Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([C:25]([O:27]C)=[O:26])[N:10]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1.[F:29][C:30]1[CH:35]=[C:34]([Sn](CCCC)(CCCC)CCCC)[CH:33]=[CH:32][N:31]=1.O([Si](C)(C)C)[K:50]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[K+:50].[F:29][C:30]1[CH:35]=[C:34]([C:2]2[C:7]3[CH:8]=[C:9]([C:25]([O-:27])=[O:26])[N:10]([CH2:11][CH2:12][O:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=4)[C:6]=3[CH:5]=[CH:4][N:3]=2)[CH:33]=[CH:32][N:31]=1
Reactant: C[Si](C)(C)O[K]
Reactant: COC(=O)c1cc2c(Cl)nccc2n1CCOc1ccc(OC(F)(F)F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnc(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: O=C([O-])c1cc2c(-c3ccnc(F)c3)nccc2n1CCOc1ccc(OC(F)(F)F)cc1
Product: [K+]
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Methyl 4-chloro-1-{2-[4-(trifluoromethoxy)phenoxy]ethyl}-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (50 mg, 0.121 mmole), 2-fluoro-4-(tributylstannyl)pyridine (61 mg, 0.158 mmole), and bis(tri-t-butylphosphine)palladium(0) (6 mg, 0.012 mmole) were combined in a screw cap vial. To this was added 1,4-dioxane (0.5 mL). N2 was bubbled through the mixture for 10 seconds. The vial was capped then heated to 100° C. After stirring overnight the mixture was cooled to RT. Excess QuadraPure was added and stirring continued at RT. After stirring 6 hr the mixture was filtered washing with EtOAc and concentrated. The residue was taken up in 1 mL THF. To this was added KOTMS (47 mg, 0.366 mmole) at RT. After 3 hr the mixture was concentrated. The residue was taken up in Et2O. The resulting off-white solid (53 mg, 88%) was collected by filtration washing with Et2O and dried in vacuo. 1H NMR (400 MHz, DMSO): δ 8.39 (d, J=5.1 Hz, 1 H); 8.35 (d, J=5.9 Hz, 1 H); 7.95 (d, J=5.1 Hz, 1 H); 7.63 (d, J=6.3 Hz, 2 II); 7.21 (d, J=8.4 Hz, 2 H); 7.04 (s, 1 H); 6.95 (d, J=8.8 Hz, 2 H); 5.12-5.05 (m, 2 H); 4.39-4.33 (m, 2 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][NH:13]2)=[CH:9][C:8]=1[CH3:16])[CH3:2].FC(F)(F)S(O[CH2:38][CH:39]([F:41])[F:40])(=O)=O>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[N:12][N:13]2[CH2:38][CH:39]([F:41])[F:40])=[CH:9][C:8]=1[CH3:16])[CH2:17][C:18]([N:20]([N:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH3:21])=[O:19])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2[nH]ncc2cc1C
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2c(cnn2CC(F)F)cc1C
Yield: 68.1 %

Procedure:
Using the compound (1.25 g, 2.97 mmol) of Example 257, step B and 2,2-difluoroethyl trifluoromethanesulfonate (859 mg, 4.01 mmol), and according to the method of Example 241, step C, the title compound (982 mg, yield 68%) was obtained as a colorless amorphous solid.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CC(=O)O)c1ccccc1
Product: CC(C)(CC(=O)Cl)c1ccccc1
Yield: 98.1 %

Procedure:
3-Methyl-3-phenylbutanoic acid (1.78 g, 10.0 mmol) was dissolved in thionyl chloride (5 mL, 68.5 mmol). The reaction mixture was heated at reflux for 6 hours. Concentration of the reaction mixture provided the title compound (1.93 g, 98%), which was used without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([Cl:10])[CH:3]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([Cl:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1Cl
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ccc(Br)cc1Cl)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 4-bromo-2-chlorobenzyl alcohol (14.48 g) in N,N-dimethylformamide (72 ml) were added imidazole (5.34 g) and tert-butylchlorodiphenylsilane (19.8 g) under ice-cooling and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the resulting product was extracted twice with hexane. The organic layers were combined, and washed successively with water, a saturated aqueous solution of sodium hydrogen-carbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (hexane) to give the objective compound (29.22 g) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][CH2:17][C:18]#[N:19])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), 3-bromopropionitrile (23 uL, 0.28 mmol, Aldrich, Cat. No. 109231) and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling, it was diluted with ethyl acetate, washed with water twice and brine once, dried over Na2SO4. After filtration the filtrate was concentrated to yield 55 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:23])=O.ClCCl>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:17]([Cl:23])=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.3 %

