Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C(C)C=C2C=1N=C(O)C=N2.[Br:14][C:15]1[CH:16]=[C:17]([CH3:26])[CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][C:21]([OH:25])=[N:20]2.[OH-].[Na+].[CH:29](Cl)([F:31])[F:30]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.CCCCCC.C(OCC)C.O>[Br:14][C:15]1[CH:16]=[C:17]([CH3:26])[CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][C:21]([O:25][CH:29]([F:31])[F:30])=[N:20]2
Reactant: Cc1cc(Br)c2ncc(O)nc2c1
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1cc(Br)c2nc(O)cnc2c1
Agent: [Br-]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(Br)c2ncc(OC(F)F)nc2c1
Reaction time: 4 h

Procedure:
To a suspension of 5.0 g (20.9 mmol) of the above isomer mixture of 8-bromo-2-hydroxy-6-methylquinoxaline and 8-bromo-3-hydroxy-6-methylquinoxaline (prepared as in Example 3) and 9.0 g(27.1 mmol) of tetra-n-butylammonium bromide stirring in 150 ml of dioxane,20 g (250.0 mmol) of 50% aqueous sodium hydroxide were added. The reaction mixture was placed under an atmosphere of chlorodifluoromethane (Freon22*)whereby slight pressure was maintained by having a balloon over the reaction flask. A slow exotherm occurred and the mixture stirred 4 h. Excess water and 300 ml of diethyl ether were added. The separated organicextract was washed with water, brine, dried over magnesium sulfate, and evaporated in vacuo to give an oil residue which quickly solidified. Hexane was added, the mixture stirred several minutes, and filtered to give 3.1 g of 8-bromo-3-difluoromethoxy-6-methylquinoxaline. Evaporating the filtrate gave 2.5 g of a crude isomer mixture of 8-bromo-2-difluoromethoxy-6-methylquinoxaline and 8-bromo-3-difluoromethoxy-6-methylquinoxaline.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=O)[O:17]C2C=CC=CC=2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[NH3:27]>O>[F:26][C:2]([F:1])([F:25])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:27])=[O:17])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:6])([F:7])[F:5]
Reactant: O=C(Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)Oc1ccccc1
Reactant: N
Solvent: O
Product: NC(=O)Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine 6.0 g (16 mmole) of phenyl N-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]carbamate (Example 12) and 65 ml of NH3 saturated ethanol. After 1/2 hour, pour the reaction mixture into 150 ml of H2O. Concentrate, cool to 0° C and filter off the white solid. Obtain 5.5 g of N-[4-(hexafluoro-2-hydroxy-2-propyl)phenyl]urea; m.p. 181°-183° C.
Reaction SMILES: [N+]([O-])([O-])=O.[Ag+:5].[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[Na]>O>[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[Ag:5]
Reactant: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na]
Agent: c1ccc2[nH]nnc2c1
Solvent: O
Product: [Ag]

Procedure:
A dispersion of silver benzotriazole was prepared by concurrently adding a solution of silver nitrate, and a solution of sodium benzotriazole into a stirred aqueous bone gelatin solution. The small particle dispersion was centrifuged and the solid phase was resuspended in water, treated with a protolytic enzyme at 35° C. to destroy the gelatin, centrifuged, washed with water, resuspended in water, sonicated, and finally freeze-dried to a free-flowing white powder.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C>[CH2:17]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(Br)ccc1OCc1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 5-bromosalicylaldehyde (12 g), potassium carbonate (16.5 g) and benzyl bromide (7.8 ml) in DMF (50 ml) was stirred for 18 hours, poured into ethyl acetate (100 ml), washed with 0.05M HCl (100 ml), sodium bicarbonate (100 ml) and brine (100 ml), dried (sodium sulphate), filtered and evaporated. The residue was triturated with hexane/diethyl ether to give 2-benzyloxy-5-bromo-benzaldehyde (15.8 g) mp.70°-72° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:24]=O.[NH2:26][C:27]1[CH:31]=[C:30]([CH3:32])[O:29][N:28]=1>C1(C)C=CC=CC=1>[CH3:32][C:30]1[O:29][N:28]=[C:27]([NH:26][CH2:24][C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:23])[CH2:16][C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:6]=3[C:2]=2[CH3:1])[CH:31]=1
Reactant: Cc1cc(N)no1
Reactant: Cc1c(C=O)oc2cccc(OCCCN(C)Cc3cccnc3)c12
Solvent: Cc1ccccc1
Product: Cc1cc(NCc2oc3cccc(OCCCN(C)Cc4cccnc4)c3c2C)no1
Yield: 67.3 %

