Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH3:9][C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:20]=[CH:21][C:22]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[CH:23][N:24]=2)[N:15]=1)([CH3:8])[C:6]([OH:5])=[O:26]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(Br)cn2)cs1
Reactant: OB(O)c1cccs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCNc2ncc(-c3cccs3)cn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 162-1 and 2-thiopheneboronic acid as starting materials and by an operation similar to that of Example 162-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the obtained solid was triturate and washed with hexane-ethyl acetate to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O>>[CH3:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
4-Trifluoromethyltoluene (12.8 g) was treated at 60°-70° C. with a mixture of concentrated nitric acid (25 ml) and concentrated sulphuric acid (25 ml) for 5 hours. The solution was poured onto ice (0.5 litres) and extracted with ether (3×100 ml). The combined ether extracts were washed with water, dried over sodium sulphate, filtered and evaporated to dryness to give 2-methyl-5-trifluoromethylnitrobenzene (14.8 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:26]Br>C(O)(=O)C>[Br:26][CH:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[N:9][C:7]=2[N:8]=1)[CH3:2]
Reactant: BrBr
Reactant: CCc1nc2ncccc2c(=O)n1-c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(Br)c1nc2ncccc2c(=O)n1-c1ccc(F)cc1
Temperature: 40 °C
Yield: 85.1 %

Procedure:
A suspension of the quinazolinone (17) (50.0 g, 0.56 mmol) and anhydrous sodium acetate (56 mg) in glacial acetic acid (1.0 mL) was heated to 40° C. and treated dropwise with a solution of bromine (90 mg, 0.56 mmol) in glacial acetic acid (5 mL). Once the starting material was fully consumed by TLC analysis, the mixture was poured onto water (5 mL), basified with saturated aqueous sodium hydrogen carbonate and extracted with tert-butylmethyl ether. The combined organic phases were dried (MgSO4), filtered, and concentrated to a solid which was purified by silica-gel column chromatography [eluent: Ethyl acetate:Hexane, 50:50, ν/ν] to give the title bromide (18) (166 mg. 85%) as an off white solid:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:16]2[CH2:19][CH:18]([NH2:20])[CH2:17]2)=[CH:11][CH:10]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:29]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:16]2[CH2:17][CH:18]([NH:20][S:34]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)(=[O:36])=[O:35])[CH2:19]2)=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccnc1
Temperature: 0 °C
Yield: 68.5 %

Procedure:
0.79 cm3 of triethylamine is added, at room temperature under an argon atmosphere, to a solution of 0.7 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine in 25 cm3 of dichloromethane. The mixture is cooled to around 0° C. before adding thereto a solution of 1.2 g of pyrid-3-ylsulfonyl chloride in 25 cm3 of dichloromethane, and then it is stirred at room temperature for 16 hours. The reaction mixture is diluted with 50 cm3 of dichloromethane and is then washed with twice 25 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluant: dichloromethane/methanol (97.5/2.5 by volume)]. 0.7 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}pyrid-3-ylsulfonamide is obtained in the form of a cream-colored foam which solidifies in the presence of isopropanol into a cream-colored powder melting at 164° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][OH:11])[CH:7]=[N:8][CH:9]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].O>O1CCCC1>[CH3:12][S:13]([O:11][CH2:10][C:6]1[CH:7]=[N:8][CH:9]=[C:4]([Br:3])[CH:5]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)OCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) suspension of sodium hydride (60% dispersion in mineral oil, 0.064 g, 1.60 mmol) in tetrahydrofuran (5 mL) was added a solution of (5-bromopyridin-3-yl)methanol (0.200 g, 1.06 mmol) in tetrahydrofuran (5 mL). After stirring for 1 hour, methanesulfonyl chloride (0.099 mL, 1.28 mmol) was added. The reaction was then warmed to room temperature and stirred until complete. The reaction was then poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with water and saturated aqueous sodium chloride solution, dried, filtered, and concentrated under reduced pressure to provide the title compound: LCMS m/z 267.86 [M+2+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=O)[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:36][NH:37][CH3:38].C(N(C(C)C)CC)(C)C>>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29](=[O:31])[N:37]([CH3:38])[CH3:36])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:33][CH:34]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and dimethylamine hydrochloride/diisopropylethylamine Rf value: 0.5 (silica gel, methylene chloride/methanol=5:1) C30H32N4O2
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.Cl[C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1>CO>[CH:1]1([CH2:4][NH:5][C:7]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=2)[CH2:3][CH2:2]1
Reactant: NCC1CC1
Reactant: O=C(O)c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: CO
Product: O=C(O)c1cnc(NCC2CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Cyclopropanemethylamine (1.70 g, 23.90 mmol) was added to a solution of 6-chloro-5-nitronicotinic acid (1.12 g, 5.53 mmol) in MeOH (25 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was dissolved in H2O (20 mL), and the solution was acidified by adding 3N HCl until pH=3. The mixture was extracted with EtOAc and CH2Cl2 (2×100 mL) and the combined extracts were washed with brine, dried over Na2SO4, concentrated in vacuo to give a bright yellow solid (1.30 g) which was used in the following reaction without further purification.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1>[C:9]([C:2]1[N:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1nc(Br)cs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1csc(C=O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 3.7 %

