Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O)([O-])=O.[H][H]>[Ni].C(O)C>[F:20][C:19]([F:22])([F:21])[C:17]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][NH:1][C:4]=2[CH:18]=1
Reactant: O=Cc1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: FC(F)(F)c1ccc2c(c1)NCc1ccccc1O2

Procedure:
A solution of 55 parts of the ether obtained in the preceding paragraph in 800 parts of ethanol was hydrogenated over Raney nickel catalyst at room temperature and atmospheric pressure. When hydrogen uptake ceased, the catalyst was removed by filtration and the ethanol solvent was evaporated. The residue was then dissolved in 500 parts by volume of hexane, filtered, and then cooled. There was then obtained yellowish-white crystals which were separated by filtration to give 8-(trifluoromethyl)10,11,-dihydrodibenz -[b,f][1,4]oxazepine melting at about 86°-88° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23][CH2:24][CH2:25]O)=[CH:21][C:20]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)=[N:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:25][CH2:24][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:29][CH:28]=4)[CH:21]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCCO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCCCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester (example 2 e]) was reacted with 3-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-propan-1-ol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give (6-{3-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-propoxy}-indol-1-yl)-acetic acid ethyl ester as colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:18]1([N:13]2[C:12]([C:36]3[CH:37]=[CH:38][C:33]([CH3:32])=[CH:34][CH:35]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Cc1ccc(-c2c3c(nn2C2CCCCC2)CCNCC3)cc1
Yield: 44.6 %

Procedure:
The title compound (60.2 mg) was prepared as in Example 177, Steps C and D, using 203.8 mg of 2-cyclohexyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 177, Step B) and 181.6 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C20H27N3, 309.45; found, m/z 310.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37 (d, J=7.7 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 3.97-3.89 (m, 1H), 3.44-3.39 (m, 2H), 3.31-3.26 (m, 2H), 3.20-3.15 (m, 2H), 2.80-2.75 (m, 2H), 1.96-1.78 (m, 6H), 1.70-1.62 (m, 1H), 1.28-1.18 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8](=[O:35])[C:9]1[C:10](=[CH:30][CH:31]=[CH:32][C:33]=1[I:34])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=1[CH3:29])=[O:12])([CH3:6])[CH2:3][S:4][CH3:5].ClC1C=CC=C(C(OO)=[O:44])C=1>C(Cl)(Cl)Cl>[CH3:6][C:2]([NH:7][C:8](=[O:35])[C:9]1[C:10](=[CH:30][CH:31]=[CH:32][C:33]=1[I:34])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:21]([F:23])([F:22])[F:24])[C:25]([F:28])([F:26])[F:27])=[CH:16][C:15]=1[CH3:29])=[O:12])([CH3:1])[CH2:3][S:4]([CH3:5])=[O:44]
Reactant: CSCC(C)(C)NC(=O)c1c(I)cccc1C(=O)Nc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(C(F)(F)F)C(F)(F)F)ccc1NC(=O)c1cccc(I)c1C(=O)NC(C)(C)CS(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
In 10 ml of chloroform was dissolved 0.63 g (1.0 mmol) of N2-(1,1-dimethyl-2-methylthioethyl)-3-iodo-N1-{2-methyl-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl}phthalamide, and the resulting solution was cooled to 0° C. To the solution was added 0.19 g (1.1 mmol) of meta-chloroperbenzoic acid. After stirring for one hour, the reaction mixture was washed with 10% aqueous solution of potassium carbonate and dried on anhydrous magnesium sulfate, and the solvent was dissolved off under reduced pressure. Thus, 0.45 g of the objective compound was obtained (yield: 69%).
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:15][C:14]([CH3:16])=[CH:13][C:12](=[O:17])[CH2:11]1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH3:16][C:14]12[O:15][CH:10]([CH2:9][O:8]1)[CH2:11][C:12](=[O:17])[CH2:13]2
Reactant: CC1=CC(=O)CC(COCc2ccccc2)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC12CC(=O)CC(CO1)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A solution of 4.4 g of the 6-benzyloxy compound from Step 2 in EtOAc was hydrogenated with H2 and Pd/C (10%). After completion, the reaction was filtered on a bed of celite and then evaporated to dryness. The cru syrup was then taken up in CH2C2 containing 1 g of camphor sulphonic acid. The reaction was stirred at r.t. overnight, filtered and evaporated. Purification by flash chromatography (30% Et2O/pentane) gave 780 mg of the title compound (30%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:23][CH3:24])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C(N(C(C)C)CC)(C)C.Br[CH2:39][C:40]([NH2:42])=[O:41]>C(Cl)Cl>[C:40]([CH2:39][N:20]1[CH2:21][CH2:22][CH:17]([O:16][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[O:23][CH3:24])[N:9]=[CH:8][N:7]=[C:6]3[NH:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[C:3]=2[F:28])[CH2:18][CH2:19]1)(=[O:41])[NH2:42]
Reactant: NC(=O)CBr
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(CC(N)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (Example 2, 70 mg, 0.17 mmol) was dissolved in DCM (10 ml), and diisopropylethylamine (45 μl, 0.26 mmol) was added. 2-Bromoacetamide (36 mg, 0.26 mmol) was added, and the solution stirred for 16 hours at ambient temperature. The solvent was evaporated, and the residue purified by chromatography, eluting with 0 to 3% (7:1 MeOH/concentrated aqueous NH4OH) in DCM. The appropriate fractions were combined and evaporated, and the residue crystallised from acetonitrile to give the product as a white crystalline solid (48 mg, 60%); 1H NMR: 1.70-1.84 (m, 2H), 1.98-2.09 (m, 2H), 2.38 (m, 2H), 2.70-2.80 (m, 2H), 2.89 (s, 2H), 3.92 (s, 3H), 4.54 (m, 1H), 7.08 (br. s, 2H), 7.20 (s, 1H), 7.26 (ddd, 1H), 7.47 (ddd, 1H), 7.51 (ddd, 1H), 7.80 (s, 1H), 8.35 (s, 1H), 9.53 (s, 1H); Mass Spectrum: 460.5, 462.4.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][CH2:25]Cl)=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(#N)C>[C:1]([NH:5][C:6]1[C:7]([CH3:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[CH:17]=[C:18]3[C:21](=[O:22])[NH:23][CH2:24][CH2:25][N:19]3[N:20]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cccc(-c3cc(C(=O)NCCCl)n[nH]3)c2nc1NC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1nc2cccc(-c3cc4n(n3)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 85 °C
Yield: 35.3 %

