Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[CH:26]=1)[CH3:24]>>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:15]2[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:27]([CH:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:33])[CH:26]=1)[CH3:24]
Reactant: COC(=O)CCc1ccc(Oc2cc(F)cc(Br)c2)cc1C
Reactant: CCc1ccc(O)c(C(C)c2ccccc2)c1
Product: CCc1ccc(Oc2cc(F)cc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(C(C)c2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 4-ethyl-2-(1-phenyl-ethyl)-phenol as in Example 18 to afford 0.078 g (29%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C32H31O4F 498, found 499 (M+1, 100%).
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:16]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[C:5]1[CH2:18][O:19][CH2:20][CH3:21].C(N(CC)CC)C.[CH:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>ClCCl.C(=O)(O)[O-].[Na+]>[NH2:17][C:8]1[C:7]2[N:6]=[C:5]([CH2:18][O:19][CH2:20][CH3:21])[N:4]([CH2:3][C:2]([NH:1][C:37]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:38])([CH3:22])[CH3:23])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)N
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Reaction time: 8 h
Yield: 65.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 1-(2-amino-2-methylpropyl)-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (1.552 g, 4.94 mmol) in dichloromethane (50 mL) was cooled to 0° C. Triethylamine (1.38 mL, 9.92 mmol) and cyclohexylcarbonyl chloride (661 μL, 4.94 mmol) were added sequentially. Two (2) days later the reaction mixture was cooled and additional cyclohexylcarbonyl chloride (40 μL) was added. The reaction mixture was stirred overnight and then diluted with saturated sodium bicarbonate and dichloromethane (50 mL). The layers were separated. The organic layer was washed sequentially with water (×2) and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by flash chromatography (4×13 cm silica gel column, eluting with 3% methanol in chloroform). The purified material was dissolved in refluxing propyl acetate (80 mL) with the aid of methanol, the methanol was boiled off, and the solution was allowed to slowly cool. The resulting precipitate was isolated by filtration, rinsed with cold propyl acetate, and dried under high vacuum at 70° C. to provide 1.37 g of N-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-1,1-dimethylethyl]cyclohexanecarboxamide as a colorless crystalline solid, mp 210-211° C. Anal. calcd for C23H32N6O2: % C, 65.07; % H, 7.60; % N, 19.80. Found: % C, 64.93; % H, 7.76; % N, 19.97.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C>[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[C:14]2[C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[CH:7]=[N:6][C:5]=2[NH:4][N:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccccc1-c1n[nH]c2ncc3c(c12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To 77 mM solution of tert-butyl 1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (1.3 mL) in toluene and absolute ethanol (2:1) was added o-tolylboronic acid (0.0136 g, 0.1 mmol) followed by 1M solution of cesium carbonate (0.6 mL) and 1,1-bis(Di-tBuppf)PdCl2 (0.005 g). The reaction mixture was shaken at 110° C. for 24 hours. On completion of the reaction, the reaction mixture was extracted with EtOAc (2×2 mL). The organic layers were combined and concentrated under reduced pressure to give the desired crude product, tert-butyl 1-o-tolyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate as an brown solid, which was used in the next step without any further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:7]1(=[O:23])=[O:22])[CH3:5].[CH3:24][NH2:25]>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:25][CH3:24])[S:7]1(=[O:22])=[O:23]
Reactant: CC(CCBr)N1c2ccccc2N(c2ccccc2F)S1(=O)=O
Reactant: CN
Product: CNCCC(C)N1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
1-(3-bromo-1-methylpropyl)-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.04 g, 0.09 mmol) was dissolved in 2 mL of MeNH2 solution (8M in EtOH). The solution was irradiated in a microwave cuvette at 100° C. for 3 minutes. The reaction mixture was concentrated then loaded directly onto silica gel and purified via Isco chromatography (Redisep, silica, gradient 0-10% 7M ammonia/MeOH solution in dichloromethane) to afford 44 mg of 3-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N-methylbutan-1-amine.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(O)C>O>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[NH:11]
Reactant: NCc1ccccn1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Agent: I
Solvent: CCO
Solvent: O
Product: N=C(NCc1ccccn1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydriodide (U.S. Pat. No. 3,657,337) and 3.24 g. of 2-(aminomethyl)pyridine in 25 ml. of absolute ethanol is heated under reflux for 20 hours and diluted while hot with 75 ml. of water, causing the separation of an oil. On standing, the oil crystallizes and filtration gives 5.00 g. of pale yellow crystals, m.p. 125°-140° C. Recrystallization from aqueous ethanol gives the desired compound as pale yellow crystals, m.p. 159.5°-161° C.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[C:11]([CH2:12][CH2:13][C:14]([O:16][CH2:17]CCC)=O)=[CH:10][CH:9]=[C:8]([O:21]C)[N:7]=1)=O.Cl.C([O-])([O-])=O.[K+].[K+]>O>[CH3:17][O:16][C:14]1[N:5]=[C:6]2[C:11]([CH2:10][CH2:9][C:8](=[O:21])[NH:7]2)=[CH:12][CH:13]=1
Reactant: CCCCOC(=O)CCc1ccc(OC)nc1NC(=O)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2c(n1)NC(=O)CC2
Temperature: 80 °C
Yield: 78.6 %

