Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[C:32]([C:39](O)=[O:40])=[N:33][C:34]([S:37][CH3:38])=[N:35][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[Cl:30][C:31]1[C:32]([C:39]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]3[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([Cl:19])[CH:18]=3)[C:4]=2[F:20])=[O:40])=[N:33][C:34]([S:37][CH3:38])=[N:35][CH:36]=1
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)n1
Reaction time: 8 h
Yield: 42.7 %

Procedure:
In a 1 dram vial, 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (25 mg, 0.080 mmol), DIPEA (0.014 mL, 0.080 mmol) and 5-chloro-2-(methylthio)-4-pyrimidinecarboxylic acid (16.44 mg, 0.080 mmol) were dissolved in DMF (1 mL). HATU was added (30.6 mg, 0.080 mmol) and the solution stirred overnight. The reaction mixture was diluted to 2 mL with MeOH. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.017 g, 38%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 8.73-8.81 (m, 2H), 7.63 (t, 1H), 7.47-7.54 (m, 1H), 7.42-7.47 (m, 1H), 7.36-7.41 (m, 2H), 4.69 (d, 2H), 2.56 (br. s., 3H). LCMS m/z 496.9 (M+1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]([C:18]3[CH:26]=[C:25]([O:27][CH3:28])[C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)[C:14]([O:16][CH3:17])=[O:15])=[CH:9][NH:10]2)=[CH:6][CH:5]=1.[C:29]1(C)C=CC(S(OC)(=O)=O)=CC=1>CN(C)C=O>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]([C:18]3[CH:26]=[C:25]([O:27][CH3:28])[C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)[C:14]([O:16][CH3:17])=[O:15])=[CH:9][N:10]2[CH3:29])=[CH:6][CH:5]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C(c1cc(OC)c2c(c1)OCO2)c1c[nH]c2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Sodium hydride (289 mg of a 60% dispersion in paraffin wax) was added in portions to a stirred solution of methyl 2-(6-bromo-1H-3-indolyl)-2-(7-methoxy-1,3-benzodioxol-5-yl)acetate (from step (c), 2.7 g, 6.5 mmol) in anhydrous dimethylformamide (20 ml) at 0° C. under a nitrogen atmosphere. After 30 minutes. methyl p-toluenesulphonate (1.34 g, 7.2 mmol) was added. After a further 1 hour the mixture was partitioned between diethyl ether and water. The organic layer was separated and washed twice with water. The organic layer was dried (magnesium sulphate) and the solvent was removed in vacuo. The residue was purified by flash column chromatography (using 30% hexane, 70% dichloromethane as eluant) to give 1.49 g of the subtitle compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:46])[CH2:16][C:17]3[NH:18][C:19]([CH2:39][CH2:40][C:41]4[S:42][CH:43]=[CH:44][N:45]=4)=[C:20]([C:35]([O:37][CH3:38])=[O:36])[CH:21]([C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:34])[C:22]=3[C:23]([O:25][CH3:26])=[O:24])[CH2:11][CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:47]1(=O)[CH2:51][CH2:50][CH2:49][CH2:48]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.CC(O)=O>[CH:47]1([NH:1][CH2:2][C:3]2([CH2:8][N:9]3[CH2:10][CH2:11][N:12]([C:15](=[O:46])[CH2:16][C:17]4[NH:18][C:19]([CH2:39][CH2:40][C:41]5[S:42][CH:43]=[CH:44][N:45]=5)=[C:20]([C:35]([O:37][CH3:38])=[O:36])[CH:21]([C:27]5[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=5[Cl:33])[C:22]=4[C:23]([O:25][CH3:26])=[O:24])[CH2:13][CH2:14]3)[CH2:4][CH2:5][CH2:6][CH2:7]2)[CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: O=C1CCCC1
Reactant: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CN)CCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(CNC4CCCC4)CCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Reaction time: 0.08 h

Procedure:
To a suspension of dimethyl 2-[2-[4-[[1-(aminomethyl)cyclopentyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate (205 mg/0.298 mmol) and cyclopentanone (0.032 ml/0.36 mmol) in dichloromethane (2 ml) was added AcOH (1 drop) and the resulting mixture was stirred for 5 minutes. NaBH(OAc)3 (80 mg/0.36 mmol) was added to the mixture and the resulting mixture was stirred for 5 hours. The mixture was diluted with dichloromethane (50 ml) and the resulting solution was washed with water (10 ml) and brine (10 ml) successively. The solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (NH2 gel/dichloromethane:methanol=100:0-100:2) to give a yellow film (220 mg/98%).