Procedure:
To a 10-mL reaction vial was added 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-N-(2-chloroethyl)-1H-pyrazole-3-carboxamide (471a) (82 mg, 0.21 mmol), K2CO3 (88 mg, 0.64 mmol), DMF (1 mL), and ACN (1 mL). The vial was closed and the reaction mixture was heated at 85° C. for 5 h. The reaction mixture was cooled to RT and partitioned between water (5 mL) and EtOAc (5 mL). The organic extract was taken and washed with brine (10 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0-3% 2 M NH3/MeOH in DCM to provide 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (471) (26 mg, 35% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.51 (s, 1H), 7.86 (dd, J=1.27, 7.34 Hz, 1H), 7.75 (dd, J=1.08, 7.92 Hz, 1H), 7.36-7.42 (m, 2H), 6.07 (s, 1H), 4.36 (t, J=9.49 Hz, 2H), 3.90-3.97 (m, 2H), 2.56 (s, 3H), 1.51 (s, 9H). m/z (ESI, +ve) 351.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:20][C@@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][C@H:21]2[CH3:20])[N:3]=[C:4]([NH:9][CH3:10])[N:5]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CNc1nc(Cl)cc(N2CCOC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 48 h
Yield: 68.7 %

Procedure:
To a solution of 4,6-dichloro-N-methyl-2-pyrimidinamine (2 g, 11.23 mmol) in ethanol (50 mL) in a 200-mL RBF were added Hunig's base (5.89 mL, 33.7 mmol) and (3R)-3-methylmorpholine (1.546 g, 11.23 mmol). The reaction mixture was stirred at 100° C. in a sealed tube on a stirrer hotplate for 2 days. The reaction was concentrated in vacuo, and the residue was dissolved in EtOAc (200 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, filtered, then concentrated to afford the title compound (1.873 g) as a white solid. LC-MS (ES) m/z=243 [M+H]+.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[CH2:8]([O:10][C:11]([C:13]1[C:18]([O:19][CH2:20][CH3:21])=[C:17]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:16]=[C:15]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[N:14]=1)=[O:12])[CH3:9]>C1COCC1>[CH2:8]([O:10][C:11]([C:13]1[C:18]([O:19][CH2:20][CH3:21])=[C:17]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[N:16]=[C:15]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:6]([NH2:5])=[O:7])=[CH:32][CH:33]=2)[N:14]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1nc(-c2ccc(N)cc2)nc(N2CCOCC2)c1OCC
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(NC(N)=O)cc2)nc(N2CCOCC2)c1OCC
Yield: 40 %

