Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Br:21])(=[O:3])[CH3:2].I[CH3:23].[H-].[Na+].O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH3:23])[CH:9]=[CH:8][C:7]=1[Br:21])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)OCc1cc(Nc2ccc(C#N)cc2)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(N(C)c2ccc(C#N)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-bromo-5-(4-cyanophenylamino)benzyl acetate (1.0 g, 2.9 mmol) in N,N-dimethylformamide (11 mL) under nitrogen atmosphere was added iodomethane (0.543 mL, 8.7 mmol), and the mixture was stirred in ice-water bath for five minutes. Then sodium hydride (0.174 g, 4.35 mmol) was added, and the reaction was stirred at room temperature for 24 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crude 2-bromo-5-[N-(4-cyanophenyl)-N-methylamino]benzyl acetate.
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].Br[CH2:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]=2[N:20]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([CH2:15][O:13][C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:3](=[O:5])[CH3:4])=[CH:8][CH:9]=3)[S:17][C:18]=2[CH:24]=1
Reactant: COc1ccc2nc(CBr)sc2c1
Reactant: CC(=O)Nc1ccc(O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc2nc(COc3ccc(NC(C)=O)cc3)sc2c1
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
57.6 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 197.8 mg of 4-acetamidophenol in 4 ml of dimethylformamide cooled in an ice-water bath and the resulting mixture was stirred at this temperature for 5 minutes. A solution of 371.5 mg of 2-bromomethyl-6-methoxybenzothiazole [prepared as described in step (a) above] in 1 ml of dimethylformamide was added to the reaction mixture, the temperature of the mixture was elevated to room temperature and the mixture was stirred for 2 hours. At the end of this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and an aqueous sodium chloride solution and them dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure and the resulting residue was purified by column chromatography through silica gel using a 1:2 by volume mixture of hexane and ethyl acetate to give 399.1 mg (yield 93%) of the title compound as a solid having a melting point of 145°-147° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[CH:19]([CH3:20])[C:18]2([CH3:24])[CH:21]([CH3:23])[CH2:22][CH:15]1[CH:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17]2.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1COCC1.[Cl-].[NH4+]>[CH3:13][N:14]1[CH:19]([CH3:20])[C:18]2([CH3:24])[CH:21]([CH3:23])[CH2:22][CH:15]1[C:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17]2
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1CC2(C)C(C)CC1N(C)C2C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C(=O)OCC)CC2(C)C(C)CC1N(C)C2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of diisopropylamine (3.0 mL, 22 mmol) in THF (34 mL) at 0° C. under nitrogen was added n-BuLi (8.8 mL, 22 mmol, 2.5 M in hexane). A solution of ethyl 2,3,4,8-tetramethyl-2-azabicyclo[2.2.2]octane-6-carboxylate (4.8 g, 20 mmol) in THF (46 mL) was added to the mixture and the reaction was stirred at 0° C. for 1 hour. Ethyl chloroformate (2.3 mL, 24 mmol) in THF (3 mL) was then added and the mixture was stirred for 15 minutes. The reaction mixture was diluted with saturated ammonium chloride and partitioned between water and ether. The aqueous layer was extracted with ether (2×) and the combined organic layers were dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with ether/hexane (15/85) to afford 3.9 g (63%) of diethyl 2,3,4,8-tetramethyl-2-azabicyclo[2.2.2]octane-6,6-dicarboxylate as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](B(O)O)[CH:7]=[CH:6]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:46]([O:48][C:49](=[O:52])[CH2:50]Br)[CH3:47]>CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.O.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:50][C:49]([O:48][CH2:46][CH3:47])=[O:52])[CH:7]=[CH:6]2
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.3 %

