Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][C:17]1[C:18](B(O)O)=[CH:19][S:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:17]1[C:18]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([F:15])([F:14])[F:13])=[CH:19][S:20][CH:21]=1
Reactant: Cc1cscc1B(O)O
Reactant: COC(=O)c1ccc(Br)c(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2cscc2C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixture of methyl 4-bromo-3-(trifluoromethyl)benzoate (3.5 g; 12.4 mmol; 1 eq.), 4-methyl-3-thiopheneboronic acid (1.93 g; 13.6 mmol; 1.1 eq.), potassium carbonate (8.54 g; 61.8 mmol; 5 eq.) and Pd(PPh3)4 (1.43 g; 1.24 mmol; 0.1 eq.) in toluene (17.5 mL) and water (17.5 mL) was refluxed for 24 h whereupon 4-methyl-3-thiopheneboronic acid (0.88 g; 6.2 mmol; 0.5 eq.) was added. The reaction mixture was stirred for a further 3 hours then cooled down to room temperature and filtered through a pad of Celite® which was washed with toluene (200 mL). The filtrate was concentrated in vacuo and the residue taken up in ethyl acetate (300 mL). The organic layer was washed with sat. aq. NaHCO3 (100 mL), water (100 mL) and brine (100 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (3 g, 81%) as a brown oil.
Reaction SMILES: [F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C@H:16]([CH3:20])[C:17](Cl)=[O:18])[C:12]2=[O:21])=[CH:7][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1>ClCCl>[F:30][C:31]1[CH:32]=[C:33]([F:37])[CH:34]=[CH:35][C:36]=1[C:17](=[O:18])[C@H:16]([N:13]1[CH:14]=[CH:15][N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:25])([F:1])[CH:22]([F:24])[F:23])=[CH:6][CH:7]=2)[C:12]1=[O:21])[CH3:20]
Reactant: Fc1cccc(F)c1
Reactant: C[C@H](C(=O)Cl)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C[C@H](C(=O)c1ccc(F)cc1F)n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 0 °C

Procedure:
(2R)-2-[3-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-2,3-dihydro-2-oxo-1H-imidazol-1-yl]propanoyl chloride (1.5 g) was dissolved in 30 ml of dichloromethane, to which 3.8 ml of 1,3-difluorobenzene and 2.3 g of anhydrous aluminum chloride (powder) were added. The mixture was refluxed with heating for 5 hours. The reaction solution was cooled, poured into 100 ml of ice water and extracted with 100 ml of ethyl acetate. The extract was washed with 50 ml of 1N-hydrochloric acid and 50 ml of a saturated aqueous solution of sodium chloride successively, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate:acetic acid=2:1:0.03) and crystallized from 10 ml of diisopropyl ether to give 0.25 g of 1-[(1R)-2-(2,4-difluorophenyl)-2-oxo-1-methylethyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone as colorless powdery crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:5].[CH:23](NC(C)C)(C)C.[Li].CI>C1COCC1>[CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:23])([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][N:13]=2)[CH2:10][CH2:11]1)[CH3:5]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C(C)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-propionic acid methyl ester (1.23 g, 3.9 mmoles) from Example 14A in dry THF (3 mL) was added dropwise to a −65° C. solution of 1.8 N lithium diisopropylamine (LDA) in dry THF (2.4 mL) and stirred at this temperature for 1 hour. Methyl iodide (0.49 mL, 7.88 mmoles) was added and the mixture was allowed to slowly warm to room temperature and stir for 2 hours at room temperature. The mixture was quenched with ice/water and partitioned with ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic extracts washed with water, dried (MgSO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified (silica gel, 10-30% acetone in hexane) to provide the title compound as a yellowish solid.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[N:5]1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.[CH3:17]O>>[CH:1]([N:4]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:17])=[O:10])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)n1ccc(C(=O)O)n1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccn(C(C)C)n1
Reaction time: 5 h
Yield: 76 %

