Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C)C=O>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][CH:15]1[CH2:16][CH2:17][N:13]([S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])[CH2:14]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1
Yield: 100.1 %

Procedure:
1-(2-Nitro-benzenesulfonyl)-pyrrolidin-3-ol (12.25 g, 0.04499 mol) in N,N-dimethylformamide (40 mL) was treated with tert-butyldimethylsilyl chloride (8.137 g, 0.05399 mol) and 1H-imidazole (4.594 g, 0.06748 mol) at room temperature for 3 h. The reaction mixture was partitioned between water and ethyl ether, and the layers were separated. The aqueous layer was extracted twice with ethyl ether, and then the organic extracts were washed extensively with water, then once with brine, dried (MgSO4), filtered and concentrated to give 3-(tert-butyl-dimethyl-silanyloxy)-1-(2-nitro-benzenesulfonyl)-pyrrolidine as an off-white solid (17.4 g, 92%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)(=[O:4])=[O:3].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[C:25]([O:24][C:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:7]=2)[CH2:17][CH2:18]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)Oc1cccc(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cccc(OS(C)(=O)=O)c2)CC1
Yield: 125 %

Procedure:
The above prepared 3-methanesulfonyloxy-benzoic acid (0.400 g, 1.85 mmol) was condensed with 4-amino-1-BOC-piperidine (0.370 g, 1 eq.) in the presence of 1.1 eq. of (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (0.899 g) and 1.2 eq. of N-ethyl-diisopropylamine (0.38 ml) in 9 ml of abs. THF during one night at ambient temperature. Pouring onto crashed ice/AcOEt, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=7/3), yielded 0.920 g of the title compound as white foam, contaminated with some reagent derived impurities, but sufficiently pure for the next steps.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[CH:25]1[CH:30]=[CH:29][N+:28]([CH2:31][C:32]([NH:34][NH2:35])=[O:33])=[CH:27][CH:26]=1.[Cl-:36].CS(C)=O>C(#N)C>[Cl-:36].[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:35][NH:34][C:32](=[O:33])[CH2:31][N+:28]3[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: NNC(=O)C[n+]1ccccc1
Agent: [Cl-]
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NNC(=O)C[n+]1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) and 0.172 g (0.9166 mmol) of Girard's reagent P were placed into a 10 ml round bottom flask with 2 ml dimethylsulfoxide and a magnetic stirring bar. The solution was heated to 70° C. with stirring. As the solution began to warm up, the solids began to dissolve and the solution became progressively green in color. After about 30 minutes, the solution was completely homogeneous. The solution was allowed to react at 70° C. for four hours and was allowed to cool to room temperature. 10 ml acetonitrile was added and a white precipitate formed immediately. The solution was filtered and washed with acetonitrile and ether. The solid was allowed to dry but it absorbed H2O from the atmosphere. The hygroscopic effect could either be due to residual dimethylsulfoxide or the product itself.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]23[CH2:17][CH2:16][CH:15](O)[CH:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:14]3)[N:3]=[CH:2]1.Cl.[H][H]>C(O)C.[Pd]>[CH2:17]1[C:6]2([C:4]3[N:3]=[CH:2][NH:1][CH:5]=3)[CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:7]2[CH2:15][CH2:16]1
Reactant: OC1CCC2(c3c[nH]cn3)Cc3ccccc3C12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc2c(c1)CC1(c3c[nH]cn3)CCCC21
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A solution of 8a-(1H-imidazol-4-yl)-1,2,3,3a,8,8a-hexahydrocyclo-penta[a]inden-3-ol (0.5 g) in 20 ml of ethanol containing 5 ml of 20% hydrochloric acid was heated at reflux for 3 hours. The solution was allowed to cool to room temperature and 50 mg of 10% palladium on carbon catalyst was added. The reaction mixture was hydrogenated at 50-55° C. until no more hydrogen was consumed. The catalyst was filtered off and the solvent removed under reduced pressure. The residue was dissolved in water and the solution was basified with sodium hydroxide solution. The basic reaction solution was extracted with methylene chloride (3×100 ml), dried over sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography using methylene chloride/methanol (97:3) as eluent. Recrystallization from ethyl acetate afforded 120 mg of product, m.p. 171-174° C.
Reaction SMILES: [CH3:1][C:2]([C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])=[O:5])=[CH2:3].[Cl:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>S(=O)(=O)(O)O.O>[Cl-:13].[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N+:10]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])([CH3:12])[CH3:11])(=[O:5])[C:2]([CH3:1])=[CH2:3]
Reactant: C=C(C)C(=O)NCCCN(C)C
Reactant: CCCCCCCCCCC=CCl
Agent: O=S(=O)(O)O
Solvent: O
Product: C=C(C)C(=O)NCCC[N+](C)(C)CCCCCCCCCCCC
Product: [Cl-]
Temperature: 95 °C
Reaction time: 24 h

