Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH:11]=[CH:10][C@H:9]([N:12]2[C:16]3[N:17]=[C:18]([S:22][CH2:23][CH2:24][CH3:25])[N:19]=[C:20](Cl)[C:15]=3[N:14]=[N:13]2)[C:6]21[CH2:8][CH2:7]2)(=[O:3])[CH3:2].[C:26]1([C@@H:32]2[CH2:34][C@H:33]2[NH2:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.OC(C(O)C([O-])=O)C([O-])=O.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([O:4][C@@H:5]1[CH:11]=[CH:10][C@H:9]([N:12]2[C:16]3[N:17]=[C:18]([S:22][CH2:23][CH2:24][CH3:25])[N:19]=[C:20]([NH:35][C@@H:33]4[CH2:34][C@H:32]4[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:15]=3[N:14]=[N:13]2)[C:6]21[CH2:8][CH2:7]2)(=[O:3])[CH3:2]
Reactant: CCCSc1nc(Cl)c2nnn([C@H]3C=C[C@@H](OC(C)=O)C34CC4)c2n1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCSc1nc(N[C@@H]2C[C@H]2c2ccccc2)c2nnn([C@H]3C=C[C@@H](OC(C)=O)C34CC4)c2n1

Procedure:
To a solution of the product of step f) (0.5 g) and (1R-trans)-2-phenyl-cyclopropanamine, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1) (prepared as described by L. A. Mitscher et al., J. Med. Chem. 1986, 29, 2044) (0.4 g) in dichloromethane (50 ml) was added N,N-diisopropylethylamine (2 ml) and the resulting solution was stirred and heated at reflux for 3 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by chromatography (SiO2; 4:1 isohexane:ethyl acetate) to give the subtitle compound (0.6 g).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23]O)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:25]4[CH:29]=[N:28][CH:27]=[N:26]4)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Reactant: c1nc[nH]n1
Product: C(=C/c1nc(COc2ccc(CCn3cncn3)cc2)co1)\c1ccccc1
Yield: 75 %

Procedure:
In substantially the same manner as in Working Example 1, 2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethanol was allowed to react with 1,2,4-triazole to give 1-[2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethyl]-1,2,4-triazole. The yield was 75%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 136-137° C.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=[O:5].[H][H]>C(O)(=O)C.[C].[Pd]>[CH3:1][C:2]([CH3:16])([CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)(CC(=O)O)CC(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(CCc1ccccc1)CC(=O)O
Yield: 89.2 %

Procedure:
3,3-Dimethyl-5-oxo-5-phenylpentanoic acid (17.0 g, 77.2 mmol) was subjected to hydrogen catalytic reduction in acetic acid (170 ml) by using 10% palladium-carbon as a catalyst. After completion of the reaction, the catalyst was filtered off and the solvent was distilled off under reduced pressure to obtain 14.2 g of 3,3-dimethyl-5-phenylpentanoic acid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[C:10]([OH:12])=[O:11]>C(O)(C(F)(F)F)=O>[CH3:5][O:6][C:7]1[C:15]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[CH:14][C:13]([N+:1]([O-:4])=[O:2])=[C:9]([CH:8]=1)[C:10]([OH:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)O)ccc1OCCCN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
Fuming nitric acid (1.5 ml, 36.2 mmol) was added slowly at 0° C. to a solution of 3-methoxy-4-(3-morpholinopropoxy)benzoic acid (7.78 g, 23.5 mmol) in TFA (25 ml). The cooling bath was removed and the reaction mixture stirred at ambient temperature for 1 hour. The TFA was removed by evaporation and ice was added to the residue. The precipitate was collected by filtration, washed with a minimum of water followed by toluene and ether. The solid was dried under vacuum over phosphorus pentoxide to give 5-methoxy-4-(3-morpholinopropoxy)-2-nitrobenzoic acid (7.54 g) which was used without flirther purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[C:3]=1Cl.[NH2:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=2)[N:24]=[CH:23][N:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[C:3]=1[O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1
Reactant: CS(=O)(=O)c1cccc(Cl)c1Cl
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(Nc2ncnc3ccc(Oc4c(Cl)cccc4S(C)(=O)=O)cc23)n1

