Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.CC(C)N=C=NC(C)C.O>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:12][C:7]2[CH:6]=[C:5]([C:4]([OH:3])=[O:13])[CH:10]=[CH:9][C:8]=2[N:11]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c1
Reaction time: 2 h

Procedure:
A mixture of 3,4-diamino-benzoic acid ethyl ester (5.0 g, 27.8 mmol) and 1,3-dichloro-2-isothiocyanato-benzene (5.66 g, 27.8 mmol) in 40 mL DMF was stirred for 2 h. DIC (4.40 mL, 28.2 mmol) was added and the mixture stirred overnight. After 30 min stirring at 80° C. water was added and the mixture was concentrated i.vac. The residue was taken up in ethanol and 1 M aq. NaOH. The mixture stirred overnight at reflux. Ethanol was evaporated and the aq. phase diluted with water. The precipitate was filtered and washed with water. The filtrate was acidified with formic acid and cooled. The mixture was filtered and washed with water.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Nc2ccccc2C(=O)O)cc1
Yield: 76 %

Procedure:
A mixture of 52 g (0.33 mole) of 2-chlorobenzoic acid, 82 g (0.66 mole) of 4-methoxyaniline, 46 g (0.33 mole) of potassium carbonate, 5 g (0.025 mole) of cupric acetate and 150 ml of dimethylformamide was heated at reflux for two hours. The reaction mixture was cooled, 300 ml of water added and the mixture filtered. The filtrate was acidified with 50 ml of 6N hydrochloric acid, and the resulting solid was collected by filtration and recrystallized from acetonitrile to give 61 g of 2-(4-methoxyphenylamino)benzoic acid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[CH2:8][CH3:9].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][CH2:23][CH2:24]Cl>CS(C)=O.O>[CH2:7]([NH:10][CH2:24][CH2:23][CH2:22][O:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)[CH2:8][CH3:9]
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCNCCCOc1ccc2ccccc2c1
Temperature: 145 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-propylamine (0.28 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 145° C. for 8 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-propyl-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 112° C., (yield 0.51 gm, 91.2%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.[I-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:17][CH:16]=1
Reactant: CCOC(=O)CNc1ccccc1
Reactant: ClCc1ccc(Cl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CN(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 80 °C
Yield: 51.2 %

Procedure:
N-phenylglycine ethyl ester (781 mg, 4.3 mmol), 4-chlorobenzyl chloride (690 mg, 4.3 mmol) and sodium iodide (64 mg) were dissolved in toluene (7 mL) under argon. The reaction was heated in a graphite bath at 80° C. for 24 h. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with 1M HCl followed by brine. The solution was dried over MgSO4, filtered, and concentrated in vacuo. Purification of the resultant oil by flash chromatography (10:1 hexanes/EtOAc) afforded the title compound as a green oil (669 mg, 51%). MS (ES+) m/z 304 (MH+).
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[CH3:41][S:42][C:43]1[CH:44]=[C:45]([N:49]=[C:50]=[O:51])[CH:46]=[CH:47][CH:48]=1.[C:52]([O:56][CH2:57][CH2:58][OH:59])(=[O:55])[CH:53]=[CH2:54].[N-]=C=O>>[C:52]([O:56][CH2:57][CH2:58][O:59][C:50](=[O:51])[NH:49][C:45]1[CH:46]=[CH:47][CH:48]=[C:43]([S:42][CH3:41])[CH:44]=1)(=[O:55])[CH:53]=[CH2:54]
Reactant: CSc1cccc(N=C=O)c1
Reactant: C=CC(=O)OCCO
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [N-]=C=O
Product: C=CC(=O)OCCOC(=O)Nc1cccc(SC)c1
Temperature: 60 °C

