Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[C:9](Cl)(=O)C1C=CC=CC=1.C(=O)(OC)OC>>[O:4]([CH3:9])[S:3]([C:2]([F:8])([F:7])[F:1])(=[O:6])=[O:5]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: COC(=O)OC
Product: COS(=O)(=O)C(F)(F)F
Temperature: 90 °C
Yield: 96.6 %

Procedure:
A further 49.15 g (0.328 mol) of trifluoromethanesulfonic acid, 46.10 g (0.328 mol) of benzoyl chloride and 29.49 g (0.328 mol) of dimethyl carbonate are added to the distillation residue with stirring. The reaction mixture is subsequently heated at 90° C. using an oil bath (temperature in the oil bath) for 6 hours, giving 52.00 g (yield: 96.8%) of pure methyl triflate by distillation.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([CH:11]([NH2:16])[CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CO>[N:1]1[C:10]2[CH:9]([CH:11]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][CH2:14][NH2:15])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NCCCC(N)C1CCCc2cccnc21
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCCCC(NCc1ccccc1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of N′-(1-(2-trimethylsilyl)-ethan-1yloxymethyl)-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-1,4-butanediamine (70 mg, 0.15 mmol) in methanol (4 mL) was added benzaldehyde (0.015 mL, 0.15 mmol). The mixture was stirred overnight at room temperature, then cooled to 0° C. Sodium borohydride (38 mg, 1.0 mmol) was then added, and the reaction was stirred for one hour, gradually warming to room temperature. The solution was then concentrated. The residue was taken up in dichloromethane and washed with 1N sodium hydroxide (3 mL), then dried over anhydrous sodium sulfate, concentrated and purified by chromatography on silica gel (10:1 dichloromethane:methanol) to afford N′-(1-(2-trimethylsilyl)-ethan-1yloxymethyl)-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-N-benzyl-1,4-butanediamine (39 mg, 49%). 1H NMR (CDCl3) δ 0.10(s, 9H), 0.80 (t, 2H, J=7.0 Hz), 1.41 (m, 3H), 1.76-2.21 (m, 5H), 2.44 (m, 2H), 2.46-2.26 (m, 2H), 3.35 (t, 2H, J=7.0 Hz), 3.67 (s, 2H), 4.06 (m, 1H), 4.08 (d, 1H, J=15.8 Hz), 4.22 (d, 1H, J=15.8 Hz), 5.80 (d, 1H, J=14.6 Hz), 6.02 (d, 1H, J=14.6 Hz), 7.00 (m, 1H), 7.27 (m, 8H), 7.42 (m, 1H), 7.80 (m, 1H), 8.44 (d, 1H, J=4.8 Hz).
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4]([C:6]1[C:10]([C@@H:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][C@H:12]2[N+:25]([O-])=O)=[C:9]([Si](C)(C)C)[S:8][CH:7]=1)=[O:5])[CH3:2].Cl>C(O)C.C(Cl)Cl.[Zn]>[CH2:32]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[C:10]([C@@H:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[CH2:14][CH2:13][C@H:12]2[NH2:25])=[CH:9][S:8][CH:7]=1)=[O:5])[CH3:33]
