Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].C1(C)C=CC=CC=1.[H-].[Na+].[CH3:37][CH2:38][O-:39].[Na+]>CN(C=O)C.O.C(O)C>[CH2:38]([O:39][C:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([NH:25][CH3:26])[N:11]=2)[CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5])[CH3:37]
Reactant: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2CCOC[C@H]2C(C)C)n1
Reactant: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCOc1cc(-c2cc(N3CCOC[C@H]3C(C)C)nc(NC)n2)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
2,6-Difluoro-4-{2-(methylamino)-6-[(3R)-3-(1-methylethyl)-4-morpholinyl]-4-pyrimidinyl}benzonitrile (377 mg, 1.01 mmol) was azeotroped with toluene (2×15 mL). The residue was dissolved in 5 mL of DMF as a clear yellow solution. NaH (260 mg, 60% wt in mineral oil, 6.5 mmol) was weighted into a 50 mL 3-neck RB, to which under nitrogen was added ethanol (7.5 mL) portion-wise. The resulting clear solution was stirred at ambient temperature for 10 minutes. A portion of this solution (1.40 mL, 1.21 mmol of NaOEt, 1.2 equiv) was added to the above yellowish solution via syringe at room temperature under nitrogen in one portion. The resulting orange clear solution was stirred at room temperature for 20 hours. LCMS showed complete conversion. The mixture was concentrated in vacuo, and then pumped under vacuum to give a residue, which was taken up in 20 mL of water as a suspension. This suspension was sonicated briefly and filtered. The collected solids were dissolved in EtOAc (50 mL), and the resulting organic solution was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the resulting residue by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc gave the title compound (315 mg) as a yellowish residue. LC-MS (ES) m/z=400 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@@H:3]1[C:11]([OH:13])=O.[F:15][C:16]([F:24])([F:23])[C:17]1[CH:21]=[C:20]([NH2:22])[NH:19][N:18]=1>>[CH3:14][C:2]1([CH3:1])[C@@H:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:3]1[C:11]([NH:22][C:20]1[NH:19][N:18]=[C:17]([C:16]([F:24])([F:23])[F:15])[CH:21]=1)=[O:13]
Reactant: Nc1cc(C(F)(F)F)n[nH]1
Reactant: CC1(C)[C@@H](C(=O)O)[C@@H]1c1ccccc1
Product: CC1(C)[C@@H](C(=O)Nc2cc(C(F)(F)F)n[nH]2)[C@@H]1c1ccccc1
Yield: 92.6 %

Procedure:
2,2-Dimethyl-trans-3-phenylcyclopropanecarboxylic acid (250 mg, 1.32 mmol) and 3-trifluoromethyl-1H-pyrazole-5-ylamine (198 mg, 1.31 mmol) were reacted as described under General Procedure D to furnish the title compound (392 mg, 93%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.32-7.22 (m, 6H), 5.72-5.64 (m, 2H), 3.43 (d, J=6.1 Hz, 1H), 2.98 (d, J=6.1 Hz, 1H), 1.42 (s, 3H), 1.07 (s, 3H). mp 68-71° C. ESIMS m/z [M+H]+ 324.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.NN.[C:18]([O-])(=O)[CH3:19].[Na+].C(I)C>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH2:18][CH3:19])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(=O)[O-]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Br
Agent: NN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCI
Solvent: O
Product: CCS(=O)(=O)c1ccc(Br)c(C(=O)O)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
To 2-bromo-5-(chlorosulfonyl)benzoic acid (Preparation 72, 10.1 g, 33.8 mmol) dissolved in THF (100 mL) was added hydrazine monohydrate (3.32 mL, 67.6 mmol) cautiously at 0° C. under nitrogen. A fine precipitate formed, the reaction was allowed to warm to room temperature over 126 hours before filtering. The solid was washed with heptanes, dried under reduced pressure and dissolved in industrial methylated spirit (100 mL). To this solution was added sodium acetate (16.6 g, 203 mmol) and ethyl iodide (13.5 mL, 169 mmol) and the reaction heated to reflux for 20 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the residue partitioned between EtOAc (500 mL) and sodium hydroxide solution (1M, 500 mL). The layers were separated and the organic layer discarded. The aqueous layer was acidified to pH=1 with HCl (1M, 500 mL) and extracted with EtOAc (5×500 mL). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure to give the title compound as a tan solid in 48% yield, 4.82 g.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C=O>[CH2:1]([C:3]1[N:7]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:6]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C(F)(F)F)n[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(C(F)(F)F)cc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 5-ethyl-3-(trifluoromethyl)-1H-pyrazole (1.39 g, 8.5 mmol) (i.e. the product of Example 16, Step A) in N,N-dimethylformamide (10 mL) was added potassium carbonate (2.3 g) and ethyl bromoacetate (1.4 mL, 12.6 mmol). The reaction mixture was stirred at room temperature overnight. The resulting solids were filtered off and the filtrate was diluted with ethyl acetate, washed with water and dried over MgSO4. The resulting solution was concentrated under reduced pressure to give 1.34 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][N:12]2[S:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[CH:20][C:19]=2[CH3:27])(=[O:17])=[O:16])=[CH:8][CH:7]=1>CO.O.C(OCC)(=O)C>[CH3:26][O:25][C:21]1[CH:22]=[C:23]([CH3:24])[C:18]([S:15]([N:12]2[C:13]3[C:9](=[CH:8][CH:7]=[C:6]([CH2:5][C:1]#[N:2])[CH:14]=3)[CH2:10][CH2:11]2)(=[O:17])=[O:16])=[C:19]([CH3:27])[CH:20]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(CBr)cc32)c(C)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(CC#N)cc32)c(C)c1