Procedure:
A mixture of 350 g of DMAPMA and 280 g of chlorododecene (1.5:1) was stirred with 111.2 g of water (15%) and 6 drops of concentrated sulfuric acid. The reaction mixture was heated up to 95° C. and air was bubbled through it. The conversion was followed by chloride titration. After 24 hours the reaction was completed and the mixture was cooled off. The product is water miscible and is a mixture of 15.0% water; 69.1% MAPLDMAC and 15.9% DMAPMA. It was further used in polymerization without purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][CH:6]=1)[OH:4].[H-].[Na+].[NH2:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[C:25]([Cl:30])[N:24]=1.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:30][C:25]1[CH:26]=[C:27]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)=[CH:7][CH:6]=2)[C:2]([F:1])([F:18])[F:19])[N:28]=[C:23]([NH2:22])[N:24]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OC(c1ccc(-c2cccc(F)c2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OC(c2ccc(-c3cccc(F)c3)cc2)C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To 2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethanol (1.4 g, 5.18 mmol) in THF (50 mls) at 0° C. was added NaH (60% in mineral oil, 0.31 g, 7.77 mmol). The ice bath was removed and the mixture was stirred for 30 minutes. 2-Amino-4,6-dichloropyrimidine (1.0 g, 6.22 mmol) in THF (25 mls) was added at once. The mixture was heated to 50° C. for 5 hours. The reaction was complete by LCMS (Sunfire, TFA). The mixture was cooled, quenched with brine, and extracted 3 times with CH2Cl2. The organics were combined, washed with brine, dried over MgSO4, and concentrated. Chromatography (SiO2, CH2Cl2) afforded 1.48 g of 4-chloro-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine. Yield 73%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([CH3:13])(O)[CH3:11])[CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[OH-:19].[Na+].[Cl:21][CH2:22][C:23]#[N:24]>C(O)(=O)C>[Cl:21][CH2:22][C:23]([NH:24][C:10]([CH3:13])([CH3:11])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=1)=[O:19]
Reactant: Cc1ccc(CC(C)(C)O)cc1F
Reactant: [OH-]
Reactant: N#CCCl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(CC(C)(C)NC(=O)CCl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(3-Fluoro-4-methylphenyl)-2-methylpropan-2-ol (130.1 g) obtained in Step 5 was dissolved in chloroacetonitrile (139 ml) and acetic acid (115 ml), and concentrated sulfuric acid (33.4 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hrs and 4N-aqueous sodium hydroxide solution (16 ml) was added dropwise under ice-cooling. The mixture was extracted twice with toluene and twice with ethyl acetate. The organic layer was washed twice with 10% brine and concentrated under reduced pressure to give the title compound (131.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][C:14]([CH3:16])=[CH2:15])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[C:11]2[O:12][C:14]([CH3:16])([CH3:15])[CH2:13][C:10]=2[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1
Reactant: C=C(C)Cc1cc(C(=O)OC)cc(Br)c1O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Br)c2c(c1)CC(C)(C)O2
Yield: 74.3 %

Procedure:
A solution of methyl 3-bromo-4-hydroxy-5-(2-methylprop-2-en-1-yl)benzoate (4.1 g, 14.4 mmol) and boron trifluoride diethyl ether complex (2.0 mL, 15.8 mmol) in toluene (30 mL) was stirred at 100° C. for 90 min. After cooling, the reaction solution was diluted with ethyl acetate, washed successively with water, aqueous sodium hydrogencarbonate solution and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:97-15:85) to give the title compound (3.05 g, yield 74%) as colorless prism crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[CH3:18][O:17][C:15](=[O:16])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH2:11][C:12]([N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[CH2:21][O:20][CH3:19])=[O:14]
Reactant: COC[C@@H]1CCCN1
Reactant: COC(=O)C(CCC(=O)O)NC(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O
Product: COC[C@@H]1CCCN1C(=O)CCC(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.9 %

Procedure:
To a mixture of 4-(tert-butoxycarbonylamino)-5-methoxy-5-oxopentanoic acid (1.05 g, 4 mmol), (S)-2-(methoxymethyl)-pyrrolidine (0.46 g, 4 mmol), and 1-hydroxybenzotriazole hydrate (HOBt hydrate, 0.54 g, 4 mmol) in CH2Cl2 (10 mL) was added EDC (0.77 g, 4 mmol). The reaction mixture was stirred at ambient temperature for 12 h, diluted with CH2Cl2 (40 mL), washed sequentially with saturated aqueous sodium bicarbonate (20 mL), 0.5 N aqueous citric acid (20 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a crude viscous oil. The crude oil was purified by flash chromatography (silica gel, 50% ethyl acetate/hexanes) to give the title compound (1.36 g, 95%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14](I)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:15]=[C:14]([C:31]#[C:30][C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)=[CH:29][N:28]=2)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Brc1cc(I)ccc1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)c(Br)c3)nc2)cc1

