Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]([C:15]2[N:16]=[C:17]([CH2:20][N:21]3[CH2:26][C@H:25]([CH3:27])[O:24][C@H:23]([CH3:28])[CH2:22]3)[S:18][CH:19]=2)=[O:14])[CH:3]=1.[NH:29]1[C:37]2[C:32](=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:28][C@H:23]1[O:24][C@@H:25]([CH3:27])[CH2:26][N:21]([CH2:20][C:17]2[S:18][CH:19]=[C:15]([C:13]([NH:12][C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[C:37]5[C:32]=4[CH:31]=[CH:30][NH:29]5)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[CH3:11])=[O:14])[N:16]=2)[CH2:22]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: C[C@@H]1CN(Cc2nc(C(=O)Nc3cc(Br)cc4c3cnn4C)cs2)C[C@H](C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1CN(Cc2nc(C(=O)Nc3cc(-c4cccc5[nH]ccc45)cc4c3cnn4C)cs2)C[C@H](C)O1
Temperature: 100 °C

Procedure:
N-(6-Bromo-1-methyl-1H-indazol-4-yl)-2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-thiazole-4-carboxamide (100 mg, 0.215 mmol), 1H-indol-4-ylboronic acid (38.1 mg, 0.237 mmol), Pd(dppf)Cl2 (15.76 mg, 0.022 mmol) and tripotassium phosphate (137 mg, 0.646 mmol) were placed into a microwave vial with water (0.300 mL) and 1,4-dioxane (1.5 mL) and the mixture heated at 100° C. in a microwave for 10 mins. The solvent was blown off and the residue partitioned between water (10 ml) and DCM (10 ml). The organic layer was collected using a hydrophobic frit and the solvent blown off. The residue was purified by chromatography on silica eluting with 0-100% ethyl acetate in cyclohexane followed by 0-25% methanol to give the title compound.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][N:21]1[C:26]1[CH:31]=[C:30]([CH2:32]OS(C)(=O)=O)[N:29]=[C:28]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:45]([NH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:46])=[CH:40][CH:39]=2)[N:27]=1>C(#N)C>[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][N:21]1[C:26]1[CH:31]=[C:30]([CH2:32][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:29]=[C:28]([C:38]2[CH:39]=[CH:40][C:41]([NH:44][C:45]([NH:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:46])=[CH:42][CH:43]=2)[N:27]=1
Reactant: Sc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1COCCN1c1cc(CSc2ccccc2)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Thiophenol (0.029 mL) was dissolved in Acetonitrile (3 mL). DBU (0.043 mL) was then added to the solution and was allowed to stir at RT for 15 minutes. 1-[4-[4-[(3S)-3-Methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]-3-phenyl-urea (80 mg) was added to the reaction and stirred for 30 minutes. The reaction was concentrated in vacuo and the residue chromatographed on silica, eluting with 5% methanol in DCM, to give the desired material (62 mg) as a white solid, Mass Spectrum; M+H+ 512.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.I[CH2:17][CH2:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(C(C)=O)C(C)C>CN1CCCC1=O>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH:19]1[CH2:18][CH2:17][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: ICCC1Cc2ccccc2C1
Solvent: CN1CCCC1=O
Solvent: CC(=O)CC(C)C
Product: c1ccc2c(c1)CC(CCN1CCN(c3cccc4[nH]ccc34)CC1)C2
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A mixture of 4-(piperazin-1-yl)-1H-indole (1.5 g), 2-(2-iodoethyl)indane (2.0 g), K2C(3, methyl isobutyl ketone (150 ml), and N-methylpyrrolidone (10 ml ) was boiled under reflux for 3 h. The mixture was allowed to cool to room temperature, filtered, and concentrated in vacuo. The residue was purified on silica gel eluted with ethyl acetate-heptane (1:2) to give a crystalline compound, which was recrystallized (ethyl acetate) to give the title compound (1.2 g, 47%). Mp 146-147° C. 1H NMR (CDCl3) δ 1.70-1.85 (m, 2H), 2.40-2.70 (m, 5H), 2.75 (broad s, 4H), 3.00-3.15 (m, 2H), 3.30 (broad s, 4H), 6.55 (s, 1H), 6.60 (d, 1H), 7.00-7.30 (m, 711), 8.20 (broad s, 1H). MS m/z (%): 346 (MH+, 34%), 159 (88%), 145 (100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7](Cl)[N:6]=[CH:5]2.[O:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([NH:25][C:24]1[CH:23]=[CH:22][C:21]([N:18]3[CH2:19][CH2:20][O:15][CH2:16][CH2:17]3)=[CH:27][CH:26]=1)[N:6]=[CH:5]2
Reactant: COc1cc2nc(Cl)ncc2cc1Br
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CC(C)O
Product: COc1cc2nc(Nc3ccc(N4CCOCC4)cc3)ncc2cc1Br
Temperature: 120 °C

Procedure:
To a 0.12M suspension of 6-bromo-2-chloro-7-methoxyquinazoline (1.0 eq) in isopropanol was added 4-morpholinoaniline (1.0 eq). The reaction mixture was heated to 120° C. in an oil bath for 5 h. LCMS showed that reaction was complete under the condition. The reaction mixture was allowed to cool to room temperature and was filtered. The filter cake was rinsed with ethyl acetate and allowed air dry. Desired product was a brown solid as HCl salt. ES/MS m/z 415/417 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH:15]([CH3:17])[CH3:16])([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1>CCCCCC.CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]([CH3:16])[CH3:17])([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)C1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Solvent: CC(C)O
Solvent: CCCCCC
Product: CC(C)[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Yield: 48.9 %