Procedure:
Potassium cyanide (0.133 g, 0.0020 mol) was added to a solution of 6-(bromomethyl)-1-(4-methoxy-2,6-dimethylphenylsulfonyl)indoline (0.7 g, 0.0017 mol) in methanol (14 ml) and water (2 ml), and the resulting reaction mixture was refluxed for 4 h. The mixture was then diluted with ethyl acetate (400 ml) and washed with saturated sodium chloride solution (2×), water (2×), saturated iron sulfate solution and finally with saturated sodium chloride solution. It was then dried (Na2SO4), filtered and concentrated in vacuo. The resulting crude product was used directly in the following stage. Yield: 0.6 g (99%).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)(=[O:7])=[O:6].[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li]CCCC>C1COCC1>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][S:5]([C:8]1[CH:9]=[C:10]([B:17]([OH:22])[OH:18])[CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)COS(=O)(=O)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)COS(=O)(=O)c1cccc(B(O)O)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Step 2) To a solution of the above prepared 3-bromo-benzenesulfonic acid 2,2-dimethyl-propyl ester (9.83 g, 32 mmol) and triisopropyl borate (13.4 mL, 58 mmol) in THF (45 mL) at −78° C. was added n-BuLi (1.6 M in hexane, 20 mL, 32 mmol) keeping the internal temperature below −65° C. Stirring was continued at −78° C. for 1 h, then more n-BuLi (4.0 mL, 6.4 mmol) was added and stirring was continued at −78° C. for 30 min. The reaction mixture was quenched with 1 M H2SO4-sol. (40 mL), allowed to quickly (waterbath) warm to ca. 20° C. and stirred for 10 min. Diluted with EtOAc, layers were separated, washed organic layer with brine and dried over Na2SO4. Removal of the solvent in vacuum left the title compound as white solid (9.00 g, 103%). MS (ISN) 271.4 [(M−H)−].
Reaction SMILES: N(C1CCO1)=[N+]=[N-].[N-:8]=[N+:9]=[N-:10].Cl[CH2:12][C:13]1([CH3:17])[CH2:16][O:15][CH2:14]1>>[N:8]([CH2:12][C:13]1([CH3:17])[CH2:16][O:15][CH2:14]1)=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(CCl)COC1
Agent: [N-]=[N+]=NC1CCO1
Product: CC1(CN=[N+]=[N-])COC1
Yield: 97 %