Procedure:
0.02 g of 2,6-di-tert-butyl-4-methylphenol, 0.01 g of Desmorapid Z, 11.7 g of 3-(methylthio)phenyl isocyanate were initially introduced into a 100 ml round-bottomed flask and heated to 60° C. Thereafter, 8.2 g of 2-hydroxyethyl acrylate were added dropwise and the mixture was kept farther at 60° C. until the isocyanate content had fallen below 0.1%. Cooling was then effected. The product was obtained as a light yellow liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].II.C([O:20][C:21]1[C:25]([CH:26]=O)=[C:24]([CH3:28])[N:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:22]=1)C1C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:26][C:25]2[C:21](=[O:20])[NH:22][N:23]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:24]=2[CH3:28])=[CH:3][CH:4]=1
Reactant: Cc1c(C=O)c(OCc2ccccc2)nn1-c1ccccc1
Reactant: COc1ccc(Br)cc1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(Cc2c(C)n(-c3ccccc3)[nH]c2=O)cc1
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
A Grignard reagent was prepared from 4-bromoanisole (1.2 g), magnesium (0.16 g), a catalytic amount of iodine and tetrahydrofuran (20 mL) in the usual manner. To the obtained Grignard reagent solution was added a solution of 3-benzyloxy-4-formyl-5-methyl-1-phenyl-1H-pyrazole(1.5 g) in tetrahydrofuran (15 mL) at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (50 mL) and tetrahydrofuran (50 mL). To the solution was added 10% palladium-carbon powder, and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. Insoluble materials were removed by filtration, and the solvent of the filtrate was removed under reduced pressure. To the residue was added ethanol, and the precipitates was collected by filtration, washed with ethanol and hexane, and dried under reduced pressure to give the title compound (0.78 g).
Reaction SMILES: [CH2:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.Cl[O:13][N:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1.C(N(CC)CC)C>CCOCC>[F:23][C:22]([F:24])([F:25])[C:18]1[CH:17]=[C:16]([C:15]2[CH2:1][C:2]3([C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4](=[O:5])[O:3]3)[O:13][N:14]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1cccc(C=NOCl)c1
Reactant: C=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C1OC2(CC(c3cccc(C(F)(F)F)c3)=NO2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.8 %

Procedure:
To a solution of 109.5 g (0.75 mole) of 3-methylenephthalide and 285 g (1.27 mole) of m-trifluoromethylbenzaldehyde chlorooxime in 3.5 liters of ether was added 128.3 g (1.27 mole) of triethylamine in 250 ml. of ether at 0° C. during 3 hours. The solution was then stirred at room temperature overnight. An infrared spectrum indicated that the reaction was complete. The solid was filtered off. The ethereal solution was washed once with 10% HCl, twice with sodium chloride saturated water, dried over CaSO4 and concentrated under vacuum. Only 19.5 g of impure product was obtained. The solid material which was filtrated from the original reaction solution was stirred with 4 liters of tetrahydrofuran for 4 hours and filtered through a Buchner funnel. The tetrahydrofuran solution obtained was washed once with 10% HCl solution and twice with water saturated with sodium chloride. After being dried and concentrated, the tetrahydrofuran solution gave 140.6 g of pure product, m.p. 170° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][C:11]2[C:6]1=[N:7][C:8]([C:26]1[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1)=[N:9][C:10]=2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[CH:2]([CH3:4])[CH3:3].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH:55][C@H:56]([CH3:61])[CH2:57][C:58](O)=[O:59]>CN(C)C=O>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:8]2[N:7]=[C:6]3[C:11]([N:12]=[C:13]([N:14]4[CH2:19][CH2:18][N:17]([C:58](=[O:59])[CH2:57][C@H:56]([OH:55])[CH3:61])[CH2:16][CH2:15]4)[N:5]3[CH2:1][CH:2]([CH3:4])[CH3:3])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)=[CH:27][N:28]=1
Reactant: C[C@@H](O)CC(=O)O
Reactant: CC(C)Cn1c(N2CCNCC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)Cn1c(N2CCN(C(=O)C[C@@H](C)O)CC2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Reaction time: 16 h
Yield: 35.8 %