Procedure:
1-(2-Chloropyrimidin-4-yl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (14.1 g) obtained in Step C of Example 5 was resolved by HPLC (column: CHIRALPAK IC, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/2-propanol=200/800) to give the title compound (6.9 g) having a shorter retention time.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][C:15]([CH3:17])=[O:16].[Cl:18][C:19]1[CH:20]=[C:21]([OH:28])[C:22](=[CH:26][CH:27]=1)[C:23](O)=[O:24]>FC(F)(F)C(O)=O>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]2[C:23](=[O:24])[O:16][C:15]([CH3:17])([CH3:14])[O:28][C:21]=2[CH:20]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC1(C)OC(=O)c2ccc(Cl)cc2O1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
10 mL of trifluoroacetic anhydride and 2 mL of acetone were added to a 0° C. slurry of 4-chlorosalicylic acid (2.23 g, 13 mmol) in 16 mL of trifluoroacetic acid. The mixture was allowed to slowly warm to room temperature and stirred for 25 hours under a nitrogen atmosphere. The tan solution was concentrated under vacuum, dissolved and re-concentrated from toluene twice, and dried under vacuum. The crude solid was dissolved in ethyl acetate and washed twice with saturated sodium bicarbonate solution and once with brine. The organic fraction was dried over sodium sulfate, and concentrated to a tan semi-solid, which was partially dissolved in 10 mL of dichloromethane and filtered to remove solids. The mother liquor was concentrated to give 1.28 g of a tan semi-solid. MS: (+) m/z 215.0/213.0 (M+1, 35/37Cl)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.N[CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: NC1CCOCC1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1cc(Br)ccc1C1CCOCC1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
An eggplant flask was charged with 5-bromo-2-fluoronitrobenzene (3.0 g, 13.6 mmol), triethylamine (1.66 g, 16.3 mmol), 4-aminotetrahydropyran (1.52 g, 15.0 mmol), and ethanol (60 mL), and this was heated to reflux with stirring for 2 hours. After concentration of the reaction mixture under reduced pressure, water (60 mL) was added and this was stirred as is at room temperature for 30 minutes. The precipitated crystals were filtered off and washed with water. The crystals obtained were dried at reduced pressure with heating to yield the title compound (3.55 g, 86% yield) as a reddish-orange solid.
Reaction SMILES: [NH3:1].[C:2]([Si:6]([CH3:29])([CH3:28])[O:7][C:8]1[C:9]([O:26][CH3:27])=[C:10]([C:16]([C:18]2[C:19](Cl)=[N:20][C:21]([Cl:24])=[N:22][CH:23]=2)=[O:17])[C:11]([F:15])=[C:12]([F:14])[CH:13]=1)([CH3:5])([CH3:4])[CH3:3]>C1(C)C=CC=CC=1>[NH2:1][C:19]1[C:18]([C:16]([C:10]2[C:11]([F:15])=[C:12]([F:14])[CH:13]=[C:8]([O:7][Si:6]([C:2]([CH3:3])([CH3:5])[CH3:4])([CH3:28])[CH3:29])[C:9]=2[O:26][CH3:27])=[O:17])=[CH:23][N:22]=[C:21]([Cl:24])[N:20]=1
Reactant: N
Reactant: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C(=O)c1cnc(Cl)nc1Cl
Solvent: Cc1ccccc1
Product: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C(=O)c1cnc(Cl)nc1N

Procedure:
Ammonia gas was bubbled through a solution of [3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-phenyl]-(2,4-dichloro-pyrimidin-5-yl)-methanone (900 mg, 2.003 mmol, Example 268) in toluene (10 mL) for about 30 minutes. The reaction mixture was concentrated to dryness to give (4-amino-2-chloro-pyrimidin-5-yl)-[3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-phenyl]-methanone (1.02 g, yellow gum). The crude product was used without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([CH2:16][O:15][CH2:14][CH2:13]3)[CH2:11][CH:10]=2)O1.Br[C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22]=1[CH3:31].C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:31][C:22]1[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:24][O:25][C:21]=1[C:9]1[CH2:18][CH2:17][C:12]2([CH2:16][O:15][CH2:14][CH2:13]2)[CH2:11][CH:10]=1
Reactant: CCOC(=O)c1noc(Br)c1C
Reactant: CC1(C)OB(C2=CCC3(CCOC3)CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1noc(C2=CCC3(CCOC3)CC2)c1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
[4,4,5,5-tetramethyl-2-(2-oxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane] (0.172 g, 0.651 mmol), ethyl 5-bromo-4-methylisoxazole-3-carboxylate (Intermediate A) (0.183 g, 0.781 mmol) and Cs2CO3 (0.849 g, 2.60 mmol) were combined in DME (3 mL) and water (1.250 mL). PdCl2(dppf).CH2Cl2 adduct (0.016 g, 0.020 mmol) was added and the mixture was degassed thoroughly refilling with nitrogen. The mixture was stirred in the microwave at 90° C. for 1 hour. The biphasic reaction mixture was separated and the organic phase was adsorbed onto silica. Purification by chromatography eluting with a gradient of EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[N:5