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:29]=1[NH:30][CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])=[CH:27][CH:26]=[CH:25][CH:24]=2>C(#N)C>[CH2:2]([C:1]1[N:30]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[C:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:19]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(OC)(OC)OC
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C

Procedure:
Trimethyl orthovalerate (3.6 mL, 21 mmol) and pyridine hydrochloride (0.22 g, 1.9 mmol) were added to a solution of 1-[(3-aminoquinolin-4-yl)amino]-2-methylpropan-2-ol (prepared as described in Part A of Example 8, approximately 4.4 g, 19 mmol) in acetonitrile (96 mL). The reaction mixture was heated at reflux for 1 hour, then was allowed to cool to room temperature and was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to yield 4.1 g of 1-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[N+:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[C-:13].C(N(CC)CC)C>O1CCCC1>[CH3:18][O:17][C:15]([C:14]1[N:12]=[CH:13][O:5][C:4]=1[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1])=[O:16]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ncoc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 500 ml three neck flask fitted with mechanical stirrer under nitrogen is added 2,4-difluorobenzoyl chloride (141 mmol, 25 g), methyl isocyanoacetate (143 mmol, 13 mL), triethylamine (424 mmol, 60 mL) and tetrahydrofuran (200 mL). The mixture is stirred for 72 hours at room temperature. The reaction is concentrated to a thick slurry and then transferred to a separatory funnel using 500 mls of distilled water. The aqueous mixture is extracted with ethyl acetate (4×250 mL). The ethyl acetate washes are combined and washed with brine. The organics are dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue is disolved in hot ethanol (400 mL) and treated with decolorizing carbon and magnesium sulfate. After 15 minutes, the mixture is filtered to remove the insolubles. To the filtrate is added to one liter of distilled water. A precipitate forms and the resultant mixture is allowed to stand. The resulting solid is collected by filtration and is washed with copious amounts of water. The resulting solid is dried under vacuum to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]([CH3:39])([O:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[N:24][C:23]=3[CH3:37])=[O:21])[CH2:15]2)[CH:11]=[CH:10][C:9]=1[CH3:38])[CH3:6])C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH3:39][C:5]([O:7][C:8]1[CH:13]=[C:12]([CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([C:22]3[S:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=4)=[N:24][C:23]=3[CH3:37])=[O:21])[CH2:15]2)[CH:11]=[CH:10][C:9]=1[CH3:38])([CH3:6])[C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1cc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1OC(C)(C)C(=O)O
Temperature: 25 °C
Yield: 89.1 %

Procedure:
A mixture of 2-methyl-2-(2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenoxy)-propionic acid ethyl ester (179 mg, 0.31 mmol), potassium carbonate (86 mg, 0.62 mmol), methanol (10 mL) and water (2 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (50 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 151 mg (89%) of 2-methyl-2-(2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenoxy)-propionic acid as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([NH2:23])[C:18]([NH:21][CH3:22])=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[N+](C1C=CC=CC=1)([O-])=O.Cl>O>[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]2[N:21]([CH3:22])[C:18]3[CH:19]=[CH:20][C:15]([CH2:14][N:11]4[CH2:12][CH2:13][N:8]([CH:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:9][CH2:10]4)=[CH:16][C:17]=3[N:23]=2)=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1N
Agent: Cl