Procedure:
A solution of 4-bromo-2-thiazolecarboxaldehyde (14.8 g), 1-dodecyne (14.1 g), and triethylamine (23.5 g) in dry tetrahydrofuran (85 m) was chilled to 5° C. and degassed under nitrogen. bis(Triphenylphosphine)palladium (II) chloride (0.54 g) and copper (I) iodide (0.07 g) were added to the mixture, which was degassed, and stirred, under nitrogen, at room temperature for 2.5 hrs. The reaction mixture was heated at 40° C. for 7 hrs, during which time additional amounts of 1-dodecyne (3.9 g), bis(triphenylphosphine)palladium (II) chloride (0.11 g), and copper(I)iodide (0.02 g) were added. The mixture was cooled to room temperature, the precipitate was collected, and the filter cake was washed with ethyl acetate. The filtrate was diluted with ethyl acetate (300 ml). Water was added in portions, and the organic layer was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with heptane to heptane: 1% ethyl acetate. A portion (1.05 g) of the residue was rechromatographed, eluting with hexane:(0.3 to 1%) ethyl acetate. The appropriate fractions were collected and evaporated to yield 0.79 g (76.5% yield) of product, mp 25.5°-26° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[CH3:9][O:10][C:11]1([C:17]2[CH:18]=[C:19]([CH2:23]Br)[CH:20]=[CH:21][CH:22]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CN(C=O)C>[CH3:9][O:10][C:11]1([C:17]2[CH:18]=[C:19]([CH2:23][O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: COC(=O)CO
Reactant: COC1(c2cccc(CBr)c2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COCc1cccc(C2(OC)CCOCC2)c1
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 49.7 %

Procedure:
A solution of methyl glycolate (0.35 g, 3.9 mmol) in 5 mL of anhydrous DMF was added to a suspension of sodium hydride (0.11 g, 4.6 mmol) in 5 mL of anhydrous DMF at 5° C, and the reaction mixture was stirred for 40 minutes at 5° C. A solution of 3-[(4-methoxy)tetrahydropyran-4-yl]-α-bromotoluene (1 g, 3.9 mmol) in 10 mL of anhydrous DMF was added to the cold methyl glycolate solution while maintaining the temperature at 5° C. The mixture was stirred for 2 h at 5° C, then for 18 h at room temperature. The mixture was quenched with water (100 mL) and the aqueous solution was extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash column chromatography on silica gel, eluting with 25% ethyl acetate in hexane, to give 0.57 g (50%) of methyl 3-[(4-methoxy)-tetrahydropyran-4-yl]phenylmethoxyacetate as a clear oil: HRMS calcd for C16H22O5 295.1545. Found 295.1502.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]=1[C:11]#[N:12].[Cl-].[Cl:14][C:15](Cl)=[N+:16]([CH3:18])[CH3:17]>ClCCl>[C:7]([C:4]1[C:3]([C:11]#[N:12])=[C:2]([N:1]=[C:15]([Cl:14])[N:16]([CH3:18])[CH3:17])[S:6][N:5]=1)([CH3:9])([CH3:8])[CH3:10]
Reactant: CC(C)(C)c1nsc(N)c1C#N
Reactant: C[N+](C)=C(Cl)Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CN(C)C(Cl)=Nc1snc(C(C)(C)C)c1C#N
Yield: 67.7 %

Procedure:
In the manner of Example VI, 9.1 g of 5-amino-3-tert-butyl- 4-cyanoisothiazole and 9.8 g of N-(dichloromethylene)-N,N-dimethylammonium chloride were allowed to react in 50 ml of dichloromethane. The volatile materials were evaporated under reduced pressure. The residue was recrystallized from hexane to give 9.2 g of N'-(3-tert-butyl-4 -cyano-5-isothiazolyl)-N,N-dimethylchloroformamidine, mp 94°-100°. The ir and nmr spectra were consistent with the assigned structures.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:28])(=[O:27])[NH:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:28])=[O:27])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.4 %