Procedure:
The compound of Example 91 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 1,2-dichloro-3-methylsulfonylbenzene, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C([O-])(O)=O.[Na+].[OH-].[Na+].[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>C(OCC)C.O>[C:16]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: C=C(C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mechanically stirred mixture of L-proline (42.0 grams, g), NaHCO3 (148 g), H2O (680 milliliters, ml) and diethyl ether (280 ml) was maintained in an ambient temperature bath at pH 10.5-10.7 (adjusted by the addition of concentrated aqueous NaOH), then treated portionwise over 20 minutes with a solution of redistilled methacryloyl chloride (40 ml) in diethyl ether (20 ml). Additional concentrated aqueous NaOH was added as needed to keep the pH at 10.5-10.7. Upon addition of all of the methacryloyl chloride (and pH stabilization), the mixture was stirred for 20 minutes at ambient temperature. The resulting immiscible phases were separated and the aqueous phase was extracted with two 250 ml portions of diethyl ether. The combined organic extracts were washed with H2O (50 ml), and the aqueous extract was added to the aqueous phase which phase was then acidified to pH 1 with concentrated aqueous HCl and then extracted with four 250 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with about 100 ml of brine (saturated aqueous sodium chloride solution) and then dried over Na2SO4. The resulting solution was filtered and concentrated in vacuo to about 230 ml and then heated to boiling, diluted with hexane (80 ml) and allowed to cool. Upon cooling, the desired N-methacryloyl-L-proline spontaneously crystallized as chunky white prisms (51.3 g). The concentrated mother liquor yielded a second crop of crystals (4.26 g) when crystallized as described above. A portion of the first crop was recrystallized twice from ethyl acetate to give an analytical sample, m.p. 102°-104.5° C., having the following spectral characteristics:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([C:46](=[O:54])[CH2:47][NH:48][C:49]2[S:50][CH:51]=[CH:52][N:53]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:42][CH2:41][N:40]([C:46](=[O:54])[CH2:47][NH:48][C:49]4[S:50][CH:51]=[CH:52][N:53]=4)[CH2:45][CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(CNc1nccs1)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)CNc2nccs2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-piperazin-1-yl-2-(thiazol-2-ylamino)-ethanone dihydrochloride (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C38H44Cl2N7O3S [(M+H)+] 748.2598, observed 748.2602.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[C:9]1=[O:21].[OH-:22].[Na+]>O1CCOCC1>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][CH2:14][CH2:13][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:12])[C:9]([OH:21])=[O:22]
Reactant: C[C@H]1[C@@H](CCCc2cccs2)C(=O)N1OC1CCCCO1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](NOC1CCCCO1)[C@@H](CCCc1cccs1)C(=O)O
Temperature: 23 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-(thiophene-2-yl)-1-propyl)-4-methylazetidin-2-one (91 mg, 0.295 mmol) in dioxane (1 mL) is added 1 M aqueous sodium hydroxide (0.44 mL). The solution is stirred at 23° C. for 18 h, then extracted with hexanes (10 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 20 mL portions of ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(3-(thiophene-2-yl)-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as an oil (91 mg, 94% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:26]O>>[F:1][C:2]1[CH:3]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([OH:26])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OO
Reactant: CCCCCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1F
Product: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1F

