Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1>CN(C=O)C>[F:36][C:35]([F:37])([F:38])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:42])([F:40])[F:41])[CH:32]=1)[CH2:28][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(O)ccc12
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCCn2c1cc1cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc12
Temperature: 75 °C
Yield: 83.4 %

Procedure:
To a mixture of ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (95 mg, 0.348 mmol) and cesium carbonate (170 mg, 0.521 mmol) in DMF (2 mL) was added 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (128 mg, 0.417 mmol). The reaction mixture was heated at 75° C. for 15 h and cooled down. The solid was filtered and washed with ethyl acetate. The combined solvent was evaporated, and the residue was purified by silica gel column chromatography to give the title compound (145 mg). LCMS m/z=500.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (t, J=7.1 Hz, 3H), 1.51-1.61 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.24 (m, 2H), 2.55 (dd, J=15.6, 8.6 Hz, 1H), 2.93 (dd, J=15.6, 5.4 Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.94 (m, 1H), 4.10-4.17 (m, 1H), 4.22 (q, J=7.1 Hz, 2H), 5.19 (s, 2H), 6.18 (s, 1H), 6.90 (dd, J=8.8, 2.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.83 (s, 1H), 7.94 (s, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18]C(O)=[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:22])[CH:15]=1.Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:5]2[O:4][C:2](=[O:3])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=3)[C:21](=[O:22])[C:16]=2[CH:15]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 10 h
Yield: 13 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 6 (1.56 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stifling at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 18.
Reaction SMILES: Cl[C:2]1[C:3](=[O:21])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[C:3](=[O:21])[N:4]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:5](=[O:13])[C:6]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:26][CH:25]=1
Reactant: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1ccccn1
Reactant: COc1ccc(N)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC2=C(c3ccccc3)C(=O)N(Cc3ccccn3)C2=O)cc1
Temperature: 150 °C
Yield: 77.1 %

Procedure:
3-Chloro-4-phenyl-1-(pyridin-2-ylmethyl)-1H-pyrrole-2,5-dione (2.39 mmol, 714 mg) and 4-methoxyaniline (5.26 mmol, 648 mg) were dissolved in DMF (4 mL). The mixture was heated in a microwave reactor at 150° C. for five min. After cooling, the reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 710 mg (77%) of the title compound. 1H NMR (400 MHz, CDCl3): 8.60-8.57 (m, 1H), 7.71-7.65 (m, 1H), 7.36-7.30 (m, 1H), 7.24 (bs, 1H), 7.23-7.19 (m, 1H), 7.13-7.05 (m, 3H), 7.04-6.99 (m, 2H), 6.64-6.53 (m, 4H), 4.95 (s, 2H), 3.70 (s, 3H).
Reaction SMILES: N1C=CC=CC=1.P(Br)(Br)[Br:8].[CH2:11]([O:13][CH:14](O)[CH2:15][CH2:16][CH2:17][CH3:18])[CH3:12].O>C1C=CC=CC=1>[CH2:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][Br:8])[CH3:12]
Reactant: BrP(Br)Br
Reactant: CCCCC(O)OCC
Solvent: c1ccncc1
Solvent: O
Solvent: c1ccccc1
Product: CCOCCCCCBr
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 182 %