Procedure:
5-(9-Isobutyl-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl)pyrimidin-2-amine (150 mg, 0.33 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (128 mg, 0.67 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol), and (R)-3-hydroxybutyric acid (70 mg, 0.67 mmol) were dissolved in dimethylformamide (5 ml) and the resulting mixture was stirred for 16 hours. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (62 mg, 36%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C1C=CC2N(O)N=NC=2C=1.[CH3:28][C@@H:29]1[CH2:34][NH:33][CH2:32][C@H:31]([CH3:35])[NH:30]1.[ClH:36]>CN(C=O)C.C(Cl)Cl.C(OCC)C.C(Cl)CCl>[ClH:36].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]([N:33]3[CH2:32][C@H:31]([CH3:35])[NH:30][C@H:29]([CH3:28])[CH2:34]3)=[O:17])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cc3)CC2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Cyanophenyl)-piperidine4-carboxylic acid (D3)(6.92 g), HOBT (1.77 g), TEA (4.7 ml) and (2R,6S)-2,6-dimethylpiperazine (3.0 g) were stirred in DMF (25 ml) and then EDC (3.7 g) was added and the reaction stirred at rt overnight. The solvent was evaporated and the residue redissolved in DCM (100 ml) and washed with saturated sodium hydrogen carbonate (2×80 ml), brine (75 ml) and the organic layer dried (MgSO4) and evaporated. The crude product was then purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated to give the free base compound which was dissolved in DCM (10 ml) and treated with 1N HCl in diethyl ether to give the title compound (D13) as a white precipitate which was filtered off (1.80 g). MS electrospray (+ve) 327 (MH+).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:55])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]5[CH2:43][CH2:42][N:41](C(OCC6C=CC=CC=6)=O)[C@@H:40]([CH3:54])[CH2:39]5)[CH:32]=4)[CH:30]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3]>CO.[Pd]>[F:55][C:28]1[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]3[CH2:43][CH2:42][NH:41][C@@H:40]([CH3:54])[CH2:39]3)[CH:32]=2)=[CH:30][C:25]([CH2:24][NH:23][C:21]([C:17]2[CH:16]=[C:15]([CH2:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:4])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[CH:20]=[CH:19][CH:18]=2)=[O:22])=[CH:26][CH:27]=1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1
Yield: 4.9 %

Procedure:
A solution of phenylmethyl (2S)-4-[(5′-{[({3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (1.5 g, 2.0 mmol) and 10% Pd/C (450 mg) in methanol (50 mL) was allowed to react with H2 at room temperature under atmospheric pressure for 12 hours. The solvent was removed under vacuum. The resulting residue was purified by loading onto 20 g aminopropyl SPE cartridge and eluting sequentially with DCM (3×50 mL), EtOAc (3×50 mL), and MeOH (3×50 mL). The methanol fractions were combined and evaporated to give the title compound as a pale yellow solid (60 mg, 35%). LC/MS: m/z, 615 (M+H), 1.93 min.
Reaction SMILES: F.[C:2]([O:5][CH2:6][C:7]1[N:8]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:27]=1)(=[O:4])[CH3:3].C1C=C(Cl)C=C(C(OO)=[O:41])C=1.O>CN(C=O)C.CO>[C:2]([O:5][CH2:6][C:7]1[N:8]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:14][C:13]=3[N+:12]([O-:41])=[CH:11][C:10]=2[N:27]=1)(=[O:4])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)OCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Agent: F
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)OCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 100.5 %

Procedure:
Hydrogen fluoride (7.5 g of 48%, 0.18 mol) was added to a solution of [7-benzyloxy-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate (40.0 g, 0.0953 mol) in DMF (910 mL) and methanol (300 mL). mCPBA (60.6 g, 0.200 mol, 57% pure) was then added in one portion, and the reaction was stirred at ambient temperature for 5.5 hours. A mixture of ice and deionized water (4 L) was then added to the reaction mixture, and the resulting mixture was stirred vigorously for 30 minutes. The solid product was isolated by filtration, washed with deionized water, and dried under vacuum at 50° C. The solid was then triturated with diethyl ether (500 mL) for one hour, isolated by filtration, washed with diethyl ether (400 mL), and dried under vacuum at 40° C. to provide 41.7 g of [7-benzyloxy-1-(2-hydroxy-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate.
Reaction SMILES: O.[ClH:2].[CH3:3][C:4]1[CH:9]=[C:8]([NH:10]C(C)=O)[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[ClH:2].[CH3:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)Nc1ccc(-c2ccccc2)c(C)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(N)ccc1-c1ccccc1