Procedure:
A mixture of butyl 3-[2-[(2,2-dimethylpropanoyl)amino]-6-(methyloxy)-3-pyridinyl]propanoate (86.01 g, 256 mmol) in hydrochloric acid (500 ml, 3000 mmol) (6M aqueous), was heated at 80° C. for 6 h. Reaction was cooled, treated with water (500 ml), transferred to a 5 L conical flask and carefully neutralised with solid K2CO3 (requires around 250 g) (much effervescence was observed). The mixture was then extracted with 20% MeOH/DCM (3×500 ml). The combined organic solvents were then dried (MgSO4), filtered, evaporated to give the crude product as a yellow solid (35.84 g, 79%).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.Br[CH:18]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[CH3:20].N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Cu]I>[F:27][C:23]1[CH:22]=[C:21](/[C:19](/[CH3:20])=[CH:18]\[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(=CBr)c1cccc(F)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(C)ccc31)CCN(C)CC2)c1cccc(F)c1
Temperature: 25 °C

Procedure:
A mixture of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (234 mg, 1 mmol), 1-(1-bromoprop-1-en-2-yl)-3-fluorobenzene (258 mg, 1.2 mmol), L-proline (23 mg, 0.2 mmol), CuI (19 mg, 0.1 mmol) and potassium phosphate tribasic (424 mg, 2 mmol) in DMF was stirred at RT and purged with nitrogen. The reaction mixture was heated at 85° C. overnight. An additional 1 eq. of reagents was added and the mixture heated for an additional 24 h. The DMF was evaporated and the residue was poured into water. The precipitate obtained was filtered and purified by silica gel chromatography (100-200-mesh) using 0-5% MeOH:DCM as eluant followed by reverse phase HPLC to separate the isomers. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.30 (s, 1H), 7.16 (m, 2H), 7.0 (d, 1H), 6.92 (t, 1H), 6.85 (s, 1H), 6.70 (d, 1H), 6.62 (d, 1H), 3.60 (m, 1H), 3.40 (m, 1H), 3.25 (m, 1H), 3.10 (m, 1H), 2.95 (m, 2H), 2.90 (s, 3H), 2.70 (m, 2H), 2.42 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([O:15][C:16]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[CH:37][C:17]=1[C:18]([NH:20][C:21]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl.N1C=CC=CC=1>[C:1]([N:47]1[CH2:48][CH2:49][N:44]([CH2:43][CH2:42][O:41][C:38]2[CH:39]=[CH:40][C:16]([O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:17]([CH:37]=2)[C:18]([NH:20][C:21]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[O:19])[CH2:45][CH2:46]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCNCC2)ccc1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(C(C)=O)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, acetic anhydride (0.025 mL) was added to a solution mixture of methyl 2-(2-(benzyloxy)-5-(2-(piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.12 g) in methylene chloride (2.4 mL) and pyridine (0.027 mL), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform/methanol] to obtain methyl 2-(5-(2-(4-acetylpiperazin-1-yl)ethoxy)-2-(benzyloxy)benzamido)-4-phenylbenzoate as a colorless oily substance.
Reaction SMILES: [C:1]([O-])(=O)C.[CH3:5][C:6]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:7][C:8](=[O:12])[CH:9]=[CH:10][CH3:11]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(O)(=O)C>[CH3:5][C:6]1[CH:7]([C:8](=[O:12])[CH:9]=[CH:10][CH2:11][CH3:1])[C:16]([CH3:17])([CH3:18])[CH2:15][CH2:14][CH:13]=1
Reactant: CC(=O)[O-]
Reactant: CC=CC(=O)C=C(C)CCC=C(C)C
Agent: [Cu+2]
Solvent: CC(=O)O
Product: CCC=CC(=O)C1C(C)=CCCC1(C)C