Reactant: CCN(CC)C(=O)c1csc([Si](C)(C)C)c1[C@@H]1c2cc(OC)c(OC)cc2CC[C@H]1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CCO
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cscc1[C@@H]1c2cc(OC)c(OC)cc2CC[C@H]1N
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a solution of 554 mg of trans-4-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-nitronaphthalene-1-yl) -5-trimethylsilyl-3-thiophenecarboxylic acid, N,N-diethylamide, from step 2c above, in 8 mL of ethanol and 3 mL of 6 N HCl was added 700 mg of Zn dust, and the mixture was stirred for 15 min. The mixture was diluted with 20 mL of methylene chloride, then filtered. The organic layer of the flitrate was separated. The aqueous layer was adjusted to pH 10 and extracted with methylene chloride. The extract was dried over Na2SO4, filtered and concentrated. The residue was dissolved in 7 mL of methanol, 3 mL of 6N HCl was added, and the solution was stirred for 4 hours. The methanol was evaporated off, and the residue was dissolved in 6 mL of water, which was then extracted with ether. The aqueous layer was adjusted to pH 10 and extracted with ethyl acetate. Removal of the solvent gave 256 mg of the title product. MS 389 (M+H)+. NMR (CDCl3) δ:7.24 (d, 1 H, J=6 Hz), 6.93 (d, 1 H, J=6 Hz), 6.58 (s, 1H), 6.43 (s, 1H), 4.23 (d, 1H, J=10 Hz), 3.85 (s, 3H), 3.67 (s, 3H), 3.64 (m, 1H), 3.50-3.30 (m, 4H), 3.0-2.76 (m, 2H), 2.32-2.22 (m, 1H), 1.90-1.80 (m, 1H), 1.26-1.12 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11](Cl)[O:12][CH3:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a solution of 4-bromophenol (1.0 g, 5.8 mmol) in anhydrous THF (10 mL) was added NaH (60%, 254 mg, 6.4 mmol) at 0° C. After being stirred at the temperature for 0.5 h, MOM-Cl (698 mg, 8.7 mmol) was added to the mixture. The mixture was stirred at 0° C. for 0.5 h, warmed to room temperature for 2 h, quenched with water, and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE:EtOAc=50:1) to give 1-bromo-4-(methoxymethoxy)benzene (1 g, yield 80%).
Reaction SMILES: FC1C=CC(OC)=C(C2C(C(O)=O)=CC([N+]([O-])=O)=CC=2)C=1.[Cl:22][C:23]1[C:24]([O:42][CH3:43])=[C:25]([C:29]2[C:30]([C:38]([O:40]C)=[O:39])=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[C:24]([O:42][CH3:43])=[C:25]([C:29]2[C:30]([C:38]([OH:40])=[O:39])=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cccc(Cl)c1OC
Agent: COc1ccc(F)cc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Product: COc1c(Cl)cccc1-c1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 95.5 %

