O:5])=[O:3])[CH:9]=[C:8]([O:7][CH3:6])[C:14]=1[O:15][CH3:16]
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Product: COc1cc(NS(=O)(=O)Cl)cc(OC)c1OC
Reaction time: 1 h
Yield: 6 %

Procedure:
At −5° C., chlorosulfonic acid (0.22 mL, 3.33 mmol) was slowly added to a chloroform solution (10 mL) of 3,4,5-trimethoxyaniline (1.83 g, 10 mmol). After 1 hour at 25° C., the suspension was filtered, and the solid was washed with CH2Cl2. The residue was dissolved in Na2CO3 solution (0.5M, 20 mL), which was washed with ethyl ether (2×20 mL). The aqueous solution was concentrated to give a solid, which was extracted with boiling ethanol (20 mL). After evaporation of ethanol, the solid (200 mg) was treated with PCl5 (200 mg) in refluxing benzene (15 mL). The precipitate was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (50% EtOAc in hexanes), affording 56 mg (5% yield) of the sulfamoyl chloride as a off-white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:15](=O)[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[C:13]#[N:14])=[CH:11][C:6]=2[N:5]([CH2:24][CH3:25])[C:4]1=[O:26])[CH3:2].Cl.[NH2:28][OH:29]>N1C=CC=CC=1>[NH2:14][C:13]1[O:29][N:28]=[C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[C:12]=1[C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4](=[O:26])[N:5]([CH2:24][CH3:25])[C:6]=2[CH:11]=1
Reactant: CCn1c(=O)n(CC)c2cc(C(C#N)C(=O)c3cccc(C)c3)ccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCn1c(=O)n(CC)c2cc(-c3c(-c4cccc(C)c4)noc3N)ccc21
Temperature: 30 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a pyridine (1.5 mL) solution of 2-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3-oxo-3-m-tolyl-propionitrile (0.113 g) at 23° C. was added hydroxylamine hydrochloride (0.071 g). The reaction was heated to 30° C. for 1 hour then to 55° C. for 3 hours, cooled and extracted into ethyl acetate from 10% citric acid. The organic layer was dried over sodium sulfate and concentrated. The resulting powder was triturated with methanol and filtered to give 5-(5-Amino-3-m-tolyl-isoxazol-4-yl)-1,3-diethyl-1,3-dihydro-benzoimidazol-2-one (0.085 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].[OH-].[Na+].Br[CH2:10][CH2:11][Cl:12]>C(OCC)C>[Cl:12][CH2:11][CH2:10][S:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCBr
Reactant: Sc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: ClCCSc1cccs1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
4.72 cm3 of thiophene-2-thiol were run, with stirring at a temperature in the region of 20° C., into a stirred solution of 8.25 cm3 of 20% aqueous sodium hydroxide solution and 14.6 cm3 of 1-bromo-2-chloroethane. The mixture was subsequently stirred for 6 hours at a temperature in the region of 20° C. 40 cm3 of ethyl ether were subsequently added and the organic phase was washed with water and then dried over magnesium sulfate. After filtering through paper, the organic solution was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography, under a pressure reduced to 50 kPa of nitrogen, on a column of silica gel (particle size 20-45 μm; diameter 4.5 cm; weight of silica 250 g), elution was carried out with a cyclohexane/ethyl acetate (95/5 by volume) mixture. 7.27 g of 2-(2-chloroethylthio)thiophene were obtained in the form of a mobile oil with a yellow color.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][C:24]([O:27][CH3:28])=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[CH2:36][OH:37]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[CH2:36][OH:37])[NH:12][C:11]([C:22]2[S:23][C:24]([O:27][CH3:28])=[CH:25][N:26]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(OC)s2)=NC1c1ccc(F)cc1Br
Reactant: OCC1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CO)NC(c2ncc(OC)s2)=NC1c1ccc(F)cc1Br
Yield: 47.4 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-methoxythiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.53 g, 1 mmol) was reacted with morpholin-3-ylmethanol hydrochloride (0.18 g, 1.2 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellowish solid (0.27 g, 48%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(-c2cccc(F)c2)cn1
Temperature: 100 °C