Procedure:
This was prepared using a similar method to that described for compound 12. Quantities: 3-fluoro-4-octoxybiphenyl-4'-yl-boronic acid (11) (4.40 g, 0.012 mol), 10% hydrogen peroxide (16 ml, 0.036 mol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[N:26]3[C@@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>CN(C=O)C>[CH2:20]1[C@H:21]2[N:26]([CH2:25][CH2:24][CH2:23][CH2:22]2)[C@H:18]([C:15]2[CH:14]=[CH:13][C:12]([S:8][C:4]3[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=3)=[CH:17][CH:16]=2)[CH2:19]1
Reactant: Nc1cccc(S)c1
Reactant: Brc1ccc([C@@H]2CC[C@@H]3CCCCN32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cccc(Sc2ccc([C@@H]3CC[C@@H]4CCCCN43)cc2)c1
Temperature: 25 °C
Yield: 46.2 %

Procedure:
A solution of 2 g (0.016 mole) of 3-aminothiophenol in 25 mL of dry DMF was added to 0.016 mole of sodium hydride (from 0.77 g of 50% sodium hydride washed with hexane to remove the oil). After all the sodium hydride has reacted, a solution of 2.8 g (0.01 mole) of trans-3-(4-bromophenyl)octahydroindolizine in 20 ml of dry DMF and 0.72 g (0.005 mole) of cuprous oxide were added. The mixture was refluxed overnight. Then an additional 0.35 g (0.002 mole) of cuprous oxide was added to the reaction mixture, and the mixture was refluxed for two days. The reaction was the cooled to room temperature, filtered and the DMF evaporated in vacuo to give a brown oil. The oil was flash chromatographed in SiO2 using 75% hexane, 25% EtOAc as the eluant. The product bearing fractions were pooled and the solvent evacuated in vacuo to give 1.5 g (46% yield) of the title compound as a red oil.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:25])(=[O:24])[NH:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH:7]=1.CO>>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[NH:13][S:12]([C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:26])=[O:2])[CH:11]=[CH:10][CH:9]=1)(=[O:24])=[O:25]
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Solvent: CO
Product: O=C(O)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Reaction time: 0.5 h

Procedure:
To a suspension of 3-[3-(naphthalen-2-ylsulfamoyl)-phenyl]-acrylic acid methyl ester (14e) (0.25 g, 0.68 mmol) in methanol (3.5 ml) 2N NaOH solution (1.0 ml, 2.0 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and stirred for 30 min. The precipitated solid was filtered, washed with water and dried in desiccator over P2O5. The title compound was obtained as a white solid (0.21 g, 87%). 1H NMR (DMSO-d6, HMDSO), δ: 6.56 (1H, d, J=16.0 Hz), 7.21-8.01 (11H, m); 8.12 (1H, s); 10.56 (1H, br s); 12.54 (1H, br s).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]#[N:10])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C=O)C>[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][N:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]#[N:10])=[N:2]1
Reactant: Fc1ccccc1CBr
Reactant: N#Cc1n[nH]c2c1CCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1nn(Cc2ccccc2F)c2c1CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.320 g (77.50 mmol) of 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile were dissolved in 100 ml of DMF, 30.304 g (93.01 mmol) of caesium carbonate and 16.116 g (85.26 mmol) of 2-fluorobenzyl bromide were added, and the mixture was stirred at RT overnight. The mixture was concentrated and taken up in dichloromethane, and water was added. The organic phase was removed and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, filtered through a silicone filter and concentrated. The residue was purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate, gradient). 11.37 g (60% of theory) of the target compound were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10]1([CH2:16][SH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.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>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:16]([S:17][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: SCc1ccccc1
Reactant: COc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(SCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 26 h
Yield: 35.9 %

Procedure:
To a solution of 2-chloro-4-methoxypyridine (786 mg) in toluene (10 mL) were added phenylmethanethiol (683 mg), N,N-diisopropylethylamine (1.56 g), tris(dibenzylideneacetone)dipalladium(0) (202 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (256 mg), and the mixture was stirred at 80° C. for 26 hr under an argon atmosphere. The reaction mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane→hexane-ethyl acetate=19:1) to give the title compound as an orange oil (yield 454 mg, 38%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH:5]=[C:6](F)[C:7]=1[F:8].BrC1C=CC([F:22])=CC=1F.BrC1C=C(F)C(F)=C(F)C=1>>[F:22][C:5]1[CH:6]=[C:7]([F:8])[CH:2]=[CH:3][C:4]=1[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1
Reactant: Fc1cc(-c2ccsc2)cc(F)c1F
Reactant: Fc1ccc(Br)c(F)c1
Agent: Fc1cc(Br)cc(F)c1F
Product: Fc1ccc(-c2ccsc2)c(F)c1
Temperature: 80 °C
Yield: 97 %