Procedure:
Into a 1 L round bottomed flask containing THF (335 mL) was added 6-methoxynaphthalen-2-ylboronic acid (20.15 g, 99.7 mmol, 1.2 eq), Pd(OAc)2 (563 mg, 2.51 mmol, 0.03 eq), tri-o-tolylphosphine (2.3 g, 7.56 mmol, 0.09 eq), K3PO4 (89 g, 419 mmol, 5 eq), and ethylbromoacetate (9.2 mL, 82.6 mmol, 1 eq). The resulting mixture was stirred for 24 h at room temperature. Water and EtOAc were added to the reaction and the mixture was stirred for 1 h. The layers were separated and both were saved. The aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford a crude material, which was subjected to silica gel chromatography (gradient elution 0% to 20% EtOAc in hexanes) to afford ethyl 2-(6-methoxynaphthalen-2-yl)acetate (15.4 g, 76%) as a white, crystalline solid.
Reaction SMILES: Cl.[F:2][CH2:3][CH2:4][N:5]([CH3:16])[C:6]1[N:15]=[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][N:8]2[N:7]=1.[CH2:17]([O:19][C:20]([C:22]1[CH:26]=[N:25][N:24]([CH3:27])[C:23]=1[C:28](O)=[O:29])=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[CH:26]=[N:25][N:24]([CH3:27])[C:23]=1[C:28](=[O:29])[NH:14][C:11]1[CH:12]=[CH:13][N:8]2[N:7]=[C:6]([N:5]([CH2:4][CH2:3][F:2])[CH3:16])[N:15]=[C:9]2[CH:10]=1)=[O:21])[CH3:18]
Reactant: CN(CCF)c1nc2cc(N)ccn2n1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Agent: Cl
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N(C)CCF)nc2c1
Yield: 76.1 %

Procedure:
The product was prepared in the same manner as described in example 65c) using N2-(2-fluoro-ethyl)-N2-methyl-[1,2,4]triazolo[1,5-a]pyridine-2,7-diamine hydrochloride (1.3 g, 5.3 mmol) and 2-methyl-2H-pyrazole-3,4-dicarboxylic acid-4-ethyl ester (1.08 g, 5.45 mmol) as starting materials. The solvent was evaporated and the resulting yellowish oil was triturated with sat. sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water 4 times and dried in vacuo affording 5-{2-[(2-fluoro-ethyl)-methyl-amino]-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl}-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.57 g, 76.2%) as a light yellow solid. MS: m/z=390.5 (M+H+).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:15]([O:17]C)=[O:16].Cl>O.CO>[F:3][C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1cccc2c(F)c(O)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2c(F)c(O)ccc12
Temperature: 80 °C

Procedure:
Sodium hydroxide (116 g, 2.9 mol) was dissolved in 100 mL water and added to a solution of methyl 5-fluoro-6-hydroxy-1-naphthoate (8.56 g, 38.9 mmol) in methanol (200 mL). The mixture was refluxed at 80° C. for 2 h. The mixture was allowed to cool to RT, then poured into 6N HCl in ice. The pH was adjusted to 3 to give a fine purple/pink solid. The title compound was isolated by centrifuge (with some salts).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=[C:4]2[N:3]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:5]2[N:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:11]=[C:4]2[N:3]=1
Reactant: CCOC(=O)c1cc2nc(Cl)cc(Cl)n2n1
Reactant: NC1CCOCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(Cl)cc(NC3CCOCC3)n2n1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a solution of ethyl 5,7-dichloropyrazolo[1,5-a]pyrimidine-2-carboxylate (7.82 g, 30.1 mmol) in N,N-dimethylformamide (100 mL) was added 4-amino-tetrahydropyran (3.65 g, 36.1 mmol) and triethylamine (9.12 g, 90.2 mmol) at 0° C. The reaction mixture was stirred for 70 min at room temperature, and then pored into water. The resulting precipitate was collected to give ethyl 5-chloro-7-(tetrahydro-2H-pyran-4-ylamino)pyrazolo[1,5-a]pyrimidine-2-carboxylate. MS (APCI): m/z 325 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:3]=1.[Li]CCCC.CO[N:18](C)[C:19](=O)[CH3:20]>C1COCC1>[CH:8]([C:4]1[CH:3]=[C:2]([C@@H:19]([NH2:18])[CH3:20])[CH:7]=[CH:6][CH:5]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1cccc(Br)c1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)c1cccc([C@H](C)N)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-3-isopropylbenzene (10 g, 0.05 mol) in THF was added dropwise with BuLi (47 mL, 0.075 mol) at −60° C. After stirred 30 minutes, N-methoxy-N-methylacetamide (6.22 g, 0.06 mol) was added. The mixture was stirred at −30° C. for 3 hours. Then the mixture was quenched with H2O, the mixture was partitioned between EtOAc and water. The layer was separated and washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to obtained the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:12]2[CH2:17][C:16]([CH3:18])=[CH:15][CH2:14][NH:13]2)([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[CH2:19](I)[CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:19]([N:13]1[CH2:14][CH:15]=[C:16]([CH3:18])[CH2:17][CH:12]1[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)([CH3:11])[CH3:10])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCI
Reactant: COc1ccc(C(C)(C)C2CC(C)=CCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCN1CC=C(C)CC1C(C)(C)c1ccc(OC)cc1
Yield: 75.1 %