Procedure:
This compound was prepared in a manner similar to that of 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid (EXAMPLE 107) from methyl (3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate) (230 mg) to afford 0.21 g (99%) of 3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid as a white solid. Data for 3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylic acid: 1H NMR (400 MHz, acetone-d6) 8.76 (d, J=2.5, 1H), 8.50 (dd, J=8.4, 2.5, 1H), 7.74 (d, J=8.5, 1H), 7.51 (dd, J=7.9, 1.8, 1H), 7.31 (dd, J=7.4, 1.8, 1H), 7.24 (t, J=7.9), 3.47 (s, 3H).
Reaction SMILES: [CH:1]12[C:9](=[O:10])[NH:8][C:7](=[O:11])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[H-].[Na+].[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][Cl:29])[CH2:22][CH2:21]1.Cl>CN(C)C=O>[ClH:29].[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][N:8]2[C:7](=[O:11])[CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]3[C:9]2=[O:10])[CH2:22][CH2:21]1
Reactant: O=C1NC(=O)C2CCCCC12
Reactant: ClCCCN1CCN(c2ncccn2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C2CCCCC2C(=O)N1CCCN1CCN(c2ncccn2)CC1

Procedure:
To a solution of cyclohexane-1,2-dicarboximide (6.50 g) in anhydrous dimethylformamide (65 ml), a 60% mineral oil suspension of sodium hydride (1.60 g) was added at room temperature while stirring, and the resultant mixture was continuously stirred for 30 minutes. A solution of 3-[4-(2-pyrimidinyl)piperazinyl]propyl chloride (11.30 g) in anhydrous dimethylformamide (30 ml) was dropwise added thereto, and the resultant mixture was stirred at room temperature for 4.5 hours. The solvent was removed under reduced pressure, and the residue was purified by chromatography to give an oily substance, which was then treated with hydrogen chloride to give N-[3-{4-(2-pyrimidinyl)-1-piperazinyl}propyl]cyclohexane-1,2-dicarboximide hydrochloride. M.P., 180°-182° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]([C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[OH:19])[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:18]([C:20]2[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[O:19])[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: COc1ccc(COc2cc(Br)cc(C(O)c3ccc(OC)nc3)c2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COc1ccc(COc2cc(Br)cc(C(=O)c3ccc(OC)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [3-bromo-5-(4-methoxy-benzyloxy)-phenyl]-(6-methoxy-pyridin-3-yl)-methanol in methylene chloride (5 mL) at room temperature was added Dess-Martin reagent. The resulting reaction mixture was stirred at room temperature for 1 h. Sat. NaHCO3 and Na2S2O3 were then added and the stirring was continued until both phases become clear. The organic phase was separated, dried and concentrated to provide [3-bromo-5-(4-methoxy-benzyloxy)-phenyl]-(6-methoxy-pyridin-3-yl)-methanone which was carried on to the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](#[N:10])[CH:8]=[CH2:9].N1(C(C)C#N)CCCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(O)C.O1CCCC1>[NH2:10][CH2:7][CH2:8][CH2:9][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: C=CC#N
Agent: CC(C#N)N1CCCCC1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCO
Product: NCCCN1CCCCC1

Procedure:
Reaction of piperidine (Aldrich, 8.4 g, 100 mmol) with acrylonitrile (7.96 g, 150 mmol) in ethanol (25 mL), reduction of the resulting piperidinopropionitrile with lithium aluminum hydride (5 g, 125 mmol) in tetrahydrofuran (150 mL), work-up and distillation under reduced pressure as described for Example 3 gave the title compound. Yield: 3 g (21%); bp. 65°-66° (6 Torr); [lit. bp. 110°-115° C. (31 Torr), J. Corse et al., J. Amer. Chem. Soc., 68, 1911 (1946)].
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([OH:21])=[O:20])[C:3]=1[Cl:22].C(C1NC=CN=1)(C1NC=CN=1)=O.C(=O)=O.[CH2:38](O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:20])[C:3]=1[Cl:22]
Reactant: OCc1ccccc1
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)O)c(Cl)c(N)c2F)c1F
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: O=C=O
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)c(Cl)c(N)c2F)c1F
Temperature: 90 °C
Yield: 78 %

Procedure:
To a solution of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinic acid (prepared by the methods described in U.S. Pat. No. 7,314,849 B2; 100 milligrams (mg), 0.29 millimoles (mmol)) in tetrahydrofuran (THF; 1 milliliter (mL)) was added carbonyl diimidazole (51 mg, 0.32 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes (min) when carbon dioxide (CO2) evolution ceased. Benzyl alcohol (62 mg, 0.58 mmol) was added, and the reaction mixture was heated in a benchtop microwave at 90° C. for 20 min. The reaction mixture was purified by silica gel chromatography (applied directly to an Isco 40 gram (g) RediSep® column eluting with 0-100% diethyl ether (Et2O) in hexanes) to yield a white solid (147 mg, 78%): mp 132-133° C., 1H NMR (400 MHz, DMSO-d6) δ 7.50-7.33 (m, 6H), 7.29 (dd, J=8.5, 7.1 Hz, 1H), 7.13 (s, 2H), 5.37 (s, 2H), 3.92 (s, 3H); ESIMS m/z 439 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>N1C=CC=CC=1>[CH3:23][O:22][C:16]1[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:2]([O:1][C:24](=[O:27])[CH2:25][CH3:26])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: COc1ccc(C=CC(=O)c2c(O)cc(OC)cc2OC)cc1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Product: CCC(=O)Oc1cc(OC)cc(OC)c1C(=O)C=Cc1ccc(OC)cc1
Yield: 90 %