Procedure:
300 g of water and 296 g of HCl (37%) are added to the 2-methyl-4-acetaminobiphenyl prepared as described in Example 1. Any chlorobenzene still present is distilled off azeotropically, and the mixture is subsequently refluxed until HPLC monitoring indicates complete conversion (about 4 hours). The suspension obtained can be reacted further without further purification and without removal of the acetic acid formed as coproduct in the cleavage. The yield is (calculated from HPLC percentages by area) 99%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35](F)[CH:34]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:2].C([O:51]C(=O)CCCOC1C=CC=C(CCCCCCOC2C=C(C(=O)N(C)C)C=C(Br)C=2)C=1CCC(OCC)=O)C.FC1C=CC(B(O)O)=CC=1O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[C:35]([OH:51])[CH:34]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(F)c3)c2)c1CCC(=O)OCC
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N(C)C)cc(-c3ccc(F)c(O)c3)c2)c1CCC(=O)OCC
Yield: 95 %

Procedure:
The title compound was prepared by the same method as 4-{3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester starting from 4-{3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (150 mg, 0.236 mmol), 4-fluoro-3-hydroxyphenylboronic acid (74 mg, 0.472 mmol), PdCl2(dppf) (29 mg, 0.04 mmol) and cesium carbonate (153 mg, 0.472 mmol) in dimethoxyethane (5 mL) to obtain 4-{3-[6-(5-dimethylcarbamoyl-4′-fluoro-3′-hydroxy-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (150 mg, 95%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[C-:24]#[N:25].[K+].C(OCC)(=O)C>CS(C)=O.O>[C:24]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)#[N:25]
Reactant: [C-]#N
Reactant: COc1ccc(-c2noc(CCl)c2-c2ccc(OC)cc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2noc(CC#N)c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.2 %

Procedure:
A 500 mg of 5-chloromethyl-3,4-bis(4-methoxyphenyl)isoxazole was dissolved in a mixed solvent of dimethylsulfoxide (3 ml) and water (1 ml). To the solution, 122 mg of potassium cyanide was added, and the mixture was stirred at room temperature for 18 hours. A 80 ml of ethyl acetate was added to the mixture. The resulting mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 210 mg (yield 43.1%) of a desired 5-cyanomethyl-3,4-bis(4-methoxyphenyl)isoxazole.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:22]3[S:23][C:24]([NH:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[N:25][N:26]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][S:21][C:22]1[S:23][C:24]([NH:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[N:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3nnc(NCC4CC4)s3)c2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2c(c1CSc1nnc(NCC3CC3)s1)CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-[5-(cyclopropylmethyl-amino)-[1,3,4]thiadiazol-2-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.082 g, 0.171 mmol) in anhydrous DCM (3.5 mL) at room temperature add trifluoroacetic acid (3.5 mL) and stir the solution at room temperature overnight. Concentrate in. vacuo and elute the residue through a SCX column (20 g). Dissolve the residue in DCM, load the solution on to a RediSep® column (12 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 90:10 DCM/2M ammonia in methanol over 33 min; 35 mL/min) to afford 7-chloro-6-[5-(cyclopropylmethyl-amino)-[1,3,4]thiadiazol-2-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.051 g, 78%). MS (ES+) m/z: 381.1 (M+H)+. To a solution of 7-chloro-6-[5-(cyclopropylmethyl-amino)-[1,3,4]thiadiazol-2-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.044 g, 0.116 mmol) in absolute ethanol (5 mL), add succinic acid (0.014 g, 0.116 mmol). After acid dissolves, concentrate the reaction mixture in vacuo. Combine the residue with MTBE, concentrate in vacuo several times and dry under high vacuum at room temperature overnight to obtain the title compound (0.058 g, 100%) as a white foam. MS (ES+) m/z: 381.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].Br[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][CH2:29][CH2:28]2.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH2:30][CH2:29][CH2:28]3)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Reactant: BrCCc1ccc2c(c1)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccc3c(c2)CCC3)C1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1,-diphenylmethyl)-piperidine (0.28 g), 5-(2-bromoethyl)indane (0.23 g--see Preparation 4), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (20 ml), the layers separated, and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound as colorless rhombs, yield 0.13 g, m.p. 88-91° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]1([CH2:17]CCO)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: OCCCc1ccccc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(CCl)CC(=O)OCCCc1ccccc1
Reaction time: 18 h
Yield: 103.1 %

Procedure:
A solution of ethyl 4-chloroacetoacetate (134 g, 815 mmol) and 3-phenyl-1-propanol (111 mL, 821 mmol) was heated in toluene, with azeotropic removal of ethanol, for 4 h. The solution was allowed to cool with stirring for 18 h and was then concentrated to give the title compound (214 g). Electrospray MS m/z 219 [M−Cl+H]+.