Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[H-].[Na+].[CH3:25][S-:26].[Na+]>CN(C)C=O>[CH3:25][S:26][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20]
Reactant: O=C(O)C(CC1CCCCO1)c1ccc(F)c(C(F)(F)F)c1
Reactant: C[S-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(C(CC2CCCCO2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
A solution of 2-(4-fluoro-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (5.20 g, 16.24 mmol) in dry N,N-dimethylformamide (90 mL) at 25° C. under argon was carefully treated with 95% sodium hydride (410 mg, 17.05 mmol). The reaction mixture was stirred at 25° C. for 30 min and then was treated with sodium thiomethoxide (2.40 g, 32.48 mmol). This mixture was heated at 100° C. for 4.5 h and then concentrated in vacuo to remove N,N-dimethylformamide. The residue was diluted with water (100 mL) and then was acidified to pH=2 using a 1N aqueous hydrochloric acid solution. The resulting aqueous layer was extracted with ethyl acetate (2×600 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 chloroform/methanol to 9/1 chloroform/methanol) afforded 2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-3-(tetrahydro-pyran-2-yl)-propionic acid (5.70 g, 100%) as a yellow gum: EI-HRMS m/e calcd for C16H19F3O3S (M+Na)+ 371.0899. found 371.0902.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][OH:11])[CH3:8])([CH3:4])[CH3:3].[S:13](Cl)([CH3:16])(=[O:15])=[O:14]>N1C=CC=CC=1.C(Cl)Cl>[C:2]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][O:11][S:13]([CH3:16])(=[O:15])=[O:14])=[O:12])([CH3:1])([CH3:3])[CH3:4]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Hydroxyethyl)methylcarbamic acid 1,1-dimethylethyl ester (350 mg, 2.0 mmol) was dissolved in pyridine (2 ml). Mesyl chloride (0.229 ml, 2.1 mmol) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with methylene chloride, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over MgSO4 and concentrated under reduced pressure to give methanesulfonic acid 2-(tert-butoxycarbonyl-methyl-amino)-ethyl ester. This was used in the next reaction without complete purification.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16]([CH2:18][C:19]([C:21]([F:24])([F:23])[F:22])=[O:20])=O.[NH2:25]/[C:26](/[CH3:35])=[CH:27]\[C:28]([O:30][CH:31]1[CH2:34][CH2:33][CH2:32]1)=[O:29].C(O)(=O)C>CC(O)C>[CH3:35][C:26]1[NH:25][C:16]([CH3:15])=[C:18]([C:19](=[O:20])[C:21]([F:24])([F:23])[F:22])[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:27]=1[C:28]([O:30][CH:31]1[CH2:32][CH2:33][CH2:34]1)=[O:29]
Reactant: C/C(N)=C/C(=O)OC1CCC1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C(=O)OC2CCC2)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)C(F)(F)F)=C(C)N1

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 143.3 mg (0.93 mmol) of 1,1,1-trifluoroacetylacetone, 82.4 mg (0.53 mmol) of cyclobutyl 3-aminocrotonate and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated to reflux under argon for 10 h. The solvent is removed in vacuo, and the residue is purified by column chromatography (mobile phase: dichloromethane/methanol 95:5). 8 mg (3.2% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C(Cl)Cl>[C:26]([Si:23]([CH3:25])([CH3:24])[O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(CCc1cccc(O)c1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(CCC(=O)c2ccccc2)c1

Procedure:
The title compound was prepared as described in General Method 5 using 4.11 g (18.2 mmol) of 3-(3-hydroxy-phenyl)-1-phenyl-propan-1-one from Example M, 1.5 g (22 mmol) of imidazole, 3.0 g (20 mmol) of t-butyldimethylsilyl chloride and 75 mL of CH2Cl2. The product was carried on crude to the next step (see Example UU).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]=[CH2:26])[C:20]([O:22][CH3:23])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:40]>C(Cl)Cl.C(=O)(O)[O-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:25]3[O:40][CH2:26]3)[C:20]([O:22][CH3:23])=[O:21])(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(OCc1ccccc1)C(NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)C(OCc1ccccc1)C1CO1
Reaction time: 2 h