Procedure:
Trimethylsilyl isocyanate (0.1 ml, 5 eq.) was added to a stirred solution of 2-(4-amino-phenyl)-5-ethoxy-6-morpholin-4-yl-pyrimidine-4-carboxylic acid ethyl ester (60 mg, 1 eq.) in THF (2 ml) and the mixture was reacted to reflux overnight. The reaction mixture was extracted with EA and washed with brine. The crude was purified by chromatography to give a product (26.2 mg, 40%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH:5]([NH2:7])[CH3:6].N1C=CC=CC=1.Cl[C:18]([O:20][CH3:21])=[O:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:7][C:18](=[O:19])[O:20][CH3:21])[CH3:6])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(N)c1cccc(Br)c1
Reactant: COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)NC(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
To a solution of 23.8 g of 3-bromo-α-methylbenzylamine in toluene (120 ml), 14.1 g of pyridine was added at room temperature. To this solution, 18.6 g of methyl chloroformate was dropwise added under cooling with ice, followed by stirring at room temperature for 2 hours. The reaction solution was poured into a citric acid aqueous solution and extracted with ethyl acetate. The organic layer was washed with a citric acid aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 10.5 g of methyl N-[1-(3-bromophenyl)ethyl]carbamate as a colorless transparent viscous liquid.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:18]([OH:20])[CH3:19].S(OC)(O[CH3:25])(=O)=O>O>[CH3:25][O:3][C:4]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:18]([OH:20])[CH3:19]
Reactant: COS(=O)(=O)OC
Reactant: CC(O)c1cccc(Sc2ccccc2F)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(Sc2ccccc2F)cccc1C(C)O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
A solution of potassium hydroxide (1.6 g) in water (20 ml) was added slowly to a mixture of 1-[2-hydroxy-3-(2-fluorophenylthio)phenyl]ethanol (2.1 g) and dimethyl sulfate (2 g), and the mixture was stirred at room temperature for 30 minutes and at 60° C. for an hour. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with dil. aqueous solution of sodium hydroxide and water in turn, dried and evaporated under reduced pressure. The oily residue (1.8 g) was purified by column chromatography (silica gel 30 g, toluene) to give 1-[2-methoxy-3-(2-fluorophenylthio) phenyl]ethanol (1 g).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19])([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[C:3]([O:5][CH2:6][CH2:7][O:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[C:12]([C:18]([F:19])([F:20])[F:21])[CH:13]=1)(=[O:4])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)OCCOc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 114.4 %

Procedure:
Ethyl bromoacetate (1.2 g, 10.9 mmol) was added in the suspension of 4-nitro-3-trifluoromethyl phenol (2.0 g, 9.66 mmol) and potassium carbonate (2.0 g, 14.5 mmol) in acetone, and the mixture was attired at room temperature for 6 hours. After the reaction mixture had been poured in ice water and acidified with 2N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with 5% sodium hydrogencarbonate aqueous solution and then with water, and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and 4-nitro-3-trifluoromethyl-phenoxyethyl acetate (3.24 g (theoretical amount: 2.83 g), 100%) was obtained as a yellow solid and was used in the next reaction without purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: Sc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC#CCOc1cc(Sc2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.3 %

Procedure:
To 5 ml of chloroform were added 0.57 ml of triethylamine and 0.5 g of 4-chloro-6-(2-butynyloxy)pyrimidine, to which 0.6 ml of a chloroform solution containing 0.33 g of thiophenol was slowly added dropwise, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2-butynyloxy)-6-(thiophenoxy)pyrimidine (the present compound (97)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:28]2[S:29][C:30]([CH3:33])=[CH:31][CH:32]=2)O1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:28]3[S:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1ccc(-c2cc3c(cn2)C(C)(C)CN3C(=O)OC(C)(C)C)s1

Procedure:
Prepared from 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester and 4,4,5,5-tetramethyl-2-(5-methyl-thiophen-2-yl)-[1,3,2]dioxaborolane using a procedure similar to Preparation 379. MS: [M+H]+=345.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Cc2ccccc2OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 75.2 %