Procedure:
10 g of pyridine was added dropwise to a solution of 78 g (0.29 mol) of phosphorus tribromide in 130 ml of benzene. After the solution was stirred for 10 minutes and cooled to -5° C., a mixture of 102 g (0.77 mol) of pentane diol monoethyl ether and 5 g of pyridine was added dropwise. After maintaining the reaction temperature at 0° C. and stirring for 2 hours, the solution was stirred for 8 hours at the room temperature. 100 ml of water was added and extracted with diethyl ether. The organic layer was washed subsequently with 6N hydrochloric acid and an aqueous sodium hydrogen carbonate solution, then dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under the reduced pressure, to obtain 103 g of 5-bromopentyl ethyl ether. Boiling point; 47-48° C. (1 mmHg).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>C(O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCC2(CC1)OCCO2
Temperature: 5 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A stirred, cooled (5° C.) solution of 1,4-dioxaspiro[4.5]decan-8-one (20 g, 0.128 mol) in ethanol (250 ml) was treated with sodium borohydride (7.3 g, 0.192 mol) in portions over 20 minutes. The reaction mixture was stirred at 5° C. for 1 hour then at room temperature for 1 hour. Water (20 ml) was added and the mixture was stirred vigorously for 10 minutes then concentrated in vacuo. The residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated and the aqueous re-extracted with ethyl acetate (100 ml). The combined organics were dried (sodium sulphate) then evaporated to give the title alcohol as a colourless oil (17.1 g, 84%). MS ES+, m/z=159 for (M+H)+; δ(360 MHz, CDCl3) 1.52-1.71 (4H, m), 1.78-1.92 (4H, m), 3.76-3.83 (1H, m), 3.91-3.94 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[Cl:10][C:11]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:12]=1[C:13]([N:15]=[C:16]=[O:17])=[O:14]>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:12]=1[C:13]([NH:15][C:16]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1)=[O:17])=[O:14]
Reactant: O=C=NC(=O)c1ccc(F)cc1Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1ccc(F)cc1Cl)Nc1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
3.24 g (0.02 mol) of 3,4-dichloroaniline are dissolved in 60 ml of dry toluene, and 3.99 g (0.02 mol) of 2-chloro-4-fluoro-benzoyl isocyanate are added in the absence of moisture. The mixture is stirred for one hour at 80° C. and then cooled to 20°-25° C. The precipitate which separates out is filtered off under suction and dried in vacuo at 100° C. 6.8 g (94% of theory) of 1-(2-chloro-4-fluoro-benzoyl)-3-(3,4-dichlorophenyl)-urea of melting point 208° C. are obtained.
Reaction SMILES: C[N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:13][CH:12]=1)[C:3](=O)OC(C)(C)C.[H-].[Na+].[CH2:24]([S:28](Cl)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([S:28]([N:13]1[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:15][C:11]([CH2:10][NH:2][CH3:3])=[CH:12]1)(=[O:30])=[O:29])[CH2:25][CH2:26][CH3:27]
Reactant: CN(Cc1c[nH]c(-c2ccccc2)c1)C(=O)OC(C)(C)C
Reactant: CCCCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CCCCS(=O)(=O)n1cc(CNC)cc1-c1ccccc1
Yield: 24 %