Procedure:
The methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-3-phenylmethoxy-4-pentenoate 63d (1.23 g, 2.48 mmol) is dissolved in methylene chloride (9 mL) and sodium bicarbonate (252 mg), in water (4 mL), then the reaction is cooled to 0° C. 3-Chloroperoxybenzoic acid is added slowly and the reaction is stirred for two hours. The substrate is still present so additional 3-chloroperoxybenzoic acid is added (1 g) along with 175 mg sodium bicarbonate and the reaction is stirred overnight. The mixture is diluted with aqueous sodium bicarbonate solution and methylene chloride and the layers are separated. The aqueous layer is washed with ethyl acetate (3 times) and the organic layers are combined and dried under reduced pressure. The resulting material is redissolved in ethyl acetate and washed with dilute sodium bicarbonate solution and then with brine, dried over magnesium sulfate and concentrated in vacuo to a light brown oil (2 g). The crude material is adsorbed onto silica gel and purified over a silica column eluting with hexane:ethyl acetate (8:2) followed with hexane:ethyl acetate (1:1). Product fractions are combined and dried to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH3:12])=[N:6][N:5]2[CH:13]=1.ClC(Cl)C.Cl[S:19]([OH:22])(=O)=[O:20].C([N:25](CC)CC)C.P(Cl)(Cl)(Cl)=O>O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH3:12])=[N:6][N:5]2[C:13]=1[S:19]([NH2:25])(=[O:22])=[O:20]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(O)Cl
Reactant: CCCc1ccc2nc(Cl)cn2n1
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCc1ccc2nc(Cl)c(S(N)(=O)=O)n2n1
Temperature: 25 °C

Procedure:
2-Chloro-6-n-propylimidazo[1,2-b]pyridazine (0.8 g, 4.1 mmol) and dichloroethane (10 ml) were introduced into a 200-ml eggplant type flask and stirred at room temperature, and chlorosulfonic acid (0.54 g, 4.5 mmol) was added thereto all at once, and the mixture was stirred for 4 hours under reflux. The reaction solution was cooled to about 70° C., and triethylamine (0.5 g, 5 mmol) was added thereto all at once and stirred until the solid was dissolved, and phosphorus oxychloride (0.79 g, 5 mmol) was added thereto all at once, and the mixture was stirred for 2 hours under reflux with heating. After the reaction was completed, the reaction solution was left and cooled, and water (50 ml) was added thereto and the organic phase was separated. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and concentrated, and acetonitrile (10 ml) and 28% ammonia water (4 ml) were added to the residue and stirred at room temperature for 2 hours. After the reaction was completed, water (100 ml) was added to the reaction solution which was then adjusted to about pH 2 with dilute hydrochloric acid, and the formed crystals were collected by filtration, washed with water and chloroform and dried under reduced pressure, to give the title compound as pale brown crystals. The yield was 0.49 g (43.5%; 3 steps).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[F:21][C:22]([F:34])([F:33])[O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:21])([F:33])[F:34])[CH:25]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(OC(F)(F)F)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-(trifluoromethoxy)-phenylboronic acid (67 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=O)[CH3:13].[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])=[N+:26]=[N-:27].O>CN(C=O)C>[CH:19]1([C:17]2[N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[N:26]=[N:27][C:16]=2[C:15]([O:14][CH2:12][CH3:13])=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: [N-]=[N+]=Nc1ccccc1F
Reactant: CCOC(=O)CC(=O)C1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1nnn(-c2ccccc2F)c1C1CCCC1
Reaction time: 0.25 h