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cn1c(-c2ccc(Cl)cc2)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3.9 parts of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1 -methyl-1,2-benzenediamine, 2.5 parts of 4-chlorobenzaldehyde and 18 parts of nitrobenzene is stirred in an oil-bath first for 1 hour at 50° C. and further for 1.50 hours at 120° C. The reaction mixture is cooled and allowed to stand overnight at room temperature. About 100 parts of water are added and the whole is acidified with a hydrochloric acid solution 10 N. The product is extracted with 2,2'-oxybispropane. The aqueous phase is treated with activated charcoal. The latter is filtered off and the filtrate is alkalized with a sodium hydroxide solution 50%. The product is extracted with dichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is crystallized from 35 parts of 1,1'-oxybisethane. The product is filtered off, washed with 1,1'-oxybisethane and dried, yielding 1.3 parts of 2-(4-chlorophenyl)-5-[4-(diphenylmethyl)-1-piperazinylmethyl]- 1-methyl-1H-benzimidazole; mp. 198.3° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CC(C)(C)C([N:11]([CH2:21][CH2:22][O:23][CH3:24])[C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[CH:14][N:13]=1)=O.[NH2:27][C:28]1[C:29](=[O:42])[N:30]([CH:39]2[CH2:41][CH2:40]2)[C:31](=[O:38])[N:32]([CH2:35][CH2:36][CH3:37])[C:33]=1[NH2:34].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH:39]1([N:30]2[C:29](=[O:42])[C:28]3[NH:27][C:16]([C:15]4[CH:14]=[N:13][C:12]([NH:11][CH2:21][CH2:22][O:23][CH3:24])=[CH:20][CH:19]=4)=[N:34][C:33]=3[N:32]([CH2:35][CH2:36][CH3:37])[C:31]2=[O:38])[CH2:41][CH2:40]1
Reactant: COCCN(C(=O)C(C)(C)C)c1ccc(C(=O)O)cn1
Reactant: CCCn1c(N)c(N)c(=O)n(C2CC2)c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(C2CC2)c(=O)c2[nH]c(-c3ccc(NCCOC)nc3)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Oxalyl chloride (0.98 ml, 11.25 mmol, 1.05 eq) was added dropwise to a stirred solution of 6-[(2,2-Dimethyl-propionyl)-(2-methoxy-ethyl)-amino]-nicotinic acid (3 g, 10.71 mmol) in DCM (30 Ml) at 0° C. followed by one drop of DMF. Stirred at that temperature for 30 min before the addition of 5,6-Diamino-3-cyclopropyl-1-propyl-1H-pyrimidine-2,4-dione (2.4 g, 10.71 mmol, 1 eq) and followed by pyridine (0.866 ml, 10.71 mmol, 1 eq). The reaction mixture was allowed to warm to room temperature for 3 hr then the mixture was evaporated to dryness and redissolved in 30 ml of 4N NaOH. The reaction mixture was heated to reflux for a total of 5 hours. After cooling to room temperature, the pH adjusted with aqueous hydrochloric acid to 7-8. Water was evaporated to half volume then ethanol was added at 0° C. and stirred overnight (15 hr). The reaction mixture is filtered and the solid was washed with water and then ethanol. The product is then dried at 50° C. to provide 3.41 g (83%). 1H NMR (400 MHz, DMSO-d6) δ 13.68 (1H), 8.7 (1H), 8.0 (1H), 7.15 (1H), 6.6 (1H), 3.95 (2H), 3.48 (4H), 3.26 (3H), 2.6 (1H), 1.7 (2H), 1.05 (2H), 0.9 (3H), 0.7 (2H); m/z (ES+) 385.44
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[N:8][N:7]=1.CS(C)=[O:29]>CCOC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[O:29])=[N:8][N:7]=1
Reactant: CS(C)=O
Reactant: Cc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1Br
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2nnc(C(=O)c3ccncc3)c3ccccc23)cc1Br
Temperature: 25 °C
Reaction time: 240 h

Procedure:
A mixture of 1.22 g (3 mmol) 1-(3-brom-4-methyl-anilino)-4-(4-pyridyl-methyl)-phthalazine (expl. 14h) and 336 mg (3 mmol) potassium-tert.butylate in 10 ml DMSO is stirred in an open vessel for 10 days at RT. Then the yellow mixture is diluted with EtOAc and water, the aqueous layer separated off and extracted twice with EtOAc. The organic phases are washed twice with water and brine, dried (Na2SO4) and partly concentrated. After adding 10 g of SiO2, the residue is dried in vacuo and the resulting powder put on top of a SiO2-column. Eluation with dichloromethane/EtOAc (5:1→1:1→EtOAc) yields [4-(3-brom-4-methyl-anilino)phthalazin-1-yl](pyridin-4-yl)ketone (A) followed by [4-(3-brom-4-methyl-anilino)phthalazin-1-yl](pyridin-4-yl)methanol (B). A: m.p. 249-250° C.; FAB MS (M+H)+=419/421. B: m.p. 240° C.; FAB MS (M+H)+=421/423.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1C=CC(O)=[C:6](O)[CH:5]=1.[CH2:12]1[N:17]([CH2:18][CH2:19]O)[CH2:16][CH2:15]N(CCS(O)(=O)=O)C1>C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>[N:1]1[CH:2]=[C:3]([C@@H:16]2[CH2:15][CH2:19][CH2:18][N:17]2[CH3:12])[CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)CCN1CCN(CCO)CC1