Procedure:
To a round bottom flask was added methyl 5-bromopicolinate 6-5 (900 mg, 4.2 mmol), 3-fluorophenylboronic acid 6-6 (875 mg, 6.3 mmol), Pd(PPh3)4 (482 mg, 0.42 mmol), saturated Na2CO3 (3 mL), ethanol (3 mL) and toluene (9 mL). The reaction was refluxed at 100° C. for 3 hours. The reaction was cooled down to room temperature, and the precipitate was collected by filtration and briefly washed with ethyl acetate. The sodium salt was acidified with 1N HCl to give 5-(3-fluorophenyl)picolinic acid 6-7 as a white solid. MS m/z 218.1 (M+1).
Reaction SMILES: N.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[N:6]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH2:24][CH3:25])[N:4]=1.C1COCC1.C(#[N:33])C>O>[NH2:33][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([F:16])([F:15])[F:14])=[CH:10][CH:11]=2)[N:6]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][CH2:24][CH3:25])[N:4]=1
Reactant: CCSc1ccccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Reactant: CC#N
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CCSc1ccccc1-c1nc(N)c2ccc(C(F)(F)F)cc2n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
4.5 ml of a 28% aqueous ammonia solution was added to a mixture of 500 mg of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline, 8 ml of THF and 5 ml of acetonitrile, and the mixture was stirred at 50° C. for 2 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 396 mg of 4-amino-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline (Compound of Present Invention 5).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][NH:14]3)=[O:8])[N:6]=1.Br[C:29]1[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[N:33][CH:34]=1>CC(O)C.C(=O)(O)[O-].[Na+].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>[NH2:38][S:35]([C:31]1[CH:30]=[C:29]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)[CH:34]=[N:33][CH:32]=1)(=[O:37])=[O:36]
Reactant: Cc1nc(C(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cc3[nH]ncc23)cs1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1nc(C(=O)Nc2cc(-c3cncc(S(N)(=O)=O)c3)cc3[nH]ncc23)cs1
Temperature: 120 °C

Procedure:
2-Methyl-N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (23 mg, 0.06 mmol), 5-bromo-3-pyridinesulfonamide (18 mg, 0.078 mmol) and Pd(PPh3)4 (7 mg, 0.006 mmol) were combined in IPA (0.5 ml) and 1 M sodium bicarbonate (aq) (0.18 ml). The reaction was heated in a Biotage microwave at 120° C. for 10 mins. After cooling the solvent was removed under a stream of nitrogen and the solid partitioned between water (10 ml) and ethyl acetate:DCM (3×10 ml, 1:1, v/v). A few drops of brine were added to aid separation. The organic layers were combined, passed through a hydrophobic frit and dried under a stream of nitrogen. The residue was dissolved in MeOH:DMSO (0.5 ml, 1:1, v/v) and purified by MDAP (Method B). The solvent was removed under a stream of nitrogen to give the title compound, 1.5 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[NH:24]1[CH2:27][CH2:26][C:25]1=[O:28]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:24]3[CH2:27][CH2:26][C:25]3=[O:28])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1CCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCC4=O)cc3)CC2)c(C)c1
Yield: 27.5 %

Procedure:
Using (4-bromophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (747 mg) described in Preparation Example 170 and azetidin-2-one (142 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (200 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.CN(C)C(N(C)C)=N.[N+:23]([CH3:26])([O-:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([CH2:26][N+:23]([O-:25])=[O:24])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1
Agent: CN(C)C(=N)N(C)C
Product: CCOC(=O)CC(C[N+](=O)[O-])c1ccc(Cl)cc1
Yield: 92.9 %

Procedure:
The solution of ethyl 4-chlorocinnamate (12.6 g) and N,N,N′,N′-tetramethylguanidine (1.2 g) in nitromethane (36.6 g) was kept at rt for three days. The excess of nitromethane was evaporated and the residue dissolved in diethyl ether (250 ml). The organic layer was washed with 2M HCl (2×150 ml), dried (sodium sulfate), and evaporated. The residue was subjected to purification by flash chromatography on silica gel (petrol ether/ethyl acetate 10:1) to give ethyl 3-(4-chlorophenyl)-4-nitrobutanoate (15.1 g) as yellowish oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].[C:29](ON1C(=O)CCC1=O)([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>O1CCCC1>[CH2:32]([O:31][C:29]([N:3]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[CH:10][C:9]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:1][CH3:2])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCNCCCOc1cc(CNC(=O)OC(C)(C)C)ccc1-c1ccccc1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CCN(CCCOc1cc(CNC(=O)OC(C)(C)C)ccc1-c1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 85 %