Procedure:
DBU (2.99 ml; 20.06 mmol; 1.10 eq.) was dissolved in DMF (25 ml) and put under nitrogen atmosphere. 3-Cyclopentyl-3-oxo-propionic acid ethyl ester (Pharmacore, 3.695 g; 20.06 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (2.5 g; 18.23 mmol; 1 eq.) in DMF (5 mL) was added dropwise to the solution at room temperature. The mixture was stirred at 90° C. for 2 hours. Water (50 mL) was added to the cooled reaction mixture and the aqueous layer was extracted with EtOAc (3×50 mL). Combined organics were washed with water and brine, dried over MgSO4 and concentrated under vacuum affording the title compound as a yellow oil. It was used in the next step without further purification. LC/MS (Method B): 304.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[C:28](B(O)O)=[CH:29][S:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[C:27]([CH3:26])=[CH:31][S:30][CH:29]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cscc1B(O)O
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cscc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3-thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 200 mg, 64%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3-thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 200 mg, 64%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH3:8])[CH:2]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].C1C=CC=CC=1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH2:16]([O:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:8])[CH3:17]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1cccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)c1cccnc1

Procedure:
1-Pyridin-3-yl-ethanone, ethyl cyanoacetate, benzene, ammonium acetate, and acetic acid were refluxed for 16 hrs in a 250 mL round bottomed flask fitted with a Dean-Stark trap. The solutions were washed with water and brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography to yield the product as an oil. MS (ESI+) for C12H12N2O2 m/z 217.2 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:9]3C=CC=C[C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[N:3][C:2]=1[OH:15].Cl[C:17]1[N:26]=[CH:25][C:24]2[CH2:23][CH2:22]C3C=C(OC)C=C[C:20]=3[C:19]=2[N:18]=1.C(=O)([O-])[O-:34].[K+].[K+]>C(#N)C>[CH2:19]([N:3]1[C:2](=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:34])[CH3:24].[N:26]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[N:18]1[CH2:19][CH2:20][NH:1][CH2:10][CH2:5]1
Reactant: Oc1ncc2c(n1)-c1ccccc1CC2
Reactant: COc1ccc2c(c1)CCc1cnc(Cl)nc1-2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1C(=O)c2ccccc2C1=O
Product: c1ccc(N2CCNCC2)nc1

Procedure:
To a solution of bromoethyl phthalimide 1 (5 mmol) and 2-pyridyl piperazine 2 (5 mmol) in acetonitrile (10 mL) was added potassium carbonate (0.690 g, 5 mmol) and resulting reaction mixture was stirred under reflux. After completion of the reaction, solvent was removed on rotavap and residue was dissolved in chloroform (20 mL). Then washed with water (5 mL) and saturated sodium bicarbonate solution (5 mL), dried over anhydrous sodium sulfate. Filtered and evaporation of solvent gave pyridinylpiperazine ethyl-1H-isoindole-1,3(2H)-dione. Then dissolved in methanol (10 mL), hydrazine hydrate (0.48 mL, 15 mmol) was added and stirred under reflux to give a precipitate. Filtered, washed with methanol (5 mL) and evaporation of solvent gave 2-(4-pyridin-2-ylpiperazin-1-yl)ethanamine 3 which was used as such in the next step.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.[CH2:26]([OH:35])[CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33]O>ClCCl>[OH:35][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:23][C:22](=[O:24])[C:21](=[O:25])[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:16][CH:17]=1
Reactant: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Reactant: OCCOCCOCCO
Solvent: ClCCl
Product: O=C(OCCOCCOCCO)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The acid chloride, prepared from 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzene-acetic acid (0.5 g) as described in Example 6, was dissolved in dichloromethane (10 mL) and added dropwise to a stirred, cold (<-50° C.) mixture of triethylene glycol (0.9 g) in dichloro-methane (10 mL). The cooling bath was removed and the mixture stirred for 1 hour at room temperature. The mixture was diluted with dichloromethane and washed once with saturated aqueous sodium bicarbonate, once with water, and the organic solution was dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (dichloro-methane-ethyl acetate; 2:1) to provide, after crystallization from ethyl acetate-hexane, 0.36 g of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid 2-[2-(2-hydroxyethoxy)ethoxy]ethyl ester as a colorless solid, mp 70°-71° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:13]([NH:15][C:16]2[C:17]3[N:18]=[CH:19][N:20]([C:29]=3[N:30]=[CH:31][N:32]=2)[C@@H:21]2[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[CH2:22]2)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([N+:46]([O-:48])=[O:47])[C:41]=1[CH2:49][CH2:50][O:51][C:52](Cl)=[O:53].CC(O)C.N#N>C(Cl)Cl>[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([N+:46]([O-:48])=[O:47])[C:41]=1[CH2:49][CH2:50][O:51][C:52]([O:27][CH2:26][C@H:25]1[O:28][C@@H:21]([N:20]2[C:29]3[N:30]=[CH:31][N:32]=[C:16]([NH:15][C:13]([O:12][CH2:11][CH2:10][C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)=[O:14])[C:17]=3[N:18]=[CH:19]2)[CH2:22][C@@H:23]1[OH:24])=[O:53]
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)OCCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)OCCc1c(Cl)cccc1[N+](=O)[O-]
Agent: N#N
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COC(=O)OCCc2c(Cl)cccc2[N+](=O)[O-])O1)OCCc1ccc([N+](=O)[O-])cc1
Temperature: -60 °C
Yield: 83.2 %