Procedure:
The same procedures set forth above in Example A(1)(a) for synthesizing 3(3,4,5-trifluorophenyl)thiophene were followed, with the exception that 1-bromo-2,4-difluorobenzene was substituted for 1-bromo-3,4,5-trifluorobenzene as the 1-bromo-substituted fluorobenzene, and the coupling reaction mixture was heated to reflux in an oil bath for 10 hours with stirring at 80° C. (as opposed to being heated in an oil bath for 0.5 hour with periodically stirring). No further purification by recrystallization was required to obtain a 97 to 98% pure product.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH:15]=O.[NH:17]1[CH2:20][CH:19]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[CH2:18]1.C(O)(=O)C.[BH3-]C#N.[Na+].[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39]>CO.CC(C)=O>[C:37]([OH:42])(=[O:41])[C:38]([OH:40])=[O:39].[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:17]1[CH2:20][CH:19]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[CH2:18]1
Reactant: O=CCc1ccccc1N1CCCCC1=O
Reactant: N#Cc1cccc(C2CNC2)c1
Agent: O=C(O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1cccc(C2CN(CCc3ccccc3N3CCCCC3=O)C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To [2-(2-oxopiperidin-1-yl)phenyl]acetaldehyde a3-1 (108.6 mg, 0.5 mmol, 1 eq) and 3-(azetidin-3-yl)benzonitrile a3-2 (97.33 mg, 0.5 mmole, 1 eq) in methanol (4 ml) are added acetic acid (42.9 μl, 0.75 mmol, 1.5 eq) then NaBH3CN (94.3 mg, 1.5 mmol, 3 eq). The reaction mixture is stirred overnight at room temperature. The crude reaction mixture is then loaded on an ion exchange acidic resin cartridge (2 g) prewashed with methanol. The cartridge is washed twice with approximately 3 column volumes of methanol, then eluted with 3 column volumes of 1M NH3 in methanol. This eluate is evaporated to dryness to give 141 mg of a crude material which is purified by reverse phase chromatography (basic mode; gradient: H2O/acetonitrile/NH4OH from 60/40/0.1 to 30/70/0.1 in 10 minutes). The residue obtained is redissolved in acetone (approximately 3 ml), and after addition of oxalic acid (22.7 mg, 0.25 mmol, 1 eq), a precipitate slowly appeared. This precipitate is filtered, washed with diethylether and dried overnight under vacuum at 40° C. to afford 69.6 mg of 3-(1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}azetidin-3-yl)benzonitrile oxalate 31.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].C(N(CC)CC)C.[C:31]([O:34][CH2:35][C:36](Cl)=[O:37])(=[O:33])[CH3:32]>O1CCCC1>[F:20][C:8]1[C:9]([F:19])=[C:10]([C:15]([F:17])([F:18])[F:16])[C:11]([F:14])=[C:12]([F:13])[C:7]=1[N:6]1[C:2]([NH:1][C:36]([CH2:35][O:34][C:31]([CH3:32])=[O:33])=[O:37])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Yield: 12.4 %