Procedure:
A solution of 3-methyl-4-[3-(methyl-pyridin-3-ylmethyl-amino)-propoxy]-benzofuran-2-carbaldehyde (55 mg) and 3-amino-5-methylisooxazole (160 mg) in toluene (4 ml) was refluxed overnight. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography developed by ethyl acetate and methanol to give the titled compound as a pale yellow oil (46 mg). ESI-MS: m/z 419 (MH+); 1H-NMR (CDCl3): δ 2.00-2.09 (2H, m), 2.29 (3H, s), 2.44 (3H, s), 2.48 (2H, s), 2.68 (2H, t, J=10.2 Hz), 3.53 (2H, s), 4.14 (2H, t, J=5.9 Hz), 6.16 (1H, s), 6.62 (1H, d, J=7.9 Hz), 7.05-7.17 (2H, m), 7.32 (1H, s), J=7.9 Hz), 7.59-7.63 (1H, m), 8.41 (1H, dd, J=1.7 Hz, 4.9 Hz), 8.51 (1H, d, J=2.0 Hz), 8.82 (1H, s).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)[C:14]([O-])=[O:15].C(O)(C(F)(F)F)=O.[Cl-].[Li+].[Cl-].[Mg+2].[Cl-]>CO.[Pd](Cl)Cl.CCOC(C)=O.C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:14](=[O:15])[O:10][CH2:9][C:4]=2[C:3]=1[CH3:11]
Reactant: O=C([O-])C(F)(F)F
Reactant: Cc1ccc(CO)c(C)c1Br
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(c(C)c1Br)COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3-bromo-2,4-dimethylphenyl)methanol (2.0 g, 9.3 mmol), and thalium (III) trifluoroacetate (7.50 g, 14.0 mmol) were added to a 250 mL flask containing a stir bar. The flask was then placed in a cooling bath at 0° C. To the flask was added TFA (150 mL) slowly. The resulting mixture was then stirred at room temperature overnight. The TFA was removed under reduced pressure at 30° C. and the resulting residue was redissolved in dichloroethane and concentrated twice (2×100 mL). The residue was then pumped under high vacuum for 45 min. To the dried residue was then added palladium dichloride (165 mg, 0.930 mmol), lithium chloride (788 mg, 18.6 mmol), and magnesium chloride (750 mg, 18.6 mmol). The resulting mixture was dissolved in MeOH (160 mL). The mixture was then degassed and purged with CO (3 times). The flask under CO was stirred at room temp for 4 hours; the color of the reaction mixture changed from white to cream then to brownish. The color of the reaction then finally changed from brownish to black up on which time the reaction had gone to completion as evidenced by LC as well as TLC (hexanes/EtOAc=1/0.3) analysis. The reaction mixture was then poured into a 1 L Erlenmeyer flask containing DCM (400 mL) and EtOAc (400 mL). The solution was then passed through a celite plug, and rinsed several times with DCM until all the organic material had passed through. The solution was then concentrated to dryness, re-dissolved in DCM, absorbed into silica gel, and separated over silica column to give 5-bromo-4,6-dimethyl-2-benzofuran-1(3H)-one. LC-MS: M+1=242
Reaction SMILES: [C:1]1([C@@H:7]2[CH:12]=[CH:11][CH2:10][CH2:9][C@@H:8]2[C:13]([N:15]2[CH2:19][CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:29][CH2:28]3)[CH2:16]2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C@@H:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]2[C:13]([N:15]2[CH2:19][CH:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:17]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:29][CH2:28]3)[CH2:16]2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([C@H]1CCC=C[C@H]1c1ccccc1)N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: O=C([C@H]1CCCC[C@H]1c1ccccc1)N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccccc2)C1
Reaction time: 4 h
Yield: 65.8 %