Procedure:
As such, it has been discovered that monofunctional azidooxetane compounds, i.e., 3-azidomethyl-3-R1 -oxetanes, can also be prepared by combining a neat halooxetane with an aqueous metallic azide solution and a phase transfer catalyst (PTC). For example, using the process of the present invention, 3-chloromethyl-3-methyloxetane gives the corresponding 3-azidomethyl-3-methyloxetane (AMMO) in 97% yield. Moreover, 3-bromomethyl-3-hydroxymethyloxetane was previously converted to the corresponding 3-azidomethyl-3-hydroxymethyloxetane in acetone. Using the process of the present invention, however, 3-bromomethyl-3-hydroxymethyloxetane is converted to the corresponding 3-azidomethyl-3-hydroxymethyloxetane, without the use of an organic solvent, using an aqueous sodium azide solution and a phase transfer catalyst. The process of the present invention gives the same result with a faster rate of reaction and without the use of an organic solvent. In addition, 3-chloromethyl-3-methyloxetane 3-chloromethyl-3-phenoxymethyloxetane reacts with an aqueous solution of sodium azide in water with a PTC to give 3-azidomethyl-3-phenoxymethyloxetane in 87% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[CH2:16]O.P(Br)(Br)[Br:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:19][CH2:16][C:3]1[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: OCc1c(Cl)cccc1OCc1ccccc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cccc(OCc2ccccc2)c1CBr
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of {2-chloro-6-[(phenylmethyl)oxy]phenyl}methanol (for a preparation see Intermediate 7) (1.1 g, 4.42 mmol) in DCM (12 ml) at 0-5° C. under nitrogen was added dropwise a solution of phosphorus tribromide (0.417 ml, 4.42 mmol, Aldrich) in DCM (3 ml). The solution was allowed to warm to ambient temperature and stirred for 3 h. The solution in an ice-water bath was diluted with dichloromethane (40 ml) and then treated with saturated aqueous sodium hydrogen carbonate (20 ml). The phases were separated and the organic extract dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a yellow oil (0.829 g); LCMS: (System 1) (M-H)−=311, tRET=3.84 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([F:30])([F:29])[F:28])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([OH:8])=O.Cl.CN(C)CCCN=C=NCC.[CH3:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[S:53]([NH2:56])(=[O:55])=[O:54]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][CH:25]([CH3:31])[CH2:26][C:27]([F:28])([F:30])[F:29])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([NH:56][S:53]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[CH3:46])(=[O:54])=[O:55])=[O:8]
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)NCC(C)CC(F)(F)F)cc12
Yield: 56.8 %

Procedure:
A solution of 3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-ylmethyl]benzoic acid (250 mg), 4-dimethylaminopyridine (69.8 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (127 mg) and 2-methylbenzenesulfonamide (95.4 mg) in methylene chloride (5 mL) was stirred under a nitrogen atmosphere for 24 hours. The mixture was diluted with methylene chloride, washed (10% (w/v) hydrochloric acid, water), and evaporated. The resulting rose-colored foam was dissolved in methylene chloride (5 mL), filtered through a 0.45 micron membrane filter, and precipitated by addition to hexane (50 mL). The solid was collected by filtration to give the title compound (189.2 mg, 57%) as a pale pink powder; mp 147°-149 ° C.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8](=[CH:14][NH:15][CH:16]2[CH2:18][CH2:17]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4](F)[C:3]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([CH3:22])=[C:4]2[C:5]([C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:15]2[CH:16]2[CH2:18][CH2:17]2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1ccc(Br)c(C)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(Br)ccc2c1=O
Temperature: 25 °C
Yield: 96.9 %