Procedure:
N6 -(2-(4-nitrophenyl)ethoxycarbonyl)-2'-deoxyadenosine (5 g, 11.3 mmol) was co-evaporated with pyridine (2×60 ml, pro analysi quality, additionally dried over molecular sieve 4 Å), dissolved in pyridine (60 ml, see above) and cooled to -60° C. (i-PrOH/N2). A solution of 2-(2-chloro-6-nitrophenyl)ethoxycarbonyl chloride (4.17 g, 15.8 mmol) in CH2Cl2 (60 ml, dist. over CaH2) was added dropwise for 2 h. After it had been stirred another 2 h in conditions of i-PrOH/N2 cooling (-40° to -25° C.), the mixture was diluted with CH2Cl2 (150 ml) and washed with H2O (100 ml). The aqueous phases were post-extracted with CH2Cl2 (100 ml). Drying the organic phases over Na2SO4, filtering, evaporating the solvent under reduced pressure and co-evaporating with toluene (3×50 ml) yielded the crude product (8.73 g) which was purified by column chromatography (400 g SiO2, 28×5.7 cm, solvent: CH2Cl2 /MeOH 100:3). 5'-O-(2-(2-chloro-6-nitrophenyl)ethoxycarbonyl)-N6 -(2-(4-nitrophenyl)ethoxycarbonyl)-2'-deoxyadenosine (6.318 g, 83%) was obtained as a colourless foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([F:27])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([O:25]C)=O)[CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([Mg]Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([F:27])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[OH:25])[CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN1CCC(F)(c2cccc(OCc3ccccc3)c2)CC1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: OC(CCN1CCC(F)(c2cccc(OCc3ccccc3)c2)CC1)(Cc1ccccc1)Cc1ccccc1
Reaction time: 14 h
Yield: 49 %