Procedure:
Prepared according to general working method I from 1-[2-(2-bromo-4-iodo-phenoxy)-ethyl]-pyrrolidine (278 mg, 0.34 mmol, 70%) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (110 mg, 0.52 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]([CH2:9]P(=O)(OCC)OCC)=[CH:7][CH:6]=1)=[O:4].C1OCCOCCOCCOCCOC1.[H-].[Na+].O=[C:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[C:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)=[CH:18][CH:19]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (25 g, 109 mmol) and triethyl phosphate (24.3 ml, 142 mmol) was stirred at 150° C. for 24 h. The resulting mixture was purified by distillation (165-172° C., 1 mmHg) to obtain diethyl 4-(methoxycarbonyl)benzylphosphonate (21.5 g, 69%). To a mixture of diethyl 4-(methoxycarbonyl)benzylphosphonate (20.5 g, 71.5 mmol), 15-crown-5 (1.4 ml, 7.1 mmol) and THF (120 ml) was added sodium hydride (60% in oil, 2.9 g, 71.5 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h. A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (11.9 g, 59.6 mmol) in THF (45 ml) was added dropwise to the resulting mixture over period of 10 min at 0° C. The mixture was stirred at room temperature for 20 h. The resulting mixture was poured into ice-water (200 ml) and the whole was extracted with ethyl acetate (100 ml×2). The extracts were washed with 5% aqueous sodium bicarbonate(100 ml), saturated sodium chloride solution (100 ml) successively. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 200 g, ethyl acetate/hexane=1/10) followed by recrystallization from hexane to give tert-butyl 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylate (6.9 g, 35%) as a colorless crystalline powder. A mixture of tert-butyl 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylate (6 g, 18 mmol) in methanol (150 ml) was hydrogenated over 10% palladium carbon (50% wet, 1 g) for 5 h at room temperature. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 90 g, ethyl acetate/hexane=1/10) to obtain the title compound (6.1 g, 100%) as pale yellow oil.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.Cl[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])[C:13](=[O:27])[CH:12]=[CH:11]2>CN(C=O)C.C(OCC)(=O)C.O>[CH:3]1([CH2:6][O:7][C:9]2[N:10]3[C:15]([CH:16]=[CH:17][CH:18]=2)=[C:14]([C:19]2[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=2[Cl:25])[C:13](=[O:27])[CH:12]=[CH:11]3)[CH2:5][CH2:4]1
Reactant: OCC1CC1
Reactant: O=c1ccn2c(Cl)cccc2c1-c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1ccn2c(OCC3CC3)cccc2c1-c1c(Cl)cccc1Cl
Reaction time: 0.5 h

Procedure:
To oil free sodium hydride (24 mg) suspended in DMF was added cyclopropylmethanol (0.08 mL) at room temperature and stirred for ½ hr. To this mixture was added 6-chloro-1-(2,6-dichlorophenyl)-2H-quinolizin-2-one (Example 1, 15 mg) and stirred for approximately 1-3 hours. The mixture was diluted with ethyl acetate/water. The organic layers were washed with water (3×), brine, and dried over magnesium sulfate. Upon evaporation, the residue was purified by silica gel (methylene chloride/acetone=3/1) to give title compound (15 mg).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]#N)[N:9]=[CH:8]1.[OH2:29].S(=O)(=O)(O)O.[C:35]([O-])(O)=[O:36].[Na+]>CO>[CH3:35][O:36][C:18]([C:10]1[N:9]=[CH:8][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:28])([F:27])[F:1])[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=2)[C:11]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:29]
Reactant: O=C([O-])O
Reactant: N#Cc1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Reactant: O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
In a pressure vessel dissolve 1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazole-4-carbonitrile (0.043 g, 0.11 mmol) in MeOH (1 mL), add H2O (0.1 mL), and concentrated sulfuric acid (0.3 mL), and stir at 100° C. After 24 h., neutralize with sat. aq. NaHCO3, and extract with EtOAc (3×). Dry over MgSO4, filter, and concentrate. Purify by radial chromatography on silica gel to give the title compound: MS (ES) 430.2 (M+1); 1H NMR (300 MHz, CDCl3): δ 8.68 (ap d, 1H), 8.52 (ap d, 1H), 7.80 (s, 1H), 7.78 (s, 1H), 7.56 (d, J=7.8 Hz, 1H), 7.37 (m, 1H), 7.29 (s, 2H), 5.30 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCCCBr)c(Cl)c1Cl
Temperature: 5 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 2,3-dichloroanisole (89 g., 0.50 mole) and 6-bromohexanoyl chloride (120 g., 0.59 mole) is methylene chloride (500 ml.) is cooled to 5° C. and treated with aluminum chloride (74 g., 0.56 mole) in portions during a one-half hour period. The reaction mixture is kept at 25° C. for 18 hours, then poured into ice water (1 liter) containing hydrochloric acid (100 ml.). The organic phase is separated, washed with water, 2% sodium hydroxide, and dilute hydrochloric acid. The methylene chloride is evaporated at reduced pressure, the residual oil dissolved in ether, dried over magnesium sulfate, evaporated to 200 ml. and treated with hexane (600 ml.) affording 2,3-dichloro-4-(6-bromohexanoyl)-anisole which melts at 52°-53° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)=O.B.C1COCC1.[NH4+].[Cl-].CCOCC>C1COCC1>[F:14][C:13]([F:15])([F:16])[C:12]([C:9]1[CH:8]=[CH:7][C:6]([NH:5][CH2:3][C:2]([F:1])([F:23])[F:22])=[CH:11][CH:10]=1)([OH:21])[C:17]([F:20])([F:19])[F:18]
Reactant: O=C(Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)C(F)(F)F
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccc(NCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.5 %

