Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][OH:23])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(C)=O>ClCCl>[C:1]([O:5][C:6]([C@@:8]1([CH:22]=[O:23])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CO)(C(=O)OC(C)(C)C)CC1=O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1C[C@@](C=O)(C(=O)OC(C)(C)C)CC1=O
Reaction time: 17 h
Yield: 71.7 %

Procedure:
(3S)-3-Hydroxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.0 g, 12.52 mmol) was dissolved in dichloromethane. Triethylamine (6.34 g, 62.62 mmol), dimethyl sulfoxide (3.91 g, 50.09 mmol), and a SO3-pyridine complex (3.99 g, 25.05 mmol) were sequentially added at 0° C., and the mixture was stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (60% ethyl acetate/hexane) to give 2.85 g of the title compound as a colorless solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17].[NH:32]1[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]1>CC(O)C.CCOC(C)=O>[Br:10][C:11]1[C:12]([N:32]2[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]2)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Temperature: 140 °C

Procedure:
DIPEA (73 μL, 0.42 mmol) was added to a solution of 5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 11.2, 123 mg, 0.3 mmol) and (R)-pyrrolidin-3-ol (31.4 mg, 0.36 mmol) in iPrOH (300 μL) in a vial, which was sealed and heated at 140° C. for 1 h. After cooling at RT, the RM was diluted with EtOAc, washed with brine, dried over Na2SO4 and the solvent evaporated off under reduced pressure to give a residue which was triturated with iPr2O, filtered and dried to afford the title compound as a white crystalline powder. HPLC (Condition 4) tR=5.9 min, UPLC-MS (Condition 3) tR=1.21 min, m/z=464.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:9].[H-].[Na+].S(OC)(O[CH3:28])(=O)=O.N>CN(C)P(=O)(N(C)C)N(C)C.O>[CH3:28][O:9]/[C:8](/[C:7]1[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=1[O:5][C:4]1[CH:19]=[CH:20][CH:21]=[C:2]([CH3:1])[CH:3]=1)=[CH:10]/[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CC(=O)c1ccccc1Oc1cccc(C)c1
Reactant: COS(=O)(=O)OC
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)/C=C(/OC)c1ccccc1Oc1cccc(C)c1
Yield: 22.3 %

Procedure:
A solution of 5 g (18 mmol) of methyl 2-(3-methylphenoxy)benzoylacetate in 30 ml of hexamethylphosphoric triamide (HMPT) is added dropwise to a suspension of 500 mg (21 mmol) of sodium hydride in 20 ml of HMPT, and the mixture is stirred until evolution of gas ceases. Then 2.5 g (20 mmol) of dimethyl sulfate are added dropwise, the mixture is stirred for 30 min, and then 30 ml of concentrated ammonia solution are added. The mixture is poured into water and extracted with MTB ether. The organic phase is dried and concentrated. Chromatography of the residue on silica gel with hexane/MTB ether yields in the first fractions 1.2 g (22%) of methyl (E)-β-methoxy-2-(3-methylphenoxy)cinnamate (trans product) as yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[C:8]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=3)[CH2:22][CH2:23]2)=[O:17])[CH:9]=1
Reactant: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCOCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Yield: 79.1 %

Procedure:
To a solution of (2-Morpholin-4-yl-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (preparation described in example 57, 150 mg, 0.323 mmol) in methanol (3 ml) was added Pd/C 10% (6.9 mg). The mixture was stirred under an atmospheric pressure of hydrogen at room temperature for 1 hour. Catalyst was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed over silicagel (Eluent: Heptane/Ethylacetate (0-100% in 20 minutes)) to provide the title compound (111 mg, 79% yield) as a yellow solid, MS (m/e): 435.2 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[C:67](=[NH:80])([C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:8][C:5]1[C:4]([NH:9][S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:3][C:2]([N:80]=[C:67]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[CH:7][N:6]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1cc(N=C(c2ccccc2)c2ccccc2)cnc1Cl)N1CCOCC1
Temperature: 110 °C
Yield: 23.4 %