Procedure:
A mixture of 1,2,3,6-tetrahydro-2-[1-(4-methoxyphenyl)-1-methylethyl]-4-methylpyridine (2.9 g), pentyl iodide (2.34 g), potassium carbonate (3 g) and dimethylformamide (20 ml) was heated to reflux for 4 hours while stirring. After cooling and adding water, the reaction product was extracted with benzene. The extract was washed twice with water, dried over potassium carbonate and distilled to remove benzene to obtain 2.8 g of 1,2,3,6-tetrahydro-1-pentyl-2-[1-(4-methoxyphenyl)-1-methylethyl]-4-methylpyridine as a viscous mass. To the mass was added 20 ml of 47% hydrobromic acid and the mixture was heated to reflux for 10 hours while stirring, after cooling, made alkaline with a concentrated ammonia water under cooling and extracted with chloroform. The extract was dried over sodium sulfate and distilled to remove chloroform. The residue was fed to a column chromatograph on silica gel and eluted with chloroform. Chloroform was distilled off from the eluate to obtain 2.2 g of 1,2,3,4,5,6-hexahydro-8-hydroxy-3-pentyl- 2,6-methano-1,1,6-trimethyl-3-benzazocine as a viscous mass. The product was treated as in Example 1-(5) to obtain the corresponding hydrochloride as colorless fine needles having a melting point above 230° C. (sublimable) after the recrystallization from methanol-ethyl ether.
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[C:19]([C:24](O)=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=1>>[NH2:17][C:18]1[C:19]([C:24]([NH:14][CH:12]([C:9]2[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=2)[CH3:13])=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Reactant: Nc1cccnc1C(=O)O
Agent: Cl
Product: CC(NC(=O)c1ncccc1N)c1ccc(OCC(F)(F)F)nc1
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (98 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (100 mg, 0.39 mmol, Amine-1, single enantiomer) and 3-aminopicolinic acid (54 mg, 0.39 mmol) by the similar manner in Step-1 of Example-8.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[F:20][C:21]([F:31])([F:30])[C:22]1[S:23][CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=1>>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:27]([C:25]3[N:26]=[C:22]([C:21]([F:31])([F:20])[F:30])[S:23][CH:24]=3)=[O:28])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: O=C(O)c1csc(C(F)(F)F)n1
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(C(F)(F)F)n3)n2)ccc(C#N)c1Cl
Yield: 13.35 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(trifluoromethyl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (376 mg, 1.370 mmol) and 2-(trifluoromethyl)thiazole-4-carboxylic acid (324 mg, 1.644 mmol). The product was triturated using DCM and heptane. Yield 13.35%. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 2.57 (s, 3H), 4.31 (dd, 1H), 4.46 (dd, 1H), 4.65 (m, 1H), 4.45 (d, 1H), 7.51 (d, 1H), 7.53 (d, 1H), 7.57 (d, 1H), 8.03 (d, 1H), 8.33 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([N:45]4[CH2:46][CH2:47][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:49][CH2:50]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: OCC(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(methyloxy)-4-[4-(methylsulfonyl)-1-piperazinyl]aniline (Example 232, step B) (51 mg, 0.18 mmol), and p-toluenesulfonicacid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (96 mg, 0.12 mmol, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.78 (s, 1H), 9.37 (s, 1H), 8.48 (s, 1H), 8.21 (d, J=5.13 Hz, 1H), 8.10 (d, J=1.83 Hz, 1H), 7.77 (dd, J=8.61, 2.02 Hz, 1H), 7.69 (d, J=8.80 Hz, 1H), 7.36-7.48 (m, 3H), 7.28 (d, J=8.43 Hz, 1H), 7.18 (t, J=8.07 Hz, 2H), 6.96 (t, J=6.78 Hz, 1H), 6.73 (d, J=2.20 Hz, 1H), 6.49-6.57 (m, 2H), 3.98 (s, 3H), 3.81 (s, 3H), 3.25 (br. s., 8H), 2.92 (s, 3H); MS (ESI): 741 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:16]([O-])([O-])=O.[K+].[K+].CI.O>CN(C)C=O.C(Cl)Cl>[CH3:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C=Cc2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(C=Cc2ccccc2)cc1