Procedure:
To a solution of tert-butyl N-[2-(3-ethylaminopropoxy)-biphenyl-4-ylmethyl]carbamate (0.41 g) in tetrahydrofuran (4.0 mL) was added N-carbobenzoxyoxysuccinimide (0.260 g), and the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on aminopropylated silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (0.46 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.C[O:16][B:17](OC)[O:18]C>>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([B:17]([OH:18])[OH:16])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cn1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)cn1
Temperature: -75.0999984741211 °C
Yield: 88 %

Procedure:
5-Bromo-2-methoxypyridine (152 g) was dissolved in tetrahydrofuran anhydride (1520 mL) under stirring in nitrogen atmosphere, followed by cooling to −75.1° C. as bulk temperature. Under cooling and stirring, 380 mL of a 2.46 mol/L butyl lithium solution was added dropwise thereinto, followed by the dropwise addition of 192 mL of trimethoxyborane. The cooling bath was removed 30 minutes after completion of the dropwise addition, and the mixture was stirred at room temperature overnight. On the next day, 1.5 L of a 2 mol/L aqueous solution of hydrochloric acid was added thereto, followed by stirring for 1.5 hours. Then, it was neutralized with 460 mL of a 5 mol/L aqueous solution of sodium hydroxide. It was then extracted with 1 L of ethyl acetate, and the resulting aqueous layer was extracted again with 1 L of ethyl acetate. The combined organic layer was washed twice with 1 L of 10% saline water, dried over anhydrous magnesium sulfate, and then evaporated, to give 105 g (88%) of the title compound as a slightly yellowish white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][OH:13])(=[O:3])[CH3:2].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C(=O)(O)[O-].[Na+]>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:14])[CH2:12][O:13][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)CCC=C(C)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCC=C(C)CCC=C(C)COC1CCCCO1
Yield: 95.8 %

Procedure:
A mixture of 8-acetoxy-2,6-dimethyl-2,6-octadiene-1-ol (1.81 g, 8.52 mmol) and dihydropyran (1.17 ml, 12.8 mmol) in dichloromethane (6 ml) was stirred, and p-toluenesulfonic acid (40 mg) was added thereto, and the mixture was stirred at room temperature for 30 minutes. After addition of saturated aqueous sodium bicarbonate (30 ml), the product was extracted with hexane/ether (5:1.1) (30 ml). The extract was dried over Na2SO4 and evaporated in vacuo to remove the solvent to give a residue, which was purified with silica gel column chromatography to give 1-acetoxy-8-(2-tetrahydropyranyl)oxy-3,7-dimethyl-2,6-octadiene (2.42 g, 96%). ##STR58##
Reaction SMILES: C1(C[O:8][C:9](=[O:51])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]=[C:25]([C:48](=[O:50])[NH2:49])[CH:24]=2)[CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])C=CC=CC=1.[H][H].CN(C=O)C>[Pd].C1COCC1>[C:9]([CH2:10][N:11]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]=[C:25]([C:48](=[O:50])[NH2:49])[CH:24]=1)[CH2:12][C:13]([OH:15])=[O:14])([OH:51])=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(N)=O)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(N)=O)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A mixture of 2.2 g of N-[(3-carbamoyl)-5-(octadecyloxy)phenyl]-N-[2(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester and 0.5 g of 10% palladium on carbon in 100 ml of THF was stirred in a hydrogen atmosphere at room temperature until uptake ceased after 3 hours. DMF (150 ml) was added and the mixture was heated todissolve the precipitated product. The hot mixture was filtered to remove the catalyst and the filtrate was concentrated at reduced pressure to a solid. Recrystallization from THF gave 1.1 g (69% yield, mp 213°-216°) of N-(carboxymethyl)-N-[(3-carbamoyl)-5-(octadecyloxy)phenyl]glycine.