Procedure:
To a 20 mL microwave vial was added N-(5-bromo-2-chloropyridin-3-yl)morpholine-4-sulfonamide (0.500 g, 1.40 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Acros) (0.048 g, 0.084 mmol), tris(dibenzylideneacetone)dipalladium (o) (Strem) (0.015 g, 0.017 mmol), sodium tert-butoxide (Fluka) (0.268 g, 2.8 mmol), toluene (10 mL), and benzophenone imine (Aldrich) (0.260 mL, 1.54 mmol). The resulting mixture was sealed off and microwave heated at 110° C. for 20 min. Reaction mixture was partitioned between EtOAc and Tris HCl 1M pH7. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (24 g, 10% to 20% EtOAc in hexanes) to afford the desired product as a yellow foam (150.0 mg). MS (ESI pos. ion) m/z: 457.0. 1H NMR (300 MHz, CDCl3) δ ppm 3.07 (d, J=4.38 Hz, 4H) 3.63 (d, J=4.38 Hz, 4H) 6.62 (br. s., 1H) 7.14 (d, J=3.95 Hz, 2H) 7.35 (d, J=5.85 Hz, 4H) 7.40-7.49 (m, 2H) 7.49-7.58 (m, 1H) 7.63 (s, 1H) 7.74 (d, J=7.16 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:21]1[N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:23]=[C:24]([CH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][CH3:29])[N:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=1.C[Sn](C)C.C[Sn](C)C.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O1CCOCC1.O.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.[Pd]>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:21]1[N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:23]=[C:24]([CH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][CH3:29])[N:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=2)=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)n1
Reactant: Fc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: C[Sn](C)C
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(Cc2ccc(-c3ccc(F)cn3)cc2)NC(=O)OCc2ccccc2)n1

Procedure:
Palladium tetrakis(triphenylphosphine) (69 mg, 0.06 mmol) was added to a degassed, ambient temperature solution of tert-butyl 2-[1-{[(benzyloxy)carbonyl]amino}-2-(4-bromophenyl)ethyl]-4-(2,2-dimethylbutyl)-1H-imidazole-1-carboxylate (for synthesis see Example 37) (324 mg, 0.60 mmol), 2-bromo-5-fluoropyridine (105 mg, 0.60 mmol) and hexamethylditin (195 mg, 0.60 mmol) in 1,4-dioxane (15 mL). After stirring at reflux overnight, the reaction mixture was diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Triethylamine (0.25 mL, 1.79 mmol) followed by di-tert-butyl dicarbonate (260 mg, 1.19 mmol) were added to an ambient temperature solution of the crude residue and N,N-dimethylaminopyridine (catalytic). After stirring at ambient temperature for 1 h, the reaction mixture was quenched with water and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded tert-butyl 2-{1-{[(benzyloxy)carbonyl]amino}-2-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}-4-(2,2-dimethylbutyl)-1H-imidazole-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][C:4]=2[S:5][C:6]=1[CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]1=[O:19].CC(=C)C.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:3]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:4]=2[S:5][C:6]=1[CH2:7][CH:8]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C:9]1=[O:19]
Reactant: COc1ccc2c(Cl)c(CC3CCN(C4CCCCC4)C3=O)sc2c1
Agent: BrB(Br)Br
Agent: C=C(C)C
Solvent: ClCCl
Product: O=C1C(Cc2sc3cc(O)ccc3c2Cl)CCN1C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
Dissolve 3-(3-chloro-6-methoxy-benzo[b]thiophen-2-ylmethyl)-1-cyclohexylpyrrolidin-2-one (1.122 g, 2.97 mmol) and 2-methyl-2 propene (0.5 mL) in dichloromethane (30 mL) and cool to 0° C. Slowly add boron tribromide (2.23 g, 8.91 mmol) and warm to room temperature. Stir for 1 hour and quench with ice. Extract with dichloromethane, dry with sodium sulfate, filter, and concentrate to give the title compound (1.121 g, 99%) as a light brown solid: Mass spectrum (apci) m/z=364.2 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][CH:12]=[O:13])[CH3:10].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][C@H:12]([OH:13])[C:22]([F:24])([F:23])[F:21])[CH3:10]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(CC=O)(N[S@](=O)C(C)(C)C)c1cccc(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C[C@H](O)C(F)(F)F)(N[S@](=O)C(C)(C)C)c1cccc(F)c1F
Reaction time: 0.33 h