Reactant: NCCc1ccc(O)c(O)c1
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: CN1CCC[C@H]1c1cccnc1
Reaction time: 0.17 h

Procedure:
Dopamine release was measured by preparing synaptosomes from the striatal area of rat brain obtained from Sprague-Dawley rats generally according to the procedures set forth by Nagy et al., J. Neurochem., Vol. 43, pp. 1114-1123 (1984). Striata from 4 rats were homogenized in 2 ml of 0.32M sucrose buffered with 5 mM HEPES (pH 7.5), using a glass-Teflon tissue grinder. The homogenate was diluted to 5 ml with additional homogenization solution and centrifuged at 1,000 x g for 10 min. This procedure was repeated on the new pellet and the resulting supernatant was centrifuged at 12,000 x g for 20 min. A 3 layer discontinuous Percoll gradient consisting of 16 percent, 10 percent and 7.5 percent Percoll in HEPES-buffered sucrose was made with the final pellet dispersed in the top layer. After centrifugation at 15,000 x g for 20 min., the synaptosomes were recovered above the 16 percent layer with a Pasteur pipette, diluted with 8 ml of perfusion buffer (128 mM NaCl, 2.4 mM KCl, 3.2 mM CaCl2, 1.2 mM KH2PO4, 1.2 mM MgSO4, 25 mM HEPES pH 7.4, 10 mM dextrose, 1 mM ascorbate, 0.01 mM pargyline), and centrifuged at 15,000 x g for 20 min. The new pellet was collected and re-suspended in perfusion buffer. The synaptosome suspension was incubated for 10 min. at 37° C. [3H]-Dopamine (Amersham, 40-60 Ci/mmol) was added to the suspension to give a final concentration of 0.1 uM, and the suspension was incubated for another 5 min. Using this method, 30 to 90 percent of the dopamine was taken up into the synaptosomes, as determined by scintillation counting following filtration through glass fiber filters soaked with 0.5 percent polyethyleneimine. A continuous perfusion system was used to monitor release following exposure to each ligand. Synaptosomes were loaded onto glass fiber filters (Gelman type A/E). Perfusion buffer was dripped onto the filters (0.2-0.3 ml/min.) and pulled through the filters with a peristaltic pump. Synaptosomes were washed with perfusion buffer for a minimum of 20 min. before addition of the ligand. After the addition of 0.2 ml of a solution containing various concentrations of ligand, the perfusate was collected into scintillation vials at 1 min. intervals and the dopamine released was quantified by scintillation counting Peaks of radioactivity released above background were summed and the average basal release during that time was subtracted from the total. Release was expressed as a percentage of release obtained with an equal concentration of (S)-(-)-nicotine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([O:12]C)=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH3:2].[OH-].[Li+]>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH3:2]
Reactant: CCOc1cc(C(=O)OC)ccc1-c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)O)ccc1-c1ccccc1C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