Procedure:
A solution of 500 mg of 2'-hydroxy-4,4',6'-trimethoxychalcone and 0.15 ml of propionyl chloride in 5 ml of pyridine was stirred at room temperature for 6 hours. After removal of the solvent, the residue was treated with 10 ml of ice-water and 30 ml of chloroform. The mixture was shaken, and the chloroform layer was separated, washed with three 10 ml portions of water, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The oily residue was washed with a small amount of hexane, and the resulting solid was crystallized from ethanol/hexane, yielding 530 mg (90% yield) of 2',4,4'-trimethoxy-6'-(propionyloxy)chalcone as pale yellow needles; m.p. 117°-118° C.
Reaction SMILES: O.NN.[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15](CON4C(=O)C5=CC=CC=C5C4=O)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:9]=2[CH:37]=1>C(O)C>[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[CH:15]=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:9]=2[CH:37]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: Fc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2

Procedure:
In the manner given in Example 2, solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-fluoro-1-[(phthalimidooxy)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-(aminooxy)methyl]-8-fluoro-6phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: C[O:2][C:3](=[O:24])/[C:4](/[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)=[CH:5]/[CH:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1(/[CH:5]=[C:4](\[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)/[C:3]([OH:24])=[O:2])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCCC2)C(=O)O)cc1
Temperature: 47.5 °C
Yield: 97.5 %

Procedure:
A solution of (E)-3-cyclooctyl-2-(4-(methanesulfonyl)-phenyl)-acrylic acid methyl ester (2.82 g, 8.05 mmol) in ethanol (30 mL) was treated with a 1N aqueous sodium hydroxide solution (20 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (100 mL) and extracted with diethyl ether (1×75 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×100 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×150 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford (E)-3-cyclooctyl-2-(4-(methanesulfonyl)-phenyl)-acrylic acid (2.64 g, 97%) as a light yellow solid: EI-HRMS m/e calcd for C18H24O4S (M+) 336.1395, found 336.1390.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:14]([CH2:19][OH:20])([CH2:17]O)[CH2:15][OH:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)(OCC)OCC>O1CCCC1>[CH2:7]([C:14]1([CH2:15][OH:16])[CH2:17][O:20][CH2:19]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCC(CO)(CO)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(=O)OCC
Product: OCC1(Cc2ccccc2)COC1
Temperature: 110 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
A solution of potassium t-butoxide in tetrahydrofuran (1M, 24 mL) was added into a solution of 2-benzyl-2-(hydroxymethyl)propane-1,3-diol (90 g, 0.5 mol) and diethyl carbonate (55 g, 0.5 mol) in tetrahydrofuran (500 mL) under nitrogen. The reaction mixture was refluxed for 6 h and then heated to 110° C. to distill the solvent. Then the mixture was stirred at 155° C. for 24 h. The mixture was purified via silica gel chromatography (petroleum ether/ethyl acetate 10:1 to 2:1) to afford (3-benzyloxetan-3-yl)methanol (40 g, 0.226 mol, 49%) was a white solid.
Reaction SMILES: [Cl-].[NH4+:2].CC1C=CC(S([O:13][C@H:14]2[CH2:18]O[C@@H:16]3[C@@H:19](Br)[CH2:20][O:21][C@H:15]23)(=O)=O)=CC=1.N.CO>O.CC(O)C.[Zn]>[NH2:2][CH2:18][C@H:14]([C@@H:15]1[CH:16]=[CH:19][CH2:20][O:21]1)[OH:13]
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Agent: N
Agent: [Cl-]
Agent: [Zn]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: NC[C@@H](O)[C@@H]1C=CCO1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A solution of ammonium chloride (600 mg, 11.2 mmol) in water (7.5 mL) was added to a solution of bromotosylate (47) (3.0 g, 8.26 mmol) in propan-2-ol (15 mL) under argon. Zinc dust (600 mg, 9.2 mmol) was then added in portions over 4 minutes and the mixture was stirred for 16 hours before filtering the suspension through celite in vacuo. The filter cake was washed with diethyl ether (60 mL). Hydrochloric acid (1M, 60 mL) was added to the filtrate then the organic phase separated. The aqueous layer was extracted with diethyl ether (60 mL) then the combined organic phase was washed with brine (60 mL), then dried (MgSO4), filtered and reduced in vacuo. The residue was dissolved in ammonium hydroxide (18 mL) and a solution of ammonia in propan-2-ol (12 mL, 2.0M, 24 mmol), then divided into two equal portions and heated in sealed tubes at 75° C. for 16 hours. The mixtures were combined using methanol then the solvents were removed in vacuo. The residue was azeotroped with diethyl ether (3×10 mL) to obtain (R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[CH2:25][CH:24]([CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:29][CH2:28]3)[C:22](=[O:23])[C:17]2=[CH:18][C:19]=1[O:20][CH3:21]>C(OCC)(=O)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[CH2:25][CH:24]([CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:31][CH2:32]3)[C:22](=[O:23])[C:17]2=[CH:18][C:19]=1[O:20][CH3:21].[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C