Procedure:
248 g. of the acetate prepared according to paragraph (c) were heated at 90° during 5 h. in the presence of 500 ml. of acetic acid and 10 g. of copper acetate. By means of vapour phase chromatography it was shown that the starting acetate had completely reacted. The mixture was concentrated in vacuum and the residue was treated with 300 ml. of water. After extraction with petrol-ether and the usual treatments, 190 g. of a mixture consisting of 7,11-dimethyl-5-oxo-3,6,10-dodecatriene and two isomeric ketones, 7,11-dimethyl-5-oxo-3,7,10-dodecatriene and 11-methyl-7-methylene-5-oxo-3,10-dedacadiene, were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:21])([F:20])[F:9])=[CH:12][CH:13]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)c1ccc(-c2cccc(Br)n2)cc1
Yield: 22 %

Procedure:
To a solution of 2,6-dibromopyridine (1.25 g, 5.28 mmol) in dimethoxyethane (100 mL) and water (50 mL), was added 4-trifluromethylphenylboronic acid (1 g, 5.27 mmol) and sodium carbonate (1.45 g, 13.7 mmol). The resulting mixture was flushed with nitrogen prior to addition of tetrakis(triphenylphosphine) palladium (0) (60 mg, 0.05 mmol). The reaction mixture was heated to reflux under nitrogen for 5 h and then allowed to attain room temperature. The solvents were removed in vacuo and the residue diluted with water (50 mL) and then extracted EtOAc (2×100 mL). The organic solution was dried (MgSO4), filtered and the solvents removed in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting with 4:1 cyclohexane:chloroform afforded the title compound as a white solid (0.35 g).
Reaction SMILES: [CH3:1][C:2]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].BrC(C)C(OC)=O>C(O)C.[Ni]>[CH3:1][C:2]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(C)Oc1cccc([N+](=O)[O-])c1C
Agent: [Ni]
Agent: COC(=O)C(C)Br
Solvent: CCO
Product: COC(=O)C(C)Oc1cccc(N)c1C

Procedure:
Methyl 2-(2-methyl-3-nitrophenoxy)propanoate (8.2 g, 40 mmole), prepared by the method of Example 1 using methyl 2-bromopropanoate, was hydrogenated in 250 ml of ethanol using 1.0 g of Raney nickel. After reduction was complete, insolubles were removed by filtration and the filtrate concentrated in vacuo. The resultant solid (7.7 g) was used in further reactions without further characterization.
Reaction SMILES: O.[Al].[Li].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](C2CC(=O)NC2=O)=[CH:5]1.[OH-].[Na+].O>C1COCC1>[N:4]1([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[CH2:12][CH2:7][CH2:6][CH2:5]1
Reactant: O=C1CC(c2c[nH]c3ccccc23)C(=O)N1
Agent: [Al]
Agent: [Li]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(N3CCCC3)c[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium aluminum hydrate (2.86 g, 75.6 mmole) was suspended in dry THF (50 ml) with the exclusion of atmospheric moisture. The suspension was cooled by means of an ice-salt bath to an internal temperature of ca. 0° C. 3-(1H-indol-3-yl)-pyrrolidine-2,5-dione (3.24 g, 15.12 mmole) was then added in portions within 15 minutes. After ca. 1 hour the reaction mixture had reached RT and was then boiled under reflux for 32 hours. After the reaction mixture had cooled moist THF (5 ml water in 25 ml THF) was first carefully added, followed by 5M sodium hydroxide (3 ml) and finally water (3 ml). The reaction mixture was stirred for 20 minutes and filtered through diatomaceous earth. The solvent mixture obtained after washing the filter cake several times with methanol was evaporated to dryness. The oily residue obtained was purified by column chromatography on silica gel with methanol/30% aqueous ammonia (20:1). The product was filtered again through diatomaceous earth. The solution obtained by washing the diatomaceous earth several times with chloroform was evaporated to dryness. The desired product was thereby obtained as a viscous oil in a yield of 670 mg (24%).
Reaction SMILES: [C:1](=[NH:25])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][C:21]([F:24])([F:23])[F:22])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[OH:26]/[CH:27]=[C:28](/[CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[N:38][CH:39]=1)\[C:29](OC)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:29]=[C:28]([CH2:33][C:34]4[CH:39]=[N:38][CH:37]=[N:36][CH:35]=4)[C:27](=[O:26])[N:25]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[O:20][C:21]([F:24])([F:22])[F:23]
Reactant: COC(=O)/C(=C\O)Cc1cncnc1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(OC(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 110 °C
Yield: 43.7 %