Procedure:
A solution of methyl 3-[4-(3-benzyloxyphenyl)-4-fluoropiperidin-1-yl]propionate (100 mg, 0.27 mmol) in THF (5 mL) was cooled in an ice bath and a 2M solution of benzylmagnesium chloride in THF (0.338 mL, 0.68 mmol) added dropwise over 5 minutes. The resulting yellow solution was then stirred for 14 h during which time the reaction reached room temperature. The mixture was then quenched with 25% aqueous ammonium chloride solution (10 mL) and diluted with ethyl acetate (3×10 mL). The organic layers were then combined and dried over magnesium sulfate. Subsequent filtration, concentration and purification by silica gel chromatography (SiO2, 50% ethyl acetate/heptanes) afforded 3-[4-(3-benzyloxyphenyl)-4-fluoropiperidin-1-yl]-1,1-dibenzylpropan-1-ol as a clear viscous oil in 49% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:10][N:11]([CH2:13][CH2:14]O)[CH:12]=2)=[CH:4][CH:3]=1.FC1C=CC(C2C=N[N:32]([CH2:40]CO)[C:33]=2C2C=CN=CC=2)=CC=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:10][N:11]([CH2:13][CH2:14][N:32]([CH3:40])[CH3:33])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: OCCn1ncc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: OCCn1cc(-c2ccc(F)cc2)c(-c2ccncc2)n1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(C)CCn1cc(-c2ccc(F)cc2)c(-c2ccncc2)n1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
4-(4-Fluorophenyl)-3-(4-pyridinyl)-1H-pyrazole-1-ethanol (or 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazole-1-ethanol) prepared as set forth in Example 11 (1.36 g) was dissolved in 30 mL pyridine and cooled to 0° C., whereupon methanesulfonyl chloride (0.6 mL) was added. After stirring at 0° C. for 12 hours, about 20 g of ice was added, and the mixture was extracted with toluene (300 ml). After evaporation, the residue was used directly without further purification. 0.7 g of the above obtained compound was dissolved in methanol (25 mL), and dimethylamine/THF solution (4M, 2 mL) was added. The reaction on mixture was refluxed for 12 hours, then evaporated to dryness. The residue was purified by chromatography (methanol/dichloromethane 1:10). A mixture (0.59 g) of 4-(4-fluorophenyl)-N,N-dimethyl-3-(4-pyridinyl)-1H-pyrazole-1-ethanamine and 4-(4-fluorophenyl)-N,N-dimethyl-5-(4-pyridinyl)-1H-pyrazole-1-ethanamine were obtained. 1H NMR: consistent with the assigned structure. Mass spectrum, m/z: 311 (M+1). Anal. calc'd C18H19N4F.0.55H2O: C, 67.50; H, 6.33; N, 17.49. Found: C, 67.21; H, 6.46; N, 17.14.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:6].C([O-])([O-])=O.[K+].[K+].C(O)(=O)C.[CH3:39][NH:40][CH3:41]>C1COCC1.O>[CH3:39][N:40]([CH3:41])[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:6]
Reactant: CNC
Reactant: O=C(O)CCCCCCCC(CCCCCCCC(=O)O)OC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCCC(=O)OC(CCCCCCCC(=O)O)CCCCCCCC(=O)O
Temperature: 50 °C

Procedure:
The Bromoacid 251 (2 mmol) is dissolved in 2M solution of dimethylamine in THF (20 mL) and to it 1 g of anhydrous K2CO3 was added and the mixture was heated in a pressure bottle at 50° C. overnight. The TLC showed the completion of the reaction. The reaction mixture was acidified with acetic acid and diluted with water (100 mL) and extracted with dichloromethane (2×60 mL). The combined organic layers were concentrated dried and used as such in the next reaction. MW calcd for C23H43NO6 429.59. Found 430.6 (MH)+. 1H NMR (400 MHz, DMSO) δ 11.87-11.82 (m, 7H), 5.75 (d, J=0.7 Hz, 15H), 4.85-4.69 (m, 38H), 3.64-3.55 (m, 12H), 3.35-2.83 (m, 106H), 3.01-2.90 (m, 59H), 2.94 (ddd, J=30.6, 7.7, 4.0 Hz, 63H), 2.90-2.73 (m, 9H), 2.70 (s, 221H), 2.57-2.46 (m, 91H), 2.44-2.30 (m, 76H), 2.17 (t, J=7.3 Hz, 147H), 1.89 (tq, J=15.5, 7.6 Hz, 88H), 1.79-1.69 (m, 13H), 1.65-1.32 (m, 311H), 1.28 (d, J=46.0 Hz, 598H).