Procedure:
Using tert-butyl methyl[(5-phenyl-1H-pyrrol-3-yl)methyl]carbamate (70 mg), sodium hydride (60% in oil, 98 mg) and butane-1-sulfonyl chloride (230 mg), a procedure as in Example 38 was performed to give the title compound as pale-purplish red crystals (yield 18 mg, 21%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:29]#[N:30])[CH:5]=[C:6]([CH:28]=1)[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=1[CH3:27])=[O:8].N1C=CC=CC=1.[C:37]([C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1)#[N:38].C(=O)([O-])O.[Na+]>O1CCCC1>[C:29]([C:4]1[CH:5]=[C:6]([CH:28]=[C:2]([NH:1][C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:39]([C:37]#[N:38])=[CH:40][CH:41]=2)[CH:3]=1)[C:7]([NH:9][C:10]1[C:11]([CH3:27])=[CH:12][C:13]([C:17]([F:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:14][C:15]=1[CH3:16])=[O:8])#[N:30]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(N)cc(C#N)c1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(C#N)cc(NC(=O)c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
To a solution of 5-amino-3-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.199 mg, 0.46 mmol) (Example I9) in tetrahydrofuran (3 ml) were added successively pyridine (0.117 ml, 1.45 mmol) and 4-cyano-benzoyl chloride (80 mg, 0.48 mmol). The reaction mixture was stirred for 2 hours at ambient temperature. Aqueous sodium hydrogen carbonate (saturated) was added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to give Compound No. B1 of Table B (0.186 g, 71.9% yield). 1H-NMR (400 MHz, CHCl3): 8.45 (s, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 8.00 (m, 3H), 7.84 (m, 2H), 7.63 (s, 1H), 7.37 (s, 2H), 2.34 (s, 6H) ppm.
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12](=[O:26])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([O:21][CH:22]([F:24])[F:23])[C:14]=2F)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].Cl>C(OCC)C>[CH:1]1([N:4]2[C:14]3[C:13](=[CH:18][C:17]([F:19])=[C:16]([F:20])[C:15]=3[O:21][CH:22]([F:24])[F:23])[C:12](=[O:26])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(OC(F)F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The whole of the ethyl 3-cyclopropylamino-2-(3-difluoromethoxy-2,4,5-trifluorobenzoyl)acrylate [(XIX), R1 =--OCHF2, R3' =H, R17 =C2H5, X=X'=F] [prepared as described in step (c) above] was dissolved in 150 ml of anhydrous diethyl ether, and then 0.39 g (0.0098 moles) of a 60% w/w suspension of sodium hydride in mineral oil was added in portions, whilst stirring at room temperature, to the resulting solution. After completion of the addition, the stirring was continued at room temperature for an additional 1 hour, and then the mixture was acidified by the addition of 1N aqueous hydrochloric acid with vigorous stirring. The reaction mixture was filtered and washed with water and with diethyl ether, in that order, to give 1.44 g of ethyl 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate as colorless needles, melting at 224°-226° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:15][C:16]([O:19][C:20]([O:22]N=C(C1C=CC=CC=1)C#N)=O)([CH3:18])[CH3:17]>O1CCOCC1>[C:20]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7])([O:19][C:16]([CH3:15])([CH3:17])[CH3:18])=[O:22]
Reactant: CNCCCCO
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(CCCCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.7 %

Procedure:
To a 250 mL round bottom flask, charged with 3.00 g (28.5 mmol) of N-methyl-4-aminobutanol in 75 mL of dioxane, was added 5 mL of triethylamine (35.4 mmol) followed by 7.85 g (31.9 mmol) of BOC-ON, 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile. The mixture was stirred at room temperature for 20 h and then concentrated via rotary evaporation. The residue was chromatographed on silica gel, eluting first with 20% ethyl acetate/hexane, then with 40% ethyl acetate/hexane, and finally with 75% ethyl/hexane. The fractions containing product were combined and concentrated via rotary evaporation to afford 4.85 g of the product (32) as a near colorless oil (84%): 1H-NMR (CDCl3) d 3.65 (2H, t), 3.23 (2H, t), 2.81 (3H, s), 1.67-1.45 (4H, m), and 1.42 (9H, s) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=2)[O:26][CH2:27][C:28]([O:30]CC)=[O:29])=N[C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].[OH-].[Na+].Cl.[CH2:39]1COCC1>CO>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]1[CH:39]=[C:13]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=2)[O:26][CH2:27][C:28]([OH:30])=[O:29])[CH:12]=[CH:11][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CCOC(=O)COc1cccc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(OCC(=O)O)c3)cc2CC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-(3-(((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)oxy)methyl)phenoxy)acetate (102 mg) in THF (3.0 mL) and methanol (3.0 mL) was added 1N aqueous sodium hydroxide solution (0.97 mL), and the mixture was stirred at 80° C. for 30 min. To the reaction mixture was added 1N hydrochloric acid (1.0 mL), and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (83 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.I[CH2:16][CH2:17][CH3:18].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH:14]=1
Reactant: Clc1cccc(-c2ccncc2)c1Cl
Reactant: CCCI
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCN1CC=C(c2cccc(Cl)c2Cl)CC1