Procedure:
To a mixture of 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylic acid (0.33 g, 1.13 mmol), oxalyl chloride (0.45 mL, 5.16 mmol) and dichloromethane (10 mL) was added a drop of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 6 hours. The volatiles were removed in vacuo to obtain 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carbonyl chloride (0.34 g, 1.1 mmol)
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH2:18][CH2:19][O:20][CH3:21])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].N1CCCCC1.C(O)(=O)C>C(O)(C)C>[C:13]([C:12](=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])[C:11]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[O:16])(=[O:14])[CH3:15]
Reactant: COCCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1F
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COCCOC(=O)C(=Cc1ccc(F)cc1F)C(C)=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
5.0 g (35 mmol) of 2,4-difluorobenzaldehyde are dissolved with 5.7 g (35 mmol) of 2-methoxyethyl acetoacetate in 100 ml of isopropanol. A freshly prepared solution of 1.0 ml of piperidine and 0.5 ml of glacial acetic acid in 5 ml of isopropanol is added and the mixture is stirred at 40° C. overnight. The mixture is concentrated, the residue is taken up in toluene, this mixture is concentrated again and the residue is purified by filtration over 100 ml of silica gel (mobile phase: toluene/ethyl acetate 100:1) to give 5 g of the target compound as a yellow oil, which is immediately reacted further.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=1.C(O)(=O)C>C(#N)C>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[CH:30])[CH:24]=3)=[N:3][CH:4]=[N:5][C:6]2=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21].[ClH:1]
Reactant: C#Cc1cccc(N)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Solvent: CC#N
Solvent: CC(=O)O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Product: Cl
Temperature: 27.5 °C
Reaction time: 0.5 h

Procedure:
50 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 1500 ml acetonitrile and 46 g of 3-aminophenyl acetylene was added at 25-30° C., followed by 10 ml acetic acid. The reaction mass was stirred at 25-30° C. for 30 minutes. Solid obtained was filtered, washed with water and dried under vacuum. This solid was suspended in water, basified with potassium hydroxide and stirred for 10 minutes. The resulting erlotinib base was isolated, washed with acetonitrile and dried under vacuum. The solid obtained was then suspended in water and acidified to pH 1.0-2.0 using hydrochloric acid. The reaction mixture was stirred for 2 hours, filtered, washed with water and dried at 40-45° C. to obtain 63 g of erlotinib hydrochloride.
Reaction SMILES: [F:1][C:2]1C=C[C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12](CCN)[CH2:11][CH2:10]3)=[N:7]O[C:4]=2[CH:3]=1.C([N:22](CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28].[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(Cl)Cl.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH:32]([CH2:33][C:34]([NH2:22])=[O:36])[CH3:31])[CH2:13][CH2:14]3)=[N:7][O:29][C:27]=2[CH:28]=1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: CCN(CC)CC
Reactant: CC(=O)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: ClCCl
Product: CC(CC(N)=O)N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.56 g, 9.7 mmol) and triethylamine (1.45 g, 14.5 mmol) in DCM (50 ml) was treated with dropwise addition of acetyl chloride (1.0 g, 12.7 mmol) at room temperature. The mixture was stirred for 4 hours at room temperature. The reaction mixture was diluted with DCM and washed with brine. The organic solution was dried over MgSO4 and concentrated to a crude oil. The crude oil was purified by flash chromatography over a silica gel column (SiO2, 20 g; eluted with (0-2%) CH3OH in DCM). The pure product thus obtained weighed 1.36 g (46%). It was converted to a fumarate salt by treatment with fumaric acid (517 mg) in ethanol. Recrystallization from ethanol gave white crystals; weight: 1.53 g, m.p.=132°-133° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:33])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][O:23]C)=[CH:18][CH:17]=[C:16]([O:25][S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])[CH:15]=2.B(Br)(Br)Br.O.C(OCC)(=O)C>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:33])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][OH:23])=[CH:18][CH:17]=[C:16]([O:25][S:26]([C:29]([F:31])([F:32])[F:30])(=[O:28])=[O:27])[CH:15]=2
Reactant: COCCc1c(-c2ccc(OC)cc2OC)c(=O)oc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1oc2cc(OS(=O)(=O)C(F)(F)F)ccc2c(CCO)c1-c1ccc(O)cc1O
Temperature: -30 °C
Reaction time: 4 h