Procedure:
To a solution of methyl 4-(2-benzyloxybenzyl)benzoate (1.0 g) in methanol (20 mL) was added 2 mol/L aqueous sodium hydroxide solution (7.5 mL), and the mixture was stirred at 60° C. for 5 hours. The reaction mixture was concentrated under reduced pressure. After the residue was acidified by adding dilute hydrochloric acid, the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4-(2-benzyloxybenzyl)benzoic acid (0.72 g).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:23])[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>>[ClH:1].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:23])[CH2:21][CH2:20][N:19]([CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1CNCCC1(F)c1cccc(OCc2ccccc2)c1
Reactant: BrCCOc1ccccc1
Agent: Cl
Product: CC1CN(CCOc2ccccc2)CCC1(F)c1cccc(OCc2ccccc2)c1

Procedure:
This material was prepared by the alkylation of 4-(3-benzyloxyphenyl)-4-fluoro-3-methylpiperidine hydrochloride with 1-bromo-2-phenoxyethane and subsequent salt formation with methanolic hydrogen chloride as described in Step 3 of Example 1 in 67% overall yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:15]C(=O)C)([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:14])([NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NC1(C)CCN(Cc2ccccc2)CC1
Agent: Cl
Product: CC1(N)CCN(Cc2ccccc2)CC1
Reaction time: 72 h
Yield: 100 %

Procedure:
A mixture of N-(1-benzyl-4-methyl-4-piperidinyl)acetamide obtained in Example 10-2 (3.45 g) and conc. HCl (41 mL) was heated under reflux with stirring for 72 hrs. After cooling, the mixture was quenched by adding 3N potassium hydroxide solution, and the resulting solution (pH11) was extracted with chloroform. The organic layer was washed with brine, dried over MgSO4, and concentrated to give the title compound as a pale brown oil (2.86 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].CN(C=O)C.C(N(C(C)C)CC)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][C:35]([C:40]([OH:42])=[O:41])=[CH:34]2>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][C:35]([C:40]([OH:42])=[O:41])=[CH:34]4)=[O:14])=[CH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2o1
Reactant: Nc1ccc2[nH]c(C(=O)O)cc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cc2cc(NC(=O)c3cc4cc([N+](=O)[O-])ccc4o3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the solution of 93.2 mg (0.45 mmol) 5-nitrobenzofuran-2-carboxylic acid (128) in 6 mL DMF 209.0 mg (0.45 mmol) PyBroP and 157 μL (0.9 mmol) diisopropylethylamine was added and the clear solution was stirred for 10 minutes at room temperature. The activated acid was transferred to resin 127 which was agitated for 5 hrs. The resin was drained, washed twice with DMF. The analytical sample showed no complete reaction and therefore the activation/coupling reaction was repeated once again the same way using fresh reagents. The resin was drained, washed five times with DMF to give 129 which was used immediately as described in Example 117.
Reaction SMILES: [CH2:1]1[C@@H:6](O)[C@@H:5]([OH:8])[C@H:4]([OH:9])[CH2:3][C@@:2]1([C:11]([OH:13])=[O:12])[OH:10].CO[C:16](OC)([CH3:18])[CH3:17]>CC(C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:10][C@@:2]12[CH2:1][C@@H:6]([O:13][C:11]1=[O:12])[C@H:5]1[C@H:4]([O:9][C:16]([CH3:18])([CH3:17])[O:8]1)[CH2:3]2
Reactant: O=C(O)[C@]1(O)C[C@@H](O)[C@@H](O)[C@H](O)C1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2[C@H]3C[C@@](O)(C[C@H]2O1)C(=O)O3
Yield: 86.2 %

Procedure:
A solution of quinic acid (10.0 g, 52.0 mmol), para-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol) and 2,2-dimethoxypropane (20 mL, 162.9 mmol) in acetone (150 mL) was refluxed for 4 hours. The reaction mixture was concentrated, and the concentrate was dissolved in ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered and concentrated. The concentrate was stored at 0° C. for several hours to afford 9.6 g (86%) of the desired product as white crystals.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[C:10]=1[CH3:26])=O)(C)(C)C>CCOC(C)=O.Cl>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)[C:10]=1[CH3:26]
Reactant: Cc1c(NC(=O)OC(C)(C)C)cccc1OCCc1ccc(C#N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(N)cccc1OCCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
t-Butoxycarbonylamino-3-[2-(4cyanophenyl)ethoxy]-2-methylbenzene (2.69 g, 7.64 mmol; from step (ii) above) were dissolved in EtOAc, pre-saturated with HCl(g), (150 mL) under nitrogen and stirred at room temperature overnight. After evaporation of the solvent the residue was partitioned between 10% aqueous HCl and EtOAc. The aqueous phase was washed with EtOAc, basified with NaOH (2M, aq.) and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4) and the solvent evaporated to afford 0.42 g (19%) of the sub-title compound.