Procedure:
Preparation according to preparation 10: 4-(2,3-dichlorophenyl)pyridine (1.0 g, 4.46 mmol), 1-iodopropane (6 ml), ethanol (60 ml), sodium borohydride (1.5 g, 44 mmol). Yield: 0.45 g. MS m/z (rel. intensity, 70 eV) 271 (M+, 16), 269 (M+, 28), 242 (62), 240 (bp), 127 (11).
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:19][CH2:18]1.[Br:32]C(Cl)(Cl)C(Br)(Cl)Cl>C1COCC1>[CH3:16][N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Br:32])[C:26]=2[F:31])[CH2:19][CH2:18]1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: CN1CCC(NCc2ccccc2F)CC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(NCc2cccc(Br)c2F)CC1
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
Add n-butyl lithium (1.6 M in hexanes, 4.3 mL) into a solution of 2,2,6,6-tetramethyl-piperidine (0.97 g) in THF (10 mL) at −78° C. and stir for 30 minutes. Add a solution of 1-methyl-4-(N-(2-fluorophenyl)methylamino)piperidine (Preparation 23, 1.02 g) in THF (10 mL) portionwise and stir for 10 minutes. Add 1,2-dibromo-1,1,2,2-tetrachloroethane (1.50 g) in THF (10 mL) dropwise and stir for 1 hr. Remove the cooling bath and stir for 30 minutes. Partition between ethyl acetate and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel column (110 g), using a gradient of dichloromethane-2M NH3 in methanol to give 0.49 g of the title intermediate.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:19][O:18][C:12]1[CH:17]=[CH:16][C:15]([C:4]([C:3]2[C:2]([Cl:1])=[C:10]([CH3:11])[CH:9]=[CH:8][CH:7]=2)=[O:5])=[CH:14][CH:13]=1
Reactant: Cc1cccc(C(=O)Cl)c1Cl
Reactant: COc1ccccc1
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc(C)c2Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A solution of 2-chloro-3-methylbenzoyl chloride (18.05 mmol), [prepared as described above] in dry CH2Cl2 (60 ml) was cooled to 0° C. and AICl3 (2.41 g, 1 eq.) was added. After ten minutes, anisole (1.96 ml, 1 eq.) was added. The resulting orange colored reaction mixture was allowed to warm to room temperature, stirred for 3 h and then poured on ice. The product was extracted into ether, washed with brine, and dried over MgSO4 . The solvent was evaporated in vacuo to give 3-(4-methoxybenzoyl)-2-chlorotoluene (4.55 g, 97% yield) as a solid, mp 64.7°-65.8° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH:15]=2)[OH:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH:15]=2)=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(O)c2cccc(-n3cccc3)c2)ccc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2cccc(-n3cccc3)c2)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (3-ethoxy-4-methoxy-phenyl)-(3-pyrrol-1-yl-phenyl) -methanol from above and activated MnO2 (2.6 g, 30 mmol) in methylene chloride (30 if L) was stirred at room temperature for 18 h. More MnO2 (2 g) was added and kept for overnight. The suspension was filtered thru a pad of Celite. Removal of solvent gave (3-ethoxy-4-methoxy-phenyl)-(3-pyrrol-1-yl-phenyl)-methanone as a brown oil (1.58 g, 85% crude yield 2 steps). The sample was used in the next step without further purification.
Reaction SMILES: [Br:1]Br.[Cl:3][CH2:4][CH2:5][CH2:6][C:7]1([OH:10])[CH2:9][CH2:8]1>CC(O)C.O>[Br:1][CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5][CH2:4][Cl:3]
Reactant: OC1(CCCCl)CC1
Reactant: BrBr
Solvent: O
Solvent: CC(C)O
Product: O=C(CCBr)CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (2.0 mL, 39 mmol) was added slowly to a solution of 1-(3-chloro-propyl)-cyclopropanol (5.0 g, 34 mmol) in i-PrOH (80% in water, 30 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hr then diluted with water (15 mL). The aqueous layer was extracted with EtOAc (3×30 mL) and the organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford crude 1-bromo-6-chloro-hexan-3-one.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[CH2:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1)[CH3:22]>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([CH2:29][N:26]4[CH2:25][CH2:24][N:23]([CH2:21][CH3:22])[CH2:28][CH2:27]4)=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)=[O:19])=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Reactant: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CO
Product: CCN1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3C)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (disclosed in WO 03/099771). Title compound: ES-MS: 537.0 [M+H]+; tR=3.18 min (System 1); Rf=0.16 (CH2Cl2/MeOH, 95:5+0.1% NH3aq).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[O:4].[OH-].[Na+].S(=O)(=O)(O)O>C(O)C>[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:6]1[N:7]=[CH:8][S:9][C:5]=1[C:3]([OH:4])=[O:2])([OH:18])=[O:17]
Reactant: COC(=O)CCCCCCc1ncsc1C(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCCc1ncsc1C(=O)O
Yield: 65.2 %