Procedure:
To a solution of 1-isopropyl-1 h-pyrazole-3-caboxylic acid (0.9757 g, 6.33 mmol, Matrix Scientific) in MeOH (31.6 ml) in a glass pressure vessel was added sulfuric acid (0.355 ml, 6.33 mmol Sigma Aldrich). The vessel was sealed and the rxn was brought to reflux to stir. (NOTE: A portable blast shield was used.) Rxn was allowed to stir for 5 hours. The rxn was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The organic extract was washed with water, dried over MgSO4, filtered and concentrated in vacuo to give methyl 1-isopropyl-1H-pyrazole-3-carboxylate (0.8073 g, 4.80 mmol, 76% yield) as a clear oil. MS m/z=168.9 [M+H]+. Calculated for C8H12N2O2: 168.09. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.55 (d, J=6.85 Hz, 6H) 3.93 (s, 3H) 4.63 (dt, J=13.50, 6.75 Hz, 1H) 6.83 (d, J=2.35 Hz, 1H) 7.46 (d, J=2.35 Hz, 1H)
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:6]2[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].ClC1C=CC=C(C(OO)=O)C=1.[OH-].[NH4+:37].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:37][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][C:18]3([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:6]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: [NH4+]
Reactant: CCCc1nc2cnc3cccnc3c2n1CC1(O)CCCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCCCC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
To a solution of 1-[(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol (1.43 g, 4.41 mmol) in chloroform (20 mL) at rt was added m-chloroperbenzoic acid (m-CPBA, 70%, 2.17 g, 8.82 mmol). After 1.5 h, the solution was was cooled to 0° C. and concentrated ammonium hydroxide (5 mL) was added. After 3 min, p-toluenesulfonyl chloride (TsCl, 0.920 g, 4.85 mmol) was added in portions. After 1 h, the reaction mixture was filtered and the filter cake was washed with chloroform. The filtrate was washed with saturated aqueous sodium bicarbonate (50 mL) and dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an orange foam which was purified twice by HPFC (silica gel, gradient elution with 0-25% CMA/CHCl3 where CMA is a solution comprised of 80% CHCl3, 18% MeOH, and 2% conc. NH4OH; followed by 0-30% CMA/CHCl3). The appropriate fractions were concentrated and triturated with acetonitrile. The solid was isolated by filtration and dried at 100° C. under vacuum to yield 1-[(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]cyclohexanol (567 mg, 38%) as a white powder, mp 209.0-211.0° C. Anal. Calcd for C19H25N5O .0.2H2O C, 66.35; H, 7.47; N, 20.36; Found: C, 66.62; H, 7.34; N, 20.05.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)[CH:12]([F:14])[F:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:10][C:11]([F:24])([O:15][C:16]1[CH:17]=[C:18]([CH2:19][NH:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH:21]=[CH:22][CH:23]=1)[CH:12]([F:13])[F:14]
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Reactant: N#Cc1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: N#Cc1cccc(NCc2cccc(OC(F)(F)C(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
EX-576A) A solution of 3-aminobenzonitrile (1.06 g, 9.1 mmol) and 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (2.00 g, 9.01 mmol) was dissolved in 25 mL of dichloroethane and acetic acid (536 mL, 9.37 mmol), then solid NaBH(OAc)3 (2.48 g, 11.7 mmol) was added. The mixture was stirred at room temperature for 3 hours, then quenched with water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3, then dried over MgSO4, and evaporated. The crude product was purified by MPLC on silica gel eluting with 20% to 30% ethyl acetate in hexane to give 1.58 g (54%) of the desired 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]benzonitrile product as a clear oil. 1H NMR (CDCl3) δ4.38 (s, 3H), 5.89 (dt, 1H), 6.79 (t, 1H), 6.98 (d, 2H), 7.12-7.28 (m, 4H), 7.40(t, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:17])[C:5]([C:8]2[NH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=2)=[N:6][CH:7]=1.[H-].[Na+].[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:17])[C:5]([C:8]2[N:12]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[CH:11]=[C:10]([C:13]([F:14])([F:15])[F:16])[N:9]=2)=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: FC(F)(F)c1cnc(-c2ncc(Br)cc2Cl)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In N,N-dimethylformamide (13 mL) was dissolved 5-bromo-3-chloro-2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (1.27 g), 60% sodium hydride (187 mg) was added to the solution under ice-cooling, and after raising the mixture to room temperature, the mixture was stirred for 1 hour. The reaction mixture was ice-cooled, 2-(trimethylsilyl)ethoxymethyl chloride (1.03 mL) was added to the mixture, and after raising the mixture to room temperature, the mixture was stirred for 1 hour. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and a saturated brine, and dried over anhydrous magnesium sulfate. After concentrating the mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 95:5) to obtain 5-bromo-3-chloro-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (1.56 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:31]([F:43])=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:33](O)=[O:34]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[C:33](=[O:34])[C:32]2[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=[C:30]([Cl:29])[C:31]=2[F:43])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OCc3ccccc3)c2)cc1
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OCc3ccccc3)c2)C(=O)c2cc(C(F)(F)F)cc(Cl)c2F)cc1