Procedure:
Trifluoro-methanesulfonic acid 3-(2,4-dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromen-7-yl ester (450 mg, 0.92 mol) was dissolved in CH2Cl2 (10 mL) at room temperature in a 200 ml round bottom flask. The reaction mixture was then cooled to −30° C., and BBr3 (1.8 ml) was added and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was cooled to 0° C. and water (40 mL) was added, followed by ethyl acetate (50 mL). The reaction mixture was then poured into a separation funnel. The organic layer was separated and washed with water (1×40 ml) and brine (1×30 ml). The organic layer was dried over sodium sulfate and concentrated. The product was purified on silica gel eluted with 50%-100% ethyl acetate in hexanes to yield trifluoro-methanesulfonic acid 3-(2,4-dihydroxy-phenyl)-4-(2-hydroxy-ethyl)-2-oxo-2H-chromen-7-yl ester as a light yellow foam
Reaction SMILES: [OH-].[Li+].[C:3]1([S:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])(=[O:15])=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>CO.O>[C:3]1([S:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:15])=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CCCC1CCCCN1S(=O)(=O)c1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCC1CCCCN1S(=O)(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Lithium hydroxide (1.58 g, 65.9 mmol) was added to a solution of methyl 4-(1-(naphthalene-1-ylsulfonyl)piperidine-2-yl)butanoate 3 (4.95 g, 13.18 mmol) in methanol/water (54 ml/36 ml) and the reaction mixture was stirred at room temperature overnight. The completeness of the reaction was checked by means of TLC. When the reaction was complete, the methanol was distilled off under reduced pressure and ethyl acetate was added to the residue. The mixture was acidified with dilute HCl. The aqueous phase was extracted 2× with ethyl acetate and the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to obtain the desired product 4-(1-(naphthalene-1-ylsulfonyl)piperidine-2-yl)butanoic acid (AC-21) (4.38 g, 91%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](O)=[O:15].S(Cl)([Cl:20])=O>>[ClH:20].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:15]
Reactant: OC1CCCCC1
Reactant: O=S(Cl)Cl
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OC1CCCCC1
Reaction time: 3 h

Procedure:
From cyclohexanol (6.0 ml) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 80° C. Thionyl chloride was added at room temperature. The reaction was complete after 3 h. The yield was 1.48 g (99%).
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[C:14]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH:13]=[N:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[O:50]=[C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:55][CH2:56]1)[CH2:48][NH:47][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([C:14]2[CH:13]=[N:12][CH:11]=[N:10][CH:15]=2)=[CH:24][CH:23]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2cncnc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2cncnc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 31.1 %

Procedure:
DIPEA (185 mg, 0.24 mL, 1.1 mmol) was added to a stirred solution of 4-pyrimidin-5-yl-benzoic acid (85 mg, 0.42 mmol) in DMF (2 mL). HOBT (75 mg, 0.46 mmol) and EDCI (98 mg, 0.46 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (165 mg, 0.46 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 65 mg (31% yield) of N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-4-pyrimidin-5-yl-benzamide. LCMS Purity: 97%. 1H NMR (CDCl3): δ 9.2 (s, 1H), 9.0 (s, 2H), 8.0 (dd, 2H), 7.56 (d, 1H), 7.65 (m, 4H), 7.35 (m, 2H), 4.35 (m, 1H), 4.25 (m, 1H), 4.0 (m, 2H), 3.7 (m, 2H), 3.6 (m, 2H), 3.42 (m, 1H), 3.25 (m, 2H).
Reaction SMILES: [CH3:1][Si:2]([CH3:25])([CH3:24])[O:3][Si:4]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.N1C=CC=CC=1.Cl[C:33]([O:35][CH:36]=[CH2:37])=[O:34]>CCOCC>[CH:36]([O:35][C:33]([N:11]1[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][Si:4]([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[O:3][Si:2]([CH3:24])([CH3:1])[CH3:25])[CH2:9][CH2:10]1)=[O:34])=[CH2:37]
Reactant: C=COC(=O)Cl
Reactant: C[Si](C)(C)O[Si](CCCN1CCNCC1)(O[Si](C)(C)C)O[Si](C)(C)C
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=COC(=O)N1CCN(CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 68.6 %