Procedure:
To a cooled (−78° C.) solution of (R)-N-(2-(2,3-difluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (13.5 g, 44.5 mmol) in THF (300 mL) was added (trifluoromethyl)trimethylsilane (70.7 mL, 445 mmol) via syringe in 5 min (internal temperature was up to −55° C.). After stirring for 20 min, tetrabutylammonium fluoride, 1.0M solution in THF (66.8 mL, 66.8 mmol) was added dropwise via additional funnel (internal temperature −78 to −50° C. during addition). Addition was completed in 20 min. The reaction was stirred at the same temperature for 1 h. LCMS showed the diastereomer ratio was about 2:3 with the major one as the desired product. The reaction was quenched with 1N HCl (45 ml), and then the cool bath was removed. The reaction mixture was allowed to warm to ambient temperature during which water (100 ml) was added. The solution was extracted with EtOAc (2×). The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was triturated with minimum DCM. The resulted suspension was filtered. The filter cake was rinsed a few times with DCM and dried in air to afford 6.3 g of desired product as an white solid. The filtrate was concentrated and purified by silica gel column (0-70% EtOA/hexane) to afford additional 911 mg of desired product. MS m/z=374.1 [M+H]+. Calculated for C15H20F5NO2S: 373.4
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]([F:27])([F:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[N:16]=1>C(Cl)(Cl)Cl>[F:27][C:13]([F:12])([F:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[N+:16]=1[O-:6]
Reactant: FC(F)(F)Cc1cccc(CC(F)(F)F)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1c(CC(F)(F)F)cccc1CC(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
3-Chloroperoxybenzoic acid (4.52 g, 26.2 mmol) was added to a solution of 2,6-bis-(2,2,2-trifluoro-ethyl)-pyridine (4.25 g, 17.5 mmol) in CHCl3 (70 mL). The reaction was stirred at room temperature for 4 hours and then quenched with satd Na2SO3. The layers were separated and the aqueous layer was extracted with CH2Cl2. The organic layers were washed with 1 N NaOH, brine, dried over Na2SO4 and concentrated to a yellow oil. Purification by flash column chromatography (0% to 50% EtOAc in hexanes) gave the product as a yellow solid (2.65 g, 58%). 1H NMR (400 MHz, CDCl3): δ 3.96 (q, J=10.4 Hz, 4 H), 7.27 (t, J=8.1 Hz, 1 H), 7.47 (d, J=8.1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[CH:21](O)[CH2:20]2>>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:7]([O:9][CH:21]2[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]2)=[O:8])=[CH:4][CH:3]=1
Reactant: OC1CN2CCC1CC2
Reactant: Nc1ccc(C(O)(C(=O)O)c2ccccc2)cc1
Product: Nc1ccc(C(O)(C(=O)OC2CN3CCC2CC3)c2ccccc2)cc1

Procedure:
The 4-aminobenzil may be prepared according to the method of Augl et al, Annu. Conf., SPE, Reinf. Plastic/Compos. Div. Proc., 26th, 19D, 1 (1971). The 4-aminobenzil is rearranged to yield 4-aminobenzilic acid which is in turn esterfied to produce the ethyl ester. The ethyl ester of the 4-aminobenzilic acid is then reacted with quinuclidin-3-ol to give the expected 3-quinuclidinyl 4-aminobenzilate (4-amino-QNB). The purified 4-amino-QNB is then converted to the 4-triazeno-QNB according to the procedure reported by Tewson et al, J. Nucl. Med. 20, 671 (1979). The purified 4-triazeno-QNB is then reacted with iodide or a desired gamma-emitting radionuclide to produce the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[C:18]1([N:24]2[C:28]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[CH:27][C:26]([CH:34]=O)=[N:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][CH2:34][C:26]2[CH:27]=[C:28]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)[N:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:25]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Reactant: O=Cc1cc(-c2ccco2)n(-c2ccccc2)n1
Product: Cc1ccc(N2CCN(CCNCc3cc(-c4ccco4)n(-c4ccccc4)n3)CC2)c(C)c1
Yield: 92.2 %

Procedure:
Compound 30 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 1-phenyl-5-(2-furyl)pyrazole-3-carbaldehyde were used.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[F:21].[F:22][CH:23]([F:39])[O:24][C:25]1[CH:26]=[C:27]([N:31]2[CH:35]=[C:34]([C:36](O)=[O:37])[CH:33]=[N:32]2)[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>O.CN(C=O)C>[F:39][CH:23]([F:22])[O:24][C:25]1[CH:26]=[C:27]([N:31]2[CH:35]=[C:34]([C:36]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]4[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]4)=[CH:4][C:3]=3[F:21])=[O:37])[CH:33]=[N:32]2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1cnn(-c2cccc(OC(F)F)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)c(F)c2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cnn(-c4cccc(OC(F)F)c4)c3)c(F)c2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 59 %

Procedure:
(S)-tert-Butyl 2-(4-amino-3-fluorophenyl)morpholine-4-carboxylate (104 mg, 0.35 mmol), 1-(3-(difluoromethoxy)phenyl)-1H-pyrazole-4-carboxylic acid (107 mg, 0.42 mmol), HBTU (200 mg, 0.525 mmol) and N-methylmorpholine (106 mg, 115 μl, 1.05 mmol) were combined with DMF (4 ml) to give a light yellow solution. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into 50 ml of water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (20 g Silica gel, 70 to 50% ethyl acetate in heptane) to yield a white solid (110 mg, 59%). MS (ISP): 477.1 (100%, [M-tBu+H]+), 533.2 (30%, [M+H]+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:27][CH2:28][CH2:29][OH:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([O:27][CH2:28][CH:29]=[O:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCOCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOCC=O
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 72.3 %