Procedure:
To a stirred solution of 0.68 gram (0.0020 mole) of 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl) -4-nitropyrazole and 0.42 gram (0.0042 mole) of triethylamine in 20 mL of tetrahydrofuran was added dropwise a solution of 0.55 gram (0.0040 mole) of acetoxyacetyl chloride in 8 mL of tetrahydrofuran. The reaction mixture was heated at reflux for two hours. An additional 0.43 gram of acetoxyacetyl chloride and 0.22 gram of triethylamine were added, and the mixture was heated at reflux for 20 minutes. The mixture was cooled and filtered, and the filtrate was evaporated under reduced pressure, leaving an oil. This oil was purified by column chromatography on silica gel, eluted with ethyl acetate/n-hexane (50:50) to yield 0.11 gram of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonyloxymethylcarbonylamino -4-nitropyrazole as a waxy solid, Compound 14 of Table 1. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([NH:10][C:11]([CH2:13][C:14]2[CH:15]=[C:16](O)[CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:8][CH:7]=1.[OH-:23].[Na+].[CH3:25][CH:26]([CH3:30])[C:27]([OH:29])=[O:28]>CC(C)=O>[Cl:5][C:6]1[CH:22]=[CH:21][C:9]([NH:10][C:11]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:23][C:26]([CH3:30])([CH3:25])[C:27]([OH:29])=[O:28])=[CH:18][CH:19]=2)=[O:12])=[CH:8][CH:7]=1
Reactant: O=C(Cc1cccc(O)c1)Nc1ccc(Cl)cc1
Reactant: [OH-]
Reactant: CC(C)C(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(Oc1ccc(CC(=O)Nc2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
FIG. 6b presents a similar reaction scheme to FIG. 6a, except that 3- rather than 4-hydroxyphenylacetic acid (HPAA) is used as the precursor material so that the final compound has a meta rather than a para substitution. In addition, rather than reacting with acetone (dimethyl ketone) a diethyl ketone is used to position ethyl, rather than methyl, moieties in the group substituted on one of the phenyl rings. By example, 1.5g (10 mmol) 3-HPAA and 2.6g (20 mmol) 4-chloroaniline in 20 ml of mesitylene was heated to reflux. Then 0.33 g (2.55 mmol) PCl5 was then slowly added to the above refluxing solution and the refluxing was continued for two hours. The reaction mixture was then cooled and then worked up as described above to yield 2.2 g (90% yield) of 3-[((4-chloroanilino) carbonyl)methyl]phenol. As described above, chloroform (0.8 ml) was added to a stirred and ice-cooled mixture of 1.23 grams of 3-[((4-chloroanilino)carbonyl)methyl]phenol and 1.6 g NaOH in 15 ml of acetone. The reaction mixture was allowed to warm to room temperature and stirring continued for an additional 10 hours. The usual work-up yielded 2-[3-(((4-chloroanalino)carbonyl) methyl)]phenoxy!-2-methylpropionic acid as a low temperature melting sticky solid (C,H,Cl,N analysis yielded (C18H18ClNO4); NMR δPPM: 1.42 (6H, s, CH3), 3.61 (2H, s, benzylic CH2), and 6.6-7.75 (8H, m, aromatic H)). However, rather than using acetone as the reaction solvent, diethylketone can be used in the same manner as described above to yield the butanoic acid (as opposed to propanoic acid) structure shown in FIG. 6b.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].CO.F[B-](F)(F)F.F[B-](F)(F)F.O[N+]12CC[N+]([F:31])(CC1)CC2.CC[O:34][CH2:35]C>C(#N)C>[F:31][CH2:3][C:2]([O:34][CH3:35])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: O[N+]12CC[N+](F)(CC1)CC2
Reactant: CCOCC
Reactant: C=C(C)c1ccccc1
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CC#N
Product: COC(C)(CF)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of alpha-methylstyrene (0.13 mL, 1 mmole)and methanol (0.05 mL, 1.1 mmole) in acetonitrile (10 mL) was added 1-hydroxyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (330 mg, 1.02 mmole 1.02 equ.) and the reaction stirred at room temperature for 24 h. The mixture was diluted with ether (2 mL), filtered through anhydrous MgSO4, and evaporated to afford 130 mg (85% yield) of 1-fluoro-2-methoxy-2-phenylpropane.