Procedure:
To the solution of 16 g of crude 4-(6carbomethoxyhexyl)-thiazole-5-carboxylic acid methylester (VIII, R1 = H) in 50 ml of ethanol 100 ml of 2 N sodium hydroxide solution was added, the reaction mixture was refluxed for 30 minutes, then acidified with 5 N sulphuric acid under ice-cooling. On extracting the aqueous reaction mixture with 3 × 150 of ml ethyl acetate, the extract was dried over sodium sulphate and evaporated in vacuo. Recrystallization of the obtained crude product from diethylether afforded 9.4 g of 4-(6-carboxyhexyl)-thiazole-5carboxylic acid (IX, R1 = H). M.p.: 151°-153° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([O:27][CH3:28])=[C:7]([O:25][CH3:26])[C:8]2[O:12][C:11]([CH:14]=[CH:15][CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:13])[CH2:10][C:9]=2[C:23]=1[CH3:24])(=[O:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:4][C:5]1[C:6]([O:27][CH3:28])=[C:7]([O:25][CH3:26])[C:8]2[O:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:13])[CH2:10][C:9]=2[C:23]=1[CH3:24])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C=CC=CC1(C)Cc2c(C)c(OC(C)=O)c(OC)c(OC)c2O1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCC1(C)Cc2c(C)c(OC(C)=O)c(OC)c(OC)c2O1
Temperature: 50 °C
Reaction time: 5 h
Yield: 83.8 %

Procedure:
5% palladium-carbon (0.1 g) was added to a solution of ethyl 5-(5-acetoxy-2,3-dihydro-6,7-dimethoxy-2,4-dimethylbenzofuran-2-yl)pentadienoate (1.3 g) in ethanol (30 ml), and the mixture was stirred under an atmosphere of hydrogen at 50° C. for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate 7:3) to obtain the title compound (1.1 g, 86%) as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16](OC3CCCCO3)[C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH:12][CH:11]=2)=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2].[CH:38]([Si](C(C)C)(C(C)C)OCC1C=CC(C(C2C=C(C=CC=2)C#N)=C)=CC=1)(C)C>>[C:1]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])=[CH2:38])=[CH:14][CH:15]=2)=[C:6]([CH2:34][CH2:35][CH3:36])[C:5]=1[OH:37])(=[O:3])[CH3:2]
Reactant: C=C(c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1)c1cccc(C#N)c1
Reactant: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Product: C=C(c1ccc(COc2ccc(C(C)=O)c(O)c2CCC)cc1)c1cccc(C#N)c1

Procedure:
The title compound is prepared in a similar manner as 3-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile, employing 3-[1-(4-triisopropylsilanyloxymethyl-phenyl)-vinyl]-benzonitrile to give 0.46 g, 47%, of the title compound as a white solid. LCMS M+1 412.