Procedure:
To a 250 mL 3-neck round bottom flask fitted with a magnetic stirrer, condenser, nitrogen blanket, dropping funnel, thermometer and ice-water bath was added 5.0 g (11.8 mmol) of 3-tris(trimethylsiloxy)silylpropyl piperazine, 0.98 g (12.4 mmol) pyridine and 100 mL ether. To the reaction mixture was added 1.32 g (12.4 mmol) vinyl chloroformate so that the temperature remained below 15°. After stirring for 18 hours the reaction mixture was washed with 100 mL 2N HCl, 100 mL 2N NaOH and the organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting oil was chromatographed (silica gel, methylene chloride). The product was recovered as an oil 4.0 g (8.1 mmol, 68.8% yield). FTIR (neat, capillary) 2957.40, 2900.69, 2808.30, 2770.50, 1646.32, 1460.48, 1429.87, 1373.46, 1353.45, 1334.61, 1291.27, 1249.73, 1227.01, 1187.92, 1152.02, 1100.89, 1039.50, 1000.33, 952.03, 833.45, 752.98, 712.79, 686.52, 656.44. NMR (CDCl3) 6.89-7.30 (1H,dd), 4.28- 4.76 (2H,m), 3.30-3.60 (2H,m), 2.19-2.40 (2H,m), 1.21-1.63 (2H,m), 0.17-0.63 (2H,m), 0.00 (27H,s). ##STR37##
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1COCC1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=2)[CH2:27][CH2:26]1
Reactant: CN1CCNCC1
Reactant: Nc1ccc(Br)cc1OC(F)(F)F
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 69.6 %

Procedure:
Tris(dibenzilideneacetone)dipalladium (1.1 g, 1.2 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (0.94 g, 2.4 mmol), 4-bromo-2-trifluoromethoxy-phenylamine (30.7 g, 120 mmol) in THF (50 mL) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1M in THF, 288 mL) and N-methylpiperazine (26.7 mL, 194 mmol) were added and the reaction refluxed for 1 h. The reaction mixture was then allowed to cool to room temperature and filtered through a pad of celite. The organic phase was concentrated, the residue dissolved in DCM (200 ml) and washed with water (1×100 ml). The organic phases were dried over anhydrous Na2SO4, the solvent evaporated in vacuo and the crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 23 g of 4-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenylamine (70% yield) as a light brown powder.
Reaction SMILES: [I:1][CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH2:13][CH3:14].[Cl:15][C:16]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:17]=1[CH:18]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])[CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>>[I-:1].[Cl:15][C:16]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:17]=1[CH:18]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])[CH2:19][N+:20]1[CH:24]=[CH:23][N:22]([CH2:2][C:3]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=2[O:12][CH2:13][CH3:14])[CH:21]=1
Reactant: Clc1ccc(COC(Cn2ccnc2)c2ccc(Cl)cc2Cl)c(Cl)c1
Reactant: CCOc1ccc([N+](=O)[O-])cc1CI
Product: CCOc1ccc([N+](=O)[O-])cc1Cn1cc[n+](CC(OCc2ccc(Cl)cc2Cl)c2ccc(Cl)cc2Cl)c1
Product: [I-]

Procedure:
mp. 193.6° C., by the reaction of 2-(iodomethyl)-4-nitrophenetole and 1-[2,4-dichloro-β-(2,4-dichlorobenzyloxy)phenethyl]imidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](I)=[CH:31][CH:30]=2)[N:12]([C:14]2[CH:15]=[C:16]([N:20]3[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[CH:13]=1.[Br:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1>>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([C:32]2[CH:33]=[CH:34][C:29]([CH2:28][C:11]3[N:12]([C:14]4[CH:15]=[C:16]([N:20]5[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]5)[CH:17]=[CH:18][CH:19]=4)[CH:13]=[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[N:10]=3)=[CH:30][CH:31]=2)=[CH:39][CH:38]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(I)cc3)c2)S(=O)(=O)N1
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[4-(2,4-Dichloro-phenyl)-2-(4-iodo-benzyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (3.2 g, 5 mmol) was treated as described in general procedure G using 4-bromophenylboronic acid (2.0 g, 10 mmol) to give 5-{3-[2-(4′-bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1)[CH2:25][CH3:26]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:27][CH2:24][CH2:25][CH3:26])=[CH:33][CH:32]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: CCCOc1ccc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cn1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-propoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (stage 55.1.1) to give the title compound as a white solid. (HPLC: tR 2.87 min (Method A); M+H=429 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.28 (s, 1H), 8.15-8.11 (m, 1H), 8.11-8.05 (m, 1H), 7.92-7.86 (m, 1H), 7.79-7.73 (m, 1H), 7.50-7.45 (m, 1H), 6.95-6.89 (m, 1H), 4.24 (t, 2H), 3.91 (s, 3H), 3.57 (s, 3H), 1.95 (s, 3H), 1.78-1.68 (m, 2H), 0.98 (t, 3H))