Procedure:
The title compound was prepared in analogy to Example 1, using [2-(3-benzyloxy-phenyl)-ethyl]-(4-tert-butyl-benzyl)-amine (S9-C43) and 3-chloro-2-fluoro-5-(trifluoromethyl)benzoic acid. MS: 597.3 [ISP (M+H)+].
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[Br:12])C=C.[C:13]1(C)[CH:18]=C(C)C=C(C)[CH:14]=1>>[CH2:18]([C:10]1[C:9]([F:11])=[CH:8][CH:7]=[C:6]([Br:12])[C:5]=1[OH:4])[CH:13]=[CH2:14]
Reactant: C=CCOc1cc(F)ccc1Br
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1c(F)ccc(Br)c1O
Yield: 95 %

Procedure:
Treatment of 2-(allyloxy)-1-bromo-4-fluorobenzene (12.00 g, 0.052 mol) in refluxing mesitylene generally according to the reaction procedure described for Intermediate 8 provided 11.5 g (95%) of 2-allyl-6-bromo-3-fluorophenol as a pale yellow oil. Rf=0.48 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C9H8BrFO: C, 46.78; H, 3.49. Found: C, 47.59; H, 3.47.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[OH-].[K+].[CH2:21]([SH:23])[CH3:22].Cl>CN(C)C=O.C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([S:23][CH2:21][CH3:22])[N:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: CCS
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCSc1nc2c(cc1F)c(=O)c(C(=O)O)cn2CC
Temperature: 60 °C
Yield: 182.6 %

Procedure:
A suspension of 0.54 g (2 mmol) 1-ethyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid in 10 ml N,N-dimethyl formamide was stirred at 60° C. and treated all at once with a solution of 0.56 g potassium hydroxide (10 mmol) and 1 ml (0.85 mmol) ethanethiol in 5 ml absolute ethanol. After 15 minutes the mixture was poured into 40 mmol 0.4 N hydrochloric acid containing ice. The precipitate was filtered, washed with ethanol and ether to afford 0.46 g of the title compound. A sample for analysis was crystallized from acetic acid, mp 219°-221° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.[CH3:16][C:17]1[NH:21][N:20]=[C:19]([C:22](O)=O)[N:18]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:16][C:17]1[NH:21][N:20]=[C:19]([C:22]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[CH:6][C:7]([O:10][C:11]([F:13])([F:12])[F:14])=[CH:8][CH:9]=3)[N:15]=2)[N:18]=1
Reactant: NC(=NO)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc(C(=O)O)n[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
To a solution of N′-hydroxy-4-(trifluoromethoxy)benzimidamide (1.3 g, 5.1 mmol) and 5-methyl-1H-1,2,4-triazole-3-carboxylic acid (650 mg, 5.1 mmol) in DMF (15 mL), EDC.HCl (980 mg, 5.1 mmol) and HOBT (690 mg, 5.1 mmol) were added at RT. The mixture was stirred at RT for 1 h, and then heated to 140° C. for 3 h. The resulting mixture was cooled, diluted with H2O (20 mL) and extracted with EtOAc (4×40 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure, and the residue was purified by Combiflash reverse phase chromatography (50%˜60% MeCN/H2O containing 0.01% trifluoroacetic acid) to give 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole as a white solid (590 mg, 37%). MS (ES+) C12H8F3N5O2 requires: 311. found: 312[M+H]+.
Reaction SMILES: [CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Cl>CN(C)C=O>[CH2:1]([C:8]1([N:15]([CH3:16])[CH3:17])[CH2:13][CH2:12][CH:11]([O:14][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([F:24])[CH:26]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1(Cc2ccccc2)CCC(O)CC1
Reactant: Fc1cccc(CCl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1(Cc2ccccc2)CCC(OCc2cccc(F)c2)CC1
Temperature: 0 °C
Yield: 50.5 %