Procedure:
To a solution of 14 mg (0.03 mmol) of 1-(2(R) phenylcyclohex-3-ene-1(S)-carbonyl)-3-(RS)-((4-phenyl)piperidin-1-yl)methyl 4-(SR)-phenylpyrrolidine (from Example 182, Step B) in 2 mL of MeOH was added 10% Pd/C (7.0 mg). The reaction mixture was hydrogenated at 50 psi on a Parr apparatus for 4 hrs. The reaction was filtered thru Celite, washed with MeOH and the filtrate was concentrated in vacuo to afford 10 mg of the title compound as an oil. Mass Spectrum (NH3 -CI): 507 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[I-:9].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1.Cl>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1
Reactant: [I-]
Reactant: Oc1cccnc1Cl
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: Oc1ccc(I)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
After dissolving 2-chloro-3-hydroxypyridine (5.00 g, 38.6 mmol) and sodium iodide (5.79 g, 38.6 mmol) in dimethylformamide (70 ml), Chloramine T (10.9 g, 38.6 mmol) was added while cooling on ice, and then the mixture was stirred at room temperature for 1 hour. Upon adding 2N aqueous hydrochloric acid (19.3 ml, 38.6 mmol) after the reaction, the reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:hexane=1:2), and the fraction containing the target substance was concentrated to obtain the title compound (9.00 g, 35.2 mmol, 91%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:33])[C:5]2[CH2:16][S:15][CH2:14][C@@H:13]([C:17](OC)=[O:18])[NH:12][C:11](=[O:21])[C@@H:10]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:9][O:8][C:7](=[O:30])[C:6]=2[C:31]=1[CH3:32].O.[NH2:35][NH2:36]>CO.C(OCC)(=O)C>[C:17]([C@H:13]1[NH:12][C:11](=[O:21])[C@@H:10]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:9][O:8][C:7](=[O:30])[C:6]2[C:31]([CH3:32])=[C:2]([OH:1])[CH:3]=[C:4]([OH:33])[C:5]=2[CH2:16][S:15][CH2:14]1)(=[O:18])[NH:35][NH2:36]
Reactant: COC(=O)[C@@H]1CSCc2c(O)cc(O)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1c(O)cc(O)c2c1C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)NN)CSC2

Procedure:
A solution of 97 mg of the product of Example 2 and 0.2 ml of hydrazine hydrate in 1 ml of methanol was stirred at 20° C. for 45 minutes. The solution was diluted with ethyl acetate, and washed with 0.5M sodium dihydrogenphosphate solution and with water. The organic layer was dried over sodium sulfate and evaporated in vacuo, and the residue was crystallized from methanol/ethyl acetate/hexane to give 85 mg of tert-butyl (4R, 7S)-4-carbazoyl-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid. as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH2:15])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1N
Reaction time: 18 h
Yield: 96.4 %

Procedure:
10% palladium on charcoal (6 g) was added to a solution of (4-methyl-3-nitro-phenyl)-carbamic acid tert-butyl ester 26 (60 g, 238 mmol) in ethanol (1200 mL). The mixture was hydrogenated at atmospheric pressure at room temperature for 18 h. The palladium catalyst was removed by filtration over celite and the solvent was removed by evaporation to give (3-Amino-4-methyl-phenyl)-carbamic acid tert-butyl ester 27 (51 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)cc1OC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)cc1OC
Yield: 50 %

Procedure:
A mixture of 15.2 g of 3,4-dimethoxytoluene, 17.8 g of N-bromosuccinimide and 0.3 g of dibenzoyl peroxide in 100 ml of CCl4 is heated at reflux for hours, under illumination from a UV lamp. The precipitate is drained off and the filtrate is evaporated under vacuum. The residue is taken up in ether, washed with water, dried over Na2SO4 and evaporated under vacuum. An oil is obtained which contains a mixture of 50% of the expected product and 50% of the starting material, which mixture is used without further purification in the subsequent synthesis.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[F:21][C:22]([F:43])([F:42])[C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH:35]([CH3:39])[C:36](Cl)=[O:37])=[CH:32][CH:31]=2)=[N:27][CH:28]=1>C1(C)C=CC=CC=1>[F:42][C:22]([F:21])([F:43])[C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]2[CH:41]=[CH:40][C:33]([O:34][CH:35]([CH3:39])[C:36]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:37])=[CH:32][CH:31]=2)=[N:27][CH:28]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)Cl
Reactant: CCCCCCCCCCCCO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 10 °C