Procedure:
A solution of 49.4 g of oxalyl chloride in 900 ml of methylene chloride was cooled to -60° C. and a solution of 60.82 g of dimethyl sulfoxide in 175 ml of methylene chloride was added dropwise over 1/2 hour so that the temperature did not exceed -50° C. The solution was then warmed to -20° C. and maintained at -20° C. in a dry ice-carbon tetrachloride bath as a solution of 44.6 g of 2-(hexadecyloxy) ethanol in 350 ml of methylene chloride was added over 20 minutes. The mixture was stirred at -20° C. for 20 minutes, 98.2 g of triethylamine was added and the mixture was allowed to warm to room temperature. Water was added, then the organic layer was separated, washed with dilute hydrochloric acid then dilute aqueous sodium bicarbonate until neutral, dried over sodium sulfate and activated charcoal and filtered through silica gel. The solvent was removed at a temperature not exceeding 30° C. The residue was dissolved in petroleum ether, washed with dilute aqueous sodium bicarbonate, dried over sodium sulfate and filtered through magnesium silicate. The filtrate was stored as a solution in a freezer. Immediately prior to use as the starting material in Example 4, the solvent was removed from the filtrate, giving 32 g of the desired compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8](O)[CH2:9][CH3:10])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.O=S(Cl)[Cl:24]>C(Cl)Cl>[Cl:24][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:5][CH:6]=1)[CH2:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CCC(O)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C
Solvent: ClCCl
Product: CCC(Cl)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C

Procedure:
0.468 g (1.58 mmol) of the above prepared [rac]-1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-propan-1-ol was dissolved in 7.6 ml of CH2Cl2 and treated dropwise at 0° C. with 0.23 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at RT for 30 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents yielded 0.496 g of pure title compound as light yellow oil.
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH:14]=O)=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH:14]2[NH:6][C:1](=[O:5])[CH:2]([CH3:4])[O:3]2)=[CH:10][CH:9]=1
Reactant: CC(O)C(N)=O
Reactant: O=CCOc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1OC(COc2ccc(Cl)cc2)NC1=O
Yield: 2.4 %

Procedure:
16.9g (0.19 mole) of lactamide was added to a solution containing 32.3g (0.19 mole) of (4-chlorophenoxy)acetaldehyde and 0.2g of p-toluenesulfonic acid in 500 ml of toluene. The mixture was refluxed with stirring for 5 hours while water was removed azeotropically. Toluene was removed under reduced pressure and the residue, which contained at least two major compounds, was purified by silica chromatography to give 1.1g of 2-(4-chlorophenoxymethyl)-5-methyl-4-oxazolidinone, cis isomer, as a white crystalline solid melting at 84°-86°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:15])=[CH:12][CH:13]=[O:14].[Cl-].[NH4+]>O1CCCC1.[Cu]Br>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([CH3:15])([CH3:10])[CH2:12][CH:13]=[O:14])=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)=CC=O
Agent: [Cu]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(CC=O)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Under a nitrogen atmosphere, a stirring solution of 66.6 grams (0.334 mole) of 4-fluorophenylmagnesium bromide (1M in diethyl ether) is cooled to -10° C., and 2.2 grams (0.015 mole) of copper(I) bromide is added in one portion. Upon completion of addition, a solution of 25.0 grams (0.297 mole) of 3-methyl-2-butenal in 20 mL of tetrahydrofuran is added dropwise at a rate to maintain the reaction mixture temperature at about 5° C. The complete addition requires about one hour. Upon completion of addition, the reaction mixture is stirred for one additional hour and then is stored in a refrigerator for about 18 hours. After this time the reaction mixture is poured into 500 mL of aqueous ammonium chloride and extracted with four portions of diethyl ether. The combined extracts are concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using methylene chloride as the eluant. The product-containing fractions are combined and concentrated under reduced pressure to a residue. The residue is subjected to a second column chromatography on silica gel, using 100% petroleum ether and combinations of methylene chloride in petroleum ether. The product-containing fractions are combined and concentrated under reduced pressure, yielding about 23.0 grams of 3-(4-fluorophenyl)-3-methylbutyraldehyde. The NMR spectrum is consistent with the proposed structure.