Procedure:
2.65 g of 4-benzyl-4-dimethylaminocyclohexanol were dissolved in 20 ml of dimethylformamide; 1.40 g of potassium tert.-butoxide were added and stirring was carried out for 45 minutes, before 2.0 g of 3-fluorobenzyl chloride were added dropwise in the course of 30 minutes. After stirring overnight, the mixture was added to 25 ml of ice-water and extracted repeatedly with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The resulting crude product (3.69 g) was separated on silica gel with hexane/ethyl acetate (V:V=1:1). 1.96 g of [1-benzyl-4-(3-fluoro-benzyloxy)-cyclohexyl]dimethylamine were obtained and, as described for Example 1, were converted into 1.13 g of the corresponding hydrochloride using chlorotrimethylsilane and water in 2-butanone (white solid).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([CH3:34])([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][CH:8]=1)C.[H-].[Na+].[CH3:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[CH3:47])[CH2:42]Cl>CN(C=O)C.CCOCC.Cl>[CH3:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[CH3:47])[CH2:42][N:19]1[CH2:20][CH:16]([CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:34])([O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)[C:4]([OH:3])=[O:35])=[CH:12][CH:11]=2)[N:17]([CH3:22])[C:18]1=[O:21]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(CCl)cc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1ccc(CN2CC(CCOc3ccc(CC(C)(Oc4ccc(C(F)(F)F)cc4)C(=O)O)cc3)N(C)C2=O)cc1C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To a mixture of 80 mg of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere of nitrogen, 16 mg of NaH (0.40 mmol) is added. The resulting solution is allowed to stand at r.t. for 20 min. Then 0.06 mL of 3,4-dimethylbenzyl chloride is added and resulting mixture is allowed to stand at r.t. for overnight. Reaction mixture is diluted with Et2O and 1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material is in 5 mL of EtOH and 0.5 mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organic solvent is then removed under vacuum and residue is dissolved in CH2Cl2 and 1N HCl. Aqueous layer is washed with CH2Cl2 (2×10 ml). Combined organic layer is dried over Na2SO4, filtered and concentrated under vacuum. The crude material is purified by MS/LC to give 54 mg (56%) of the title product. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, 2H, J=8.6 Hz), 7.16 (d, 1H, J=8.6 Hz), 7.10 (d, 1H, J=8.0 Hz), 7.06 (d, 1H, J=8.0 Hz), 6.99-6.94 (m, 3H), 6.75 (d, 2H, J=8.4 Hz), 4.33, 4.25 (ABq, 2H, J=14.8 Hz), 4.07 (bs, 1H), 3.97-3.93 (m, 2H), 3.70-3.65 (m, 1H), 3.41 (t, 1H, J=8.8 Hz), 3.32, 3.16 (ABq, 2H, J=13.8 Hz), 3.03 (t, 1H, J=8.8 Hz), 2.85 (s, 3H), 2.28-2.20 (m, 1H), 2.22 (s, 3H), 1.96-1.88 (m, 1H), 1.50 (s, 3H). HRMS (ES+) m/z exact mass calcd for C32H36N2O5F3 (m+1) 585.2576, found 585.2578.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[N:5]=1.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][OH:16]>O1CCCC1>[Cl:13][C:6]1[N:5]=[C:4]([O:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)CO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
2.0 g of sodium hydride was added to a mixture of 9.65 g of 2,6-dichloro-3-nitropyridine, 4.95 g of methyl glycolate and 100 ml of tetrahydrofuran at 0° C. The mixture was stirred at 0° C. for 4 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 10.86 g of 6-chloro-2-(methoxycarbonyl)methoxy-3-nitropyridine.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)=[O:12])=[CH:4][C:3]=1[CH3:28].Br[C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+]>>[CH3:8][C:7]1[CH:6]=[C:5]([CH2:9][CH2:10][C:11](=[O:12])[C:13]2[S:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=3)=[CH:16][CH:17]=2)[CH:4]=[C:3]([CH3:28])[C:2]=1[O:1][C:30]([CH3:39])([CH3:38])[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]
Reactant: Cc1cc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc(C)c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)cc(C)c1OC(C)(C)C(=O)OC(C)(C)C

Procedure:
Tert-butyl 2-(2,6-dimethyl-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoate is prepared from 3-(4-hydroxy-3,5-dimethylphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one according to general procedure D, using 15 equivalents of tert-butyl bromoisobutyrate and 15 equivalents of potassium carbonate added in portions of 3 equivalents in the course of the reaction.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Cl:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([S:19]([NH:9][C:5]2[C:4]([O:10][CH3:11])=[N:3][C:2]([Cl:1])=[C:7]([Cl:8])[N:6]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: COc1nc(Cl)c(Cl)nc1N
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: COc1nc(Cl)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5,6-dichloro-3-methoxy-2-pyrazinamine (0.1 g) and 3-chlorobenzenesulphonyl chloride (0.13 g). Yield 0.047 g.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[N:38]1([C:45](=O)[CH2:46]Cl)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:45][CH2:46][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCCC1
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCCCC3)cc2)c1
Yield: 77.8 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azepan-1-yl-2-chloroethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.2 mg) was obtained.