Procedure:
Prepared using general procedure 28, method A. A mixture of tert-butyl-1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)piperidin-4-ylcarbamate (657 mg, 1.5 mmol), TFA (1.5 mL) and CH2Cl2 (10 mL) was stirred at RT under an N2 atmosphere for 2.5 h. The reaction was poured into saturated NaHCO3 solution (50 mL) and acidified to pH 3-4 with a 1 M HCl solution. The mixture was then extracted with CH2Cl2 (3×50 mL). Since LCMS analysis showed that the product was still in the aqueous layer, it was neutralized with saturated NaHCO3 resulting in precipitation of a white solid which was filtered, washed with MeOH, and dried under vacuum to obtain 4-(4-aminopiperidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (200 mg, 38% over 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 7.57-7.45 (m, 4H), 6.94-6.89 (m, 3H), 6.44 (d, J=3.9 Hz, 1H), 3.83 (d, J=13.5 Hz, 2H), 3.20-3.14 (m, 1H), 2.83 (t, J=11.8 Hz, 2H), 1.84 (d, J=9.3 Hz, 2H), 1.51-1.41 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(N(C(C)C)CC)(C)C.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:24][NH:25][CH2:26][CH2:27][CH3:28])[CH:17]=[CH:16]1>C(Cl)Cl>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH2:24][N:25]([CH2:26][CH2:27][CH3:28])[C:3](=[O:4])[CH2:2][Cl:1])[CH:17]=[CH:16]1
Reactant: CCCNCc1cccc2cc[nH]c12
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(Cc1cccc2cc[nH]c12)C(=O)CCl
Reaction time: 2 h
Yield: 100 %

Procedure:
Add chloroacetyl chloride (1.7 ml, 21.71 mmol) and diisopropylethylamine (10.38 ml, 62.04 mmol) to a solution of (1H-Indol-7-ylmethyl)propylamine (3.89 g, 20.68 mmol) in methylene chloride. Stir for 2 hours, quench with saturated aqueous ammonium chloride and extract into ethyl acetate. Wash the organic layers with saturated aqueous sodium chloride, dry over magnesium sulfate, filter, and concentrate under reduced pressure to yield N-(1H-indol-7-yl)methyl N-propyl 2-chloroacetamide (5.47 gm, 20.68 mMol).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:28][C:29](=[O:31])[CH3:30].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:28][C:29](=[O:31])[CH3:30])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Cn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
In 20 ml of acetone was dissolved 5.0 g of the imidazole (101a) and 1.36 g (14.7 mmol) of monochloroacetone, followed by addition of 2.46 g (12.27 mmol) of potassium iodide, and the mixture was stirred at room temperature for 30 minutes. Then, to the mixture was added 2.04 g (14.8 mmol) of potassium carbonate, and the mixture was stirred with heating at 50° C. for 4 hours and worked up. The reaction mixture was distilled off under reduced pressure, and the residue was extracted with methylene chloride. The extract was washed with water, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=9:1) to provide 3.1 g (yield 54%) of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-acetylmethyl-1H-imidazole (139) as solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:17][CH:16]=1>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25][N:26]([C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]3)=[CH:19][CH:20]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Yield: 5.2 %

Procedure:
The title compound (2.2 mg, 5%) was prepared from [4-(trifluoromethyl)phenyl]boronic acid (19 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (Example 9, Step 2, 36 mg, 0.10 mmol) in a manner similar to Example 9, Step 3. LRMS (ESI), m/z 444 (M+Na).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[CH3:8].C[O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([CH3:26])[CH:20]=1>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18](=[O:17])[CH2:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:20][C:21]=1[CH3:26]
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)c1ccc(F)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CC(=O)c2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
17.3 g KOtBu was dissolved in 500 mL THF and 9 mL acetophenone was added. After 15 min at RT 25.9 g 4-fluoro-3-methyl-benzoic acid methyl ester was added and stirred for 3 h at RT. The solvent was removed and the residue was purified by chromatography on silica gel (cyclohexane/EE: 98:2) to yielded 19.3 g of the desired compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:6]=[C:7]([F:12])[C:8]=1[N+:9]([O-])=O>O1CCCC1.[Zn]>[F:12][C:7]1[CH:6]=[C:5]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[CH:4]=[C:3]([F:2])[C:8]=1[NH2:9]
Reactant: O=[N+]([O-])c1c(F)cc(N2CCOCC2)cc1F
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Nc1c(F)cc(N2CCOCC2)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
Concentrated hydrochloric acid (4.2 mL) was added slowly to a mixture of zinc dust (3.3 g) and 4-(3,5-difluoro-4-nitro-phenyl)-morpholine (2.49 g) in tetrahydrofuran (40 mL) cooled to 0° C. The reaction mixture was then stirred for 1 hour at 0° C. and 2 hours at 25° C. The reaction mixture was filtered through Celite (10 g), concentrated in vacuo and purified by flash chromatography to furnish 1.96 g (90% yield) of the title compound as a white solid. GC-MS (m/z) 214 (M+); tR=5.83. 1H NMR (500 MHz, DMSO-d6): 2.94 (t, 4H), 3.69 (t, 4H), 4.53 (s, 2H), 6.57 (m, 2H).
Reaction SMILES: Br[CH:2]=[CH:3][O:4][Si](C)(C)C.C([Li])(C)(C)C.[CH3:14][CH:15]([CH2:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17][CH2:18][C:19](=O)[CH3:20].Cl>C(OCC)C.CCCCC>[CH3:20][C:19]([CH2:18][CH2:17][CH2:16][CH:15]([CH3:14])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:2][CH:3]=[O:4]
Reactant: CC(=O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: C[Si](C)(C)OC=CBr
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC(=CC=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 80.4 %