To a stirred solution of methyl 2-ethoxy-2′-methyl-1,1′-biphenyl-4-carboxylate (11 g, 40.6 mmol) in a mixture of THF (100 mL) and water (10 mL) was added lithium hydroxide (6.82 g, 162.7 mmol) in portions. After 24 hours at RT, the reaction mixture was evaporated and the residue was taken up with water. The aqueous layer was acidified with a concentrated aqueous solution of HCl and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under vacuum to afford of the title compound as pale yellow solid (9.7 g, 93%). LC/MS, M−(ESI): 255.0. 1H NMR (DMSO-d6, 400 MHz) δ 13.02 (1H, bs), 7.57 (2H, m), 7.18-7.25 (4H, m), 7.09 (1H, d), 4.05 (2H, q), 2.05 (3H, s), 1.18 (3H, t).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12](B(O)O)[C:13]([F:16])=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[N:25][CH:26]=1.C([O-])([O-])=O.[Na+].[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.COCCOC.O>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:21]2[CH:26]=[N:25][C:24]([O:27][CH2:28][C:29]([F:31])([F:32])[F:30])=[CH:23][CH:22]=2)[C:13]([F:16])=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cnc(F)c(B(O)O)c1
Reactant: FC(F)(F)COc1ccc(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: COCCOC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cnc(F)c(-c2ccc(OCC(F)(F)F)nc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
5-((tert-Butyldimethylsilyloxy)methyl)-2-fluoropyridin-3-ylboronic acid (0.400 g, 1.40 mmol) was placed into a flask with a mixture of DME/H2O (6 mL/2 mL). To the reaction mixture was added 5-bromo-2-(2,2,2-trifluoroethoxy)pyridine (0.358 g, 1.40 mmol), Na2CO3 (1.87 g, 17.6 mmol), and Pd(PPh3)4 (0.081 g, 0.07 mmol) and the reaction was allowed to stir at 80° C. overnight. The reaction was cooled to rt and concentrated. A solution of saturated NaHCO3 (5 mL) was added, and then this mixture was extracted with EtOAc (3×20 mL). The combined organic layer was then washed with saturated NaHCO3 (1×10 mL), brine (1×10 mL), dried (MgSO4), filtered, and concentrated. Purification by column chromatography (9:1 hexane:EtOAc) gave 5-((tert-butyldimethylsilyloxy)methyl)-2-fluoro-3-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)pyridine.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].C(N(CC)CC)C.[C:14](Cl)(=[O:16])[CH3:15].O>C(OCC)C>[C:14]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: OCC(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CC(=O)OCC(F)(F)F
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
85 g (0.85 mol) of trifluoroethanol and 80 ml of diethyl ether were poured to a separable flask of 1 liter, and further 129 g (1.27 mol/1.5 eq) of triethylamine was added thereto. Then, the resultant mixture was ice-cooled and stirred while dropping a solution diluting 100 g (1.27 mol/1.5 eq) of acetyl chloride with 80 ml of diethyl ether by dropping funnel. While dropping, the temperature of the solution was kept between 27° C. and 35° C. The period of time for dropping was 20 minutes. After that, the resultant mixed solution was stirred for 1.5 hours at room temperature and 350 ml of water was added, then, the reaction was completed. Subsequently, an organic phase was separated by the reparatory funnel and dried using magnesium sulfate. Thereafter, purification by distilling was conducted to obtain 88 g of 2,2,2-trifluoroethyl acetate of which yield was 73%.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].Cl.[NH2:7][CH:8]1[CH2:20][C:19]2[C:11](=[CH:12][C:13]3[CH2:17][CH2:16][O:15][C:14]=3[CH:18]=2)[CH2:10][CH2:9]1>C1C=CC=CC=1.C(N(CC)CC)C.O>[C:1]([NH:7][CH:8]1[CH2:20][C:19]2[C:11](=[CH:12][C:13]3[CH2:17][CH2:16][O:15][C:14]=3[CH:18]=2)[CH2:10][CH2:9]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: NC1CCc2cc3c(cc2C1)OCC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: CCC(=O)NC1CCc2cc3c(cc2C1)OCC3

Procedure:
A solution of propionyl chloride in 50 ml of benzene is added dropwise to a solution of 5 g of the compound of Example 2 in 100 ml of benzene and 4.2 ml of triethylamine. After one and a half hours' refluxing, the cooled mixture is diluted with water, separated off after being left to settle and extracted with benzene, and the organic phase is washed with water, dried over anhydrous sodium sulfate and evaporated under vacuum. The dry residue is recrystallized in acetonitrile.