Procedure:
n-Dodecanol(2.5 grams; 0.134mol), toluene (80 ml) and triethylamine (5 ml) were placed into a 300 ml, 3-necked glass reaction flask equipped with stirrer, thermometer, reflux condenser, and nitrogen line. 2-[4-(5-trifluoromethyl-2-pyridinyloxy)phenoxy]propanoic acid chloride (4.45 grams; 0.0125 mol) in toluene (30 ml) was added dropwise to the reaction mixture with stirring at a temperature of about 10° C. The temperature of the reaction mixture was allowed to rise to room temperature and stirred overnight.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[S:19][C:18]([NH2:20])=[N:17][C:15]=2[N:16]=1.[CH3:22][CH2:23][CH2:24][CH2:25][CH:26]([NH2:29])[CH2:27][OH:28].C(N(CC)CC)C>>[NH2:20][C:18]1[S:19][C:14]2[C:13]([NH:29][CH:26]([CH2:25][CH2:24][CH2:23][CH3:22])[CH2:27][OH:28])=[N:12][C:11]([S:10][CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])=[N:16][C:15]=2[N:17]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: CCCCC(N)CO
Solvent: CCN(CC)CC
Product: CCCCC(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
Prepared according to the procedure in Example 1, from 5-(2,3-difluorophenylmethylthio)-7-chloro-thiazolo[4,5-d]pyrimidin-2-ylamine (WO 00/09511) and DL-2-amino-1-hexanol, with triethylamine (one equivalent) added.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([CH:19]2[CH2:21][CH2:20]2)=[CH:4][N:3]=1.[CH2:22]([N:24]1[C:28]([NH2:29])=[CH:27][C:26]([CH3:30])=[N:25]1)[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH:19]1([C:5]2[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]([NH:13][CH3:14])=[O:12])=[CH:7][C:2]([NH:29][C:28]3[N:24]([CH2:22][CH3:23])[N:25]=[C:26]([CH3:30])[CH:27]=3)=[N:3][CH:4]=2)[CH2:21][CH2:20]1
Reactant: CCn1nc(C)cc1N
Reactant: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCn1nc(C)cc1Nc1cc(Nc2ccccc2C(=O)NC)c(C2CC2)cn1
Reaction time: 0.75 h
Yield: 20.5 %

Procedure:
To a 10 mL microwave tube were added 2-(2-chloro-5-cyclopropyl-pyridin-4-ylamino)-N-methyl-benzamide (0.075 g, 0.25 mmol, 1 eq), 2-ethyl-5-methyl-2H-pyrazol-3-ylamine (0.035 g, 0.27 mmol, 1.1 eq), Cs2CO3 (0.23 g, 0.70 mmol, 2.8 eq) and 1,4-dioxane (3 mL) and the resulting mixture was degassed with N2 for 30 minutes. To this mixture was added Pd2(dba)3 (0.008 g, 0.007 mmol, 0.03 eq) and xanthphos (0.009 g, 0.015 mmol, 0.06 eq) and this mixture was degassed again with N2 for another 10 minutes. The resulting reaction mixture was irradiated in a CEM microwave at 110° C. and 150 W for 45 min. The progress of the reaction was monitored by LCMS. After completion of the reaction, Cs2CO3 was removed by filtration and the filtrate was concentrated under reduced pressure to give a crude product. It was purified using column chromatography over neutral alumina using 0.2% MeOH-DCM as the eluant. The solid compound so obtained was washed with diethyl ether and hexane to give the title compound as a white solid (20 mg, 20%). 1H-NMR (400 MHz, DMSO-d6): δ 0.50-0.62 (m, 2H), 0.88-0.99 (m, 2H), 1.15-1.28 (m, 3 H), 1.55-1.65 (m, 1H), 2.07 (s, 3H), 2.76-2.77 (d, 3H, J=4.36 Hz), 3.82-3.95 (m, 2H), 5.95 (s, 1H), 6.68 (s, 1H), 6.99-7.10 (m, 1H), 7.42-7.50 (m, 1H), 7.50-7.55 (m, 1H) 7.64-7.66 (d, 1H, J=7.6 Hz), 7.71 (s, 1H), 8.30 (s, 1H), 8.55-8.70 (brs, 1H), 9.95 (s, 1H). LC-MS [M+H]+=391.4.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[CH:3]=1.[CH:18]1(B2OC(C)(C)C(C)(C)O2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[CH:18]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]3[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=3[F:17])[CH:3]=2)[CH2:20][CH2:19]1
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: Fc1cccc(F)c1COc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Fc1cccc(F)c1COc1cc(C2CC2)ccn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 500 mg (1.66 mmol) of 4-bromo-2-[(2,6-difluorobenzyl)oxy]pyridine (Example 145A), 365 μl (2.0 mmol) of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 139 mg (0.17 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride-dichloromethane complex and 1.63 g (5.0 mmol) of caesium carbonate in 0.5 ml of water and 4 ml of dioxane was degassed with argon for 5 min and stirred in a sealed tube at 100° C. for 2 h. The reaction mixture was cooled to room temperature and the residue was partitioned between ethyl acetate and water. The organic phase was removed and washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel (40 g silica gel cartridge, mobile phase: methanol/ethyl acetate, gradient 0% to 25%). This gave 350 mg of the target compound (80% of theory).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[CH3:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28]Cl)[CH2:22][CH2:21]2)=[CH:17][CH:16]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:28][CH2:27][CH2:26][N:23]3[CH2:22][CH2:21][N:20]([CH2:19][C:18]4[CH:17]=[CH:16][C:15]([CH3:14])=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2ccc(O)cc12
Reactant: Cc1ccc(CN2CCN(CCCCl)CC2)cc1
Product: Cc1ccc(CN2CCN(CCCOc3ccc4[nH]c(=O)cc(C)c4c3)CC2)cc1