Procedure:
1-Bromo-2-trimethylsilyloxyethylene (1 g, 5.3 mmol) in anhydrous ethyl ether (10 cc) is introduced under an argon atmosphere into a 50-cc round-bottomed flask. The mixture is cooled to -70° C. and a 1.2M solution (8 cc) of tert-butyllitium in pentane is then added. Stirring is performed for 90 minutes at -70° C. and then 6,10,14-trimethyl-2-pentadecanone (1.19 g) is added in solution in anhydrous ethyl ether (3 cc). The temperature is allowed to rise to about -15° C. and stirring is continued for 1 hour. The solution is cooled to -60° C. and 3N hydrochloric acid (7 cc) is then added over 15 minutes. Stirring is performed for 30 minutes at 10° C. After extracting with ether, washing the ether phases until neutral, drying the ether phases over magnesium sulphate, filtering and evaporating off the solvents, a product is obtained and is purified by flash chromatography. 3,7,11,15-Tetramethyl-2-hexadecenal (1.05 g) is thus obtained and is characterized by its infrared spectrum and its proton nuclear magnetic resonance spectrum.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]([OH:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1.FC(F)(F)C(O)=O>CS(C)=O>[CH3:1][N:2]([CH3:21])[S:3]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([OH:31])[CH3:30])[CH:24]=3)[N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc(-c2ccnc(S(C)(=O)=O)n2)s1
Reactant: CC(O)c1cccc(N)c1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(O)c1cccc(Nc2nccc(-c3ccc(S(=O)(=O)N(C)C)s3)n2)c1
Temperature: 100 °C
Yield: 62.5 %

Procedure:
5-(2-Methanesulfonyl-pyrimidin-4-yl)-thiophene-2-sulfonic acid dimethylamide (19.8 mg, 0.057 mmol), 1-(3-aminophenyl)ethanol (11.7 mg, 0.085 mmol) and trifluoroacetic acid (6.5 uL, 0.085 mmol) were combined in DMSO (0.5 M) and the mixture was heated in a capped vial at 100° C. for 16 hours. The dark solution was diluted with DMSO and purified by preparative LC. 5-{2-[3-(1-Hydroxyethyl)-phenylamino]-pyrimidin-4-yl}-thiophene-2-sulfonic acid dimethylamide (14.4 mg, 62.6%) was obtained as a brown solid after lyophilization. 1H NMR (500 MHz, DMSO-d6) δ1.35 (d, J=6 Hz, 3H), 2.70 (s, 6H), 4.70 (m, 1H), 5.12 (d, J=4 Hz, 1H), 6.97 (br d, J=7 Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 7.46 (d, J=5.5 Hz, 1H), 7.49 (br d, J=6.5 Hz, 1H), 7.71 (d, J=4 Hz, 1H), 7.91 (br s, 1H), 8.12 (d, J=4 Hz, 1H), 8.58 (d, J=5.0 Hz, 1H), 9.75 (s, 1H). MS: m/z 405 (M+H+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[CH2:16]([N:19]=[C:20]=[O:21])[CH2:17][CH3:18]>C1C=CC=CC=1>[CH2:16]([NH:19][C:20]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[O:21])[CH2:17][CH3:18]
Reactant: CCCN=C=O
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Solvent: c1ccccc1
Product: CCCNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 79.6 %

Procedure:
To a stirred and chilled (10°-15° C.) solution of 0.027 mole of 3-[3-(trifluoromethyl)phenoxy]azetidine in 100 ml of dry benzene was added dropwise 4.0 g (0.047 mole) of n-propyl isocyanate. The reaction mixture was stirred at room temperature for 30 minutes. The benzene was washed with dilute sodium bicarbonate (50 ml), water (25 ml), saturated sodium chloride (25 ml), and dried (sodium sulfate). The solution volume was reduced to 50 ml, and 30 ml of petroleum ether was added, yielding 6.5 g (81%) of product. Recrystallization from isopropyl ether-isopropyl alcohol gave 6.0 g of small white needles, m.p. 115°-117° C.