Procedure:
A solution of 4.2 g (11.8 mmol) of 2,2,2-trifluoro-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-acetamide in 30 mL of THF was treated with 24.2 mL of a 1M BH3.THF-complex solution in THF. The mixture was stirred for 72 hours at RT and then refluxed for 2 hours. After cooling to RT, the mixture was distributed between a saturated aqueous solution of NH4Cl and Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silicagel with n-heptane/EtOAc 4:1 yielded 3.0 g (74%) of 1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-ol, light brown oil, MS: 342 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[N:6]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:5]=1)(=[O:3])[CH3:2].[OH2:26].O.O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.Cl(O)(=O)(=O)=O.[CH3:47]O>O1CCOCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([N:6]2[C:7]([C:9]3[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=3)=[CH:8][C:4]([C:1](=[O:3])[CH2:2][O:26][CH3:47])=[N:5]2)=[CH:24][CH:23]=1
Reactant: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)n1
Reactant: CO
Reactant: O
Agent: O=[N+]([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [Tl+3]
Solvent: C1COCCO1
Product: COCC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-acetyl-1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (1.1 g), thallium (III) nitrate trihydrate (1.6 g) and perchloric acid (70%; 3.3 ml) in methanol (16 ml) and dioxane (8 ml) was stirred at ambient temperature overnight. The insoluble was filtered, and the filtrate was diluted with chloroform, washed with water, dried and concentrated. The residue (1.6 g) was purified by column chromatography on silica gel (100 g) eluting with a mixture of toluene and ethyl acetate (2:1) to give pale brown crystals of 1-(4-fluorophenyl)-3-(methoxyacetyl)-5-[4-(methylsulfonyl)phenyl]pyrazole (0.13 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([CH3:15])([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[CH3:5].C(O)(=O)C>C1COCC1.[Zn]>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)([CH3:15])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)c1ccc(N)cc1
Reaction time: 1 h

Procedure:
2-Methyl-2-(4-nitro-phenyl)-propionic acid methyl ester (2.1 g) was dissolved in THF (70 ml) and acetic acid (5 ml) and Zn (10 g) were added. The mixture was stirred for 1 h and filtered through Celite®. The filtrate was rinsed with EtOAc and the organics were evaporated to a residue which was purified on silica gel chromatography (40%EtOAc/hexanes) to provide the desired compound as a yellow oil. M+H 194.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[NH:6][C:5](=[S:7])[CH2:4][S:3]1.[Na].[H][H].[CH3:12]I>CN(C)C=O>[CH3:1][C:2]1([CH3:8])[N:6]=[C:5]([S:7][CH3:12])[CH2:4][S:3]1
Reactant: [H][H]
Reactant: CI
Reactant: CC1(C)NC(=S)CS1
Agent: [Na]
Solvent: CN(C)C=O
Product: CSC1=NC(C)(C)SC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6.0 g (0.041 mol) of 2,2-dimethyl-thiazolidine-4-thione are added cautiously to a suspension of 1.0 g (0.041 mol) of oil-free sodium hydridein 20 ml of absolute dimethylformamide. After completion of the evolution of hydrogen, the mixture is heated briefly to 50° C., then cooled to 0° C. and 2.6 ml (0.042 mol) of methyl iodide are added dropwisethereto. After removing the ice-bath the mixture is stirred for an additional 3 hours, treated with water and extracted twice with methylene chloride. The organic extracts are subsequently combined, washed three times with 100 ml of water each time, dried over anhydrous sodium sulfate and evaporated at 40° C. under reduced pressure to yield crude 2,2-dimethyl-4-methylthio-3-thiazoline.