Procedure:
4-Methyl-6-hydroxy-2-oxo-1,2dihydroquinoline is reacted with 3-[4-(4-methylbenzyl)-piperazin-1-yl]-propyl chloride in a manner analogous to that described in Example 5. There is obtained 4-methyl-6-{3-[4-(4-methylbenzyl)-piperazin-1-yl]-propoxy}-2-oxo-1,2-dihydroquinoline which, after recrystallization from diethyl ether, melts at 162°-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](Br)[CH:18]=[C:13]3[N:12]=2)[CH:4]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17]([C:26]4[CH:27]=[CH:28][C:23]([C:22]([F:33])([F:32])[F:21])=[CH:24][CH:25]=4)[CH:18]=[C:13]3[N:12]=2)[CH:4]=1
Reactant: COc1ccnc(CCc2nc3cc(Br)cnc3[nH]2)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccnc(CCc2nc3cc(-c4ccc(C(F)(F)F)cc4)cnc3[nH]2)c1
Yield: 57.9 %

Procedure:
0.166 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine (example 6) and 0.285 g of 4-trifluormethylphenylboronic acid are dissolved in 8 ml of degassed dioxane. Then a solution of 0.138 g of potassium carbonate and 0.042 g of lithium chloride in 6.5 ml of degassed water and 0.058 g of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is heated to reflux under N2 for 48 hours and, after cooling and addition of water, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30–26:1). Concentration of the chromatographically pure fractions gives 0.115 g of the title compound as a colourless solid of m.p. 191–192° C. The mass spectrum shows the molecular peak MH+ at 399.4 Da.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][O:15][CH2:16][CH3:17].Cl.[CH2:20]([O:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)C>[CH2:20]([O:27][N:28]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[C:13]1[CH2:14][O:15][CH2:16][CH3:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOCC(=O)Nc1cnc2ccccc2c1Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: CCOCc1nc2cnc3ccccc3c2n1OCc1ccccc1
Temperature: 60 °C
Yield: 95 %

Procedure:
A mixture of N-(4-chloroquinolin-3-yl)-2-ethoxyacetamide (4.5 g, 18 mmol) and O-benzylhydroxylamine hydrochloride (4.3 g, 27 mmol) in propan-2-ol (100 mL) was heated at 60° C. for 2 days. The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (35 mL). The organic layer was dried over potassium carbonate, filtered, and evaporated to yield 5.7 g of crude 1-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinoline that was used directly in Part B.
Reaction SMILES: O[N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].S(Br)(Br)=O>>[Cl:11][C:8]1[CH:9]=[C:10]2[NH:2][C:3]([C:12]([F:13])([F:14])[F:15])=[N:4][C:5]2=[N:6][CH:7]=1
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Agent: O=S(Br)Br
Product: FC(F)(F)c1nc2ncc(Cl)cc2[nH]1

Procedure:
Also, 6-chloro-2-(trifluoromethyl)-1H-imidazo [4,5-b] pyridine was prepared by reduction of 1-hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo [4,5-b] pyridine with thionyl bromide.