Procedure:
19.6 grams (0.1 mole) of 4-hydroxystilbene, 135 grams of K2CO3 and 135 grams of methyl iodide were stirred in 500 ml of dimethyl-formamide for 20 hours at room temperature. After dilution with water the mixture was shaken with methylene chloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:4][CH:3]=1)=[O:36])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CCOC(=O)COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
(dd) In an analogous manner to that described in Example 44(e), by alkylating tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 61(c)] with ethyl bromoacetate there was obtained tert-butyl (3RS,4RS)-4-(4-ethoxycarbonylmethoxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 520 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])([OH:3])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O:51][C:52](=[O:64])[CH2:53][C@H:54]([NH2:63])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[Cl:62])C>C(Cl)Cl>[C:52]([CH2:53][C@H:54]([NH:63][C:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:3])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[Cl:62])([OH:64])=[O:51]
Reactant: O=C(O)CCCc1ccccc1C(=O)O
Reactant: CCOC(=O)C[C@H](N)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)C[C@@H](Cc1ccccc1Cl)NC(=O)CCCc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 7.8 %

Procedure:
2-(3-Carboxy-propyl)benzoic acid (160 mg, 790 μmol, 1.0 eq.), DIPEA (439 μL, 3.2 eq.) and HATU (300 mg, 788 μmol, 1.0 eq.) were combined in DCM (20 mL) and stirred for 5 minutes at room temperature. (R)-3-amino-4-(2-chloro-phenyl)-butyric acid ethyl ester (200 mg, 827 μmol, 1.1 eq.) was added and the resulting mixture was stirred for 1 hour. The reaction was quenched with saturated NH4Cl, and the product was extracted with DCM, dried and evaporated. THF (20 mL) and 10 M aqueous NaOH (315 μL) was added and the mixture was stirred for 1 hour. The crude material was dissolved in AcOH (1.5 mL) and purified using preparative HPLC to yield the title compound (25 mg, 95% purity). MS m/z [M+H]+ calc'd for C21H22ClNO5, 404.12. found 404.4.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11](F)=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])[N:5]2[N:24]=[CH:25][N:26]=[C:4]2[N:3]=1.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][OH:32].[H-].[Na+].O>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:32][CH2:31][CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:20])[F:21])[N:5]2[N:24]=[CH:25][N:26]=[C:4]2[N:3]=1
Reactant: CN(C)CCCO
Reactant: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](Nc1c(-c2c(F)cc(OCCCN(C)C)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Temperature: 50 °C
Yield: 67.7 %

Procedure:
To a solution of 5-chloro-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine (600 mg, 1.5 mmol) and 3-dimethylamino-1-propanol (1.03 g, 10 mmol) in 5 mL of dimethylsulfoxide at room temperature is added sodium hydride (60% in mineral oil, 400 mg, 10 mmol). The mixture is heated at 50° C. for 30 min, and cooled to room temperature. Water is added to quench the reaction, and the product is extracted with ethyl acetate (x2). The combined organic extracts are washed with saturated sodium chloride (x4), dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 20% methyl alcohol in ethyl acetate. Concentration provides 5-chloro-6-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a colorless oil (486 mg). MS: m/z 479.2 (M+H).
Reaction SMILES: C(OC(N(C[C@H](O)C1C=CC=CC=1)CCC1C=CC([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[C:19](C3SC=CC=3)[CH:18]=2)=CC=1)=O)(C)(C)C.[OH-].[Na+]>CO>[C:23]([OH:25])(=[O:24])[C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1-c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccccc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 4′-[2-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(2-thienyl)-4-bipheylcarboxylate (188 mg) in methanol (3.3 ml) was added 1N aqueous sodium hydroxide solution (1.0 ml), and the mixture was stirred at 40° C. for 3 hours. The solvent was removed by evaporation, and the aqueous solution was acidified with 1N aqueous hydrochloride solution and extracted with ethyl acetate (30 ml×2). The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give a benzoic acid product. To a solution of the product in ethyl acetate (1.0 ml) was added 4N hydrogen chloride in ethyl acetate (1.0 ml), and the mixture was stirred at room temperature for 12 hours. The resultant solid was collected by filtration and dried to give 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(2-thienyl)-4-biphenylcarboxylic acid hydrochloride (139 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:12])[C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[C:22]([O:21][C:19]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[C:4]([F:12])[C:5]([F:11])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH2:15][CH2:14]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cc(Br)cc(F)c1F
Product: CC(C)(C)OC(=O)N1CCN(c2cc(F)c(F)c(C(=O)O)c2)CC1

Procedure:
5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,3-difluorobenzoic acid was prepared as in Example 2 (Step ii) using 5-bromo-2,3-difluorobenzoic acid and tert-butyl piperazine-1-carboxylate.