Procedure:
In 7 ml of dimethyl sulfoxide was dissolved 0.72 g of ethyl 2-(4-bromo-2-fluoro-3-methylbenzoyl)-3-cyclopropylaminoacrylate, followed by adding thereto 0.48 g of potassium carbonate, and the resulting mixture was stirred at 90° C. for 30 minutes. The reaction mixture was cooled to room temperature, after which 35 ml of water was added thereto and the crystals were collected by filtration to obtain 0.66 g of colorless ethyl 7-bromo-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:16][N:17]([CH3:19])[CH3:18])[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][CH2:5][NH:4]1.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][C:29](O)=[O:30].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(Cl)CCl>CN(C=O)C.O>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH2:28][C:29]([N:4]1[CH2:5][CH2:6][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:14][C:15]=2[CH:3]1[CH2:16][N:17]([CH3:19])[CH3:18])=[O:30]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: CN(C)CC1NCCc2c1[nH]c1ccccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC1c2[nH]c3ccccc3c2CCN1C(=O)Cc1ccc(Cl)cc1Cl
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
To a stirred solution of [(1,2,3,4-tetrahydrobeta-carbolinyl)methyl]dimethylamine dihydrochloride (0.85 g, 2.80 mmole) in dry DMF (20 mL) at RT was 2,4-dichlorophenylacetic acid (0.63 g, 3.08 mmole), 1-hydroxybenzotriazole hydrate (0.42 g, 3.08 mmole) and diisopropylethylamine (1.19 g, 9.24 mmole). After 10 min, EDC (0.59 g, 3.08 mmole) was added and the reaction was allowed to stir for 12 hr. The reaction contents were poured into H2O (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed sequentially with H2O and brine. Drying the organic phase over Na2SO4 and concentration under reduced pressure gave a yellow oil. Purification on silica [(CHCl3/CH3OH, 95:5 (containing 5% NH4OH)] afforded the title compound (1.05 g, 90%) as a yellow solid: MS (ES) m/e 417 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([N:11]2[CH2:16][CH2:15][C:14]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)([CH3:17])[O:13][C:12]2=[O:26])[CH3:10])=[CH:5][CH:4]=1.[BH4-].[Na+]>>[OH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([C@:14]2([CH3:17])[O:13][C:12](=[O:26])[N:11]([C@H:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH3:10])[CH2:16][CH2:15]2)=[CH:19][CH:20]=1
Reactant: COc1ccc([C@H](C)N2CCC(C)(c3ccc(C=O)cc3)OC2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc([C@H](C)N2CC[C@](C)(c3ccc(CO)cc3)OC2=O)cc1

Procedure:
Reaction of 4-(3-((S)-1-(4-methoxyphenyl)ethyl)-6-methyl-2-oxo-1,3-oxazinan-6-yl)benzaldehyde isomer 1 with NaBH4, under conditions analogous to those described above for isomer 2, afforded (R)-6-(4-(hydroxymethyl)phenyl)-3-((S)-1-(4-methoxyphenyl)ethyl)-6-methyl-1,3-oxazinan-2-one. LC-MS Method 1 tR=1.39 min, m/z=356 (M+1); 1H NMR (CD3OD) 7.27 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 6.59 (d, J=8.8 Hz, 2H), 5.41 (q, J=7.0 Hz, 1H), 4.53 (s, 2H), 3.62 (s, 3H), 2.96-2.91 (m, 1H), 2.37-2.32 (m, 1H), 2.22-2.15 (m, 1H), 2.10-2.02 (m, 1H), 1.51 (s, 3H), 1.41 (d, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH:16](OC)(OC)[O:17]C.F[C:24](F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>[N+](C)([O-])=O.CO>[CH3:24][O:13][C:3]([O:17][CH3:16])([C:2]([F:14])([F:15])[F:1])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[F:1][C:2]([F:14])([F:15])[C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COC(OC)OC
Agent: O=C(CCc1ccc(O)cc1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C[N+](=O)[O-]
Product: COC(CCc1ccc(O)cc1)(OC)C(F)(F)F
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
To a solution of 1,1,1-trifluoro-4-[4-hydroxyphenyl]-2-butanone (40.4 g, 0.185 mol) in nitromethane (300 ml) were added methanol (40 ml), trimethyl orthoformate (100 ml) and trifluoromethanesulfonic acid (1 ml). The resulting mixture was heated to 75° C. for 20 h, then cooled to r.t. and poured into sat. sodium bicarbonate (700 ml). After stirring for 10 min., the mixture was extracted with ethyl acetate (2×2 L). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (dichloromethane/methanol 98:2 to 97:3) to afford the title compound (21.5 g, 44%) as a yellow oil and 1,1,1-trifluoro-4[4-hydroxyphenyl]-2-butanone (23 g, 57%). Analytically pure sample (20.2 g, 41%) of 4-(4,4,4-trifluoro-3,3-dimethoxybut-1-yl)phenol was obtained by bulb-to-bulb distilation (98-102° C., 0.02mmHg).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[N:4]=[C:5]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[N:20][CH:21]=2)[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.[H-].[Na+].[CH2:33]([C:35]([CH2:42]OS(C1C=CC(C)=CC=1)(=O)=O)([CH2:40][CH3:41])[C:36]([O:38][CH3:39])=[O:37])[CH3:34].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[CH2:33]([C:35]([CH2:42][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:5]3[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:13])[CH3:14])[CH:7]=[C:3]([C:2]([F:1])([F:29])[F:30])[N:4]=3)=[CH:21][N:20]=2)=[CH:27][CH:26]=1)([CH2:40][CH3:41])[C:36]([O:38][CH3:39])=[O:37])[CH3:34]
Reactant: CCC(CC)(COS(=O)(=O)c1ccc(C)cc1)C(=O)OC
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(-c2ccc(O)cc2)nc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)(COc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cn2)cc1)C(=O)OC
Reaction time: 1 h
Yield: 61.3 %