Procedure:
Para-toluenesulfonic acid (1.902 g, dissolved in 35 ml of acetone) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 170.8° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:62])([F:61])[C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:52][CH:51]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:48][C:44]1[CH:43]=[C:42]([CH:40]([OH:41])[CH:39]([NH:38][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)=[O:14])[CH2:49][C:50]2[CH:55]=[CH:54][C:53]([C:56]([F:62])([F:61])[C:57]([CH3:60])([CH3:58])[CH3:59])=[CH:52][CH:51]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CC(C)(C)C(F)(F)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)C(F)(F)c1ccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 4-fluoronaphthalene-1-carboxylic acid (216 mg, 1.15 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (220 mg, 1.15 mmol) and 1-hydroxybenzotriazole monohydrate (176 mg, 1.15 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(1,1-difluoro-2,2-dimethylpropyl)phenyl]-1-propanol (0.40 g, 1.09 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered using a glass filter filled with silica gel. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-2-hydroxyethyl}-4-fluoro-1-naphthamide (289 mg, 49%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.CN(C)C=O.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32])[CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)O
Reaction time: 18 h

Procedure:
(2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (5.31 g, 22.96 mmol) and imidazole (7.82 g, 115 mmol) were combined in dichlorormethane (106 mL) and dimethylformamide (22 mL) at ambient temperature and treated with portionwise addition of tert-butylchlorodimethylsilane (7.61 g, 50.5 mmol). The mixture was stirred for 18 hours then diluted with water and extracted into ethyl acetate and concentrated to provide the title compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[O:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]1[N:28]=[C:29]([CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[S:30][CH:31]=1.[I-].[K+]>CC(=O)CC>[F:43][C:40]([F:41])([F:42])[C:37]1[CH:38]=[CH:39][C:34](/[CH:33]=[CH:32]/[C:29]2[S:30][CH:31]=[C:27]([CH2:26][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[O:10][CH:11]=[C:7]([CH2:6][N:1]5[CH:5]=[CH:4][N:3]=[N:2]5)[N:8]=4)=[CH:13][CH:14]=3)[N:28]=2)=[CH:35][CH:36]=1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(CCl)cs2)cc1
Reactant: Oc1ccc(-c2nc(Cn3ccnn3)co2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(-c4nc(Cn5ccnn5)co4)cc3)cs2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
A mixture of 0.1212 g (0.50 mmol) 4-(4-[1,2,3]triazol-1-ylmethyl-oxazol-2-yl)-phenol and 0.10 g (0.30 mmol) cesium carbonate in 10 ml butanone was stirred at 60° C. for 30 min, then 0.152 g (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-thiazole and 0.083 g (0.50 mmol) potassium iodide were added and stirring at 60° C. continued over night. After evaporation, 15 ml water was added and the mixture extracted with two portions of 15 ml ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide and water, dried over sodium sulfate and evaporated to give 201 mg raw material which was recrystallised from ethanol to yield 171 mg (67%) 1-[2-(4-{2-[(E)-2-(4-trifluoromethyl-phenyl)-vinyl]-thiazol-4-ylmethoxy}-phenyl)-oxazol-4-ylmethyl]-1H-[1,2,3]triazole as white crystals melting at 179-181° C.