Procedure:
A mixture of 4-(4-chloro-3-(trifluoromethoxy)phenoxy)phenethyl carbamimidate (80 mg, 0.213 mmol), (Z)-methyl 3-hydroxy-2-(pyrimidin-5-ylmethyl)acrylate (124 mg, 0.640 mmol) and Cs2CO3 (174 mg, 0.534 mmol) in 1,4-dioxane (2 mL) was heated with a microwave condition at 110° C. for 2 h. After cooling, the mixture was filtered through the celite. The filtrate was concentrated and purified via reverse phase flash chromatography to afford the title compound (48 mg, 0.093 mmol, 43.3% yield). LCMS: rt=3.48 min, [M+H+]=519
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:30][O:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:26][C:24]1[CH:23]=[C:22]([CH:27]2[CH2:30][O:29][CH2:28]2)[CH:21]=[C:20]([F:19])[C:25]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(F)cc(C2COC2)c1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(C3COC3)cc2F)OC1(C)C

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 equiv.), butyllithium (1.1 equiv.) and 3-(3,5-difluorophenyl)oxetane (1.0 equiv.) to give 2-(2,6-difluoro-4-(oxetan-3-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1H NMR (400 MHz, <cdcl3>) δ ppm 6.90 (d, J=8.22 Hz, 2H), 5.07 (dd, J=6.06, 8.41 Hz, 2H), 4.70 (t, J=6.26 Hz, 2H), 4.13-4.23 (m, 1H), 1.39 (s, 12H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]([O:12][C:13]([N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1F)=[O:14])([CH3:11])([CH3:10])[CH3:9].O>CS(C)=O>[C:8]([O:12][C:13]([N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1-n1cccn1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a mixture of pyrazole (1.0 g) and dimethylsulfoxide (50 ml), sodium hydride (0.54 g) was added under ice cooling. The reaction mixture was stirred under ice cooling for 1 h and then a solution of N-(2-fluoro-5-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester (5.0 g) in dimethyl sulfoxide (50 ml) was added. The reaction mixture was stirred at room temperature for 15 h and, after addition of water, subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:n-hexane=1:4) to give the titled compound (yield, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O:32][C:33]1[C:34](=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:35]([OH:37])=[O:36])(=[O:31])[CH3:30]>C(OCC)(=O)C.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O:32][C:33]1[C:34](=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:35]([O-:37])=[O:36])(=[O:31])[CH3:30]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccccc1C(=O)[O-]
Temperature: 25 °C

Procedure:
3.79 g of Donepezil is dissolved in 70 ml of ethyl acetate, and a solution of acetylsalicylic acid (1.80 g) in acetone (35 ml) is added slowly with stirring at room temperature. The solid precipitated is filtered. Melting point: 173-176° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[F:39])[CH:34]=O.O>C1COCC1>[F:39][C:38]1[CH:37]=[CH:36][C:33]([CH:34]=[CH:8][O:9][CH3:10])=[CH:32][C:31]=1[F:30]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 46.2 %

Procedure:
Potassium tert butoxide (11 g, 0.098 mol) was added to methoxymethyl triphenyl phosphonium chloride (31.12 g, 0.091 mol) in 150 ml of dry THF at −30° C. under argon atmosphere and stirred for 1 h. 3,4-difluorobenzaldehyde (10 g, 0.07 mol) in 60 ml of THF was added dropwise at the same temperature and stirring continued for 3 h at room temperature. The reaction mixture was treated with 100 ml water, 150 ml petroleum ether and filtered through celite. Organic layer was separated and aq. layer was extracted with petroleum ether (2×100 ml). Combined organic layer was washed with brine and dried over sodium sulfate. Solvent evaporation under reduced pressure followed by purification over silica gel using petroleum ether as eluent afforded (5.5 g) of the sub-titles compound as a colorless liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH3:36][Si:37]([CH3:53])([CH3:52])[CH2:38][CH2:39][O:40][CH2:41][O:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][CH:44]=1.Cl.C(N=C=NCCCN(C)C)C>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][C:47](=[O:48])[C:46]3[CH:50]=[CH:51][C:43]([O:42][CH2:41][O:40][CH2:39][CH2:38][Si:37]([CH3:52])([CH3:36])[CH3:53])=[CH:44][CH:45]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: C[Si](C)(C)CCOCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccc(OCOCC[Si](C)(C)C)cc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described under Example 24(l), from tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate and 4-(2-trimethylsilanyl-ethoxymethoxy)-benzoic acid using N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) as the condensation agent there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[2-[4-(2-trimethylsilanyl-ethoxymethoxy)-benzoyloxy]-ethoxy]-phenyl]-piperidine-1-carboxylate as a colourless, amorphous solid; MS: 728 (M+H)+.