Procedure:
In N,N-dimethylformamide (1.4 mL) was dissolved 4-{5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenol (305 mg), 60% sodium hydride (34 mg) was added to the solution at room temperature and the mixture was stirred for one hour. To the reaction mixture was added an N,N-dimethylformamide (1 mL) solution containing methyl 2-ethyl-2-(p-tolylsulfonyloxymethyl)-butanoate (264 mg) under ice-cooling. The reaction mixture was stirred at 100° C. overnight. To the reaction mixture was added 60% sodium hydride (9 mg) under ice-cooling, and the mixture was stirred at 100° C. overnight. To the reaction mixture were added a saturated aqueous ammonium chloride solution and ethyl acetate, and the liquids were separated. The aqueous layer was separated, and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5 to 50:50) to obtain methyl 2-ethyl-2-[[4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]methyl]-butanoate (248 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[F-].[Cs+].Cl[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])=[N:20][N:21]2[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:17][CH:16]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])=[N:20][N:21]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)ccc12
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OC)cc3)ccc12
Temperature: 100 °C
Reaction time: 72 h
Yield: 83.7 %

Procedure:
900 mg of 4-methoxyphenylboronic acid, 1.24 g of caesium fluoride, 13.5 mg of palladium acetate and finally 31 mg of 2-dicyclohexylphosphine-2′-(N,N-dimethylamino)biphenyl are added to 1 g of N-[6-chloro-1-[[2-(trimethylsilyl)-ethoxy] methyl]-1H-indazol-3-yl]butanamide, described previously in Example 25, in 30 cm3 of dioxane. The mixture is then heated at about 100° C. for 20 hours, the temperature is allowed to return to about 19° C. over 72 hours and the reaction medium is then filtered on a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 50 cm3 of ethyl acetate and 50 cm3 of distilled water. The organic phase is washed again with 50 cm3 of distilled water and with 50 cm3 of saturated aqueous sodium chloride solution. The aqueous phase is dried over magnesium sulphate, filtered and then evaporated under reduced pressure under the conditions described previously. The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); after drying (90 Pa; 50° C.), 1 g of N-[6-(4-methoxyphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide is obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:9]=[C:10]([C:17]([OH:19])=O)[N:11]([CH2:13][CH2:14][CH2:15][CH3:16])[CH:12]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1>>[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[NH:20][C:17]([C:10]1[N:11]([CH2:13][CH2:14][CH2:15][CH3:16])[CH:12]=[C:8]([C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:7])[CH:9]=1)=[O:19]
Reactant: Nc1nccs1
Reactant: CCCCn1cc(C(=O)C2CCCC2)cc1C(=O)O
Product: CCCCn1cc(C(=O)C2CCCC2)cc1C(=O)Nc1nccs1
Yield: 23.2 %

Procedure:
4-Cyclopentanecarbonyl-1-butyl-pyrrole-2-carboxylic acid (132 mg) was obtained following the hydrolysis of the ester intermediate via the general procedure E. 4-Cyclopentanecarbonyl-1-butyl-pyrrole-2-carboxylic acid thiazol-2-ylamide (40 mg) was prepared from 4-cyclopentanecarbonyl-1-butyl-pyrrole-2-carboxylic acid (132 mg, 0.5 mmol) and 2-aminothiazole (51 mg, 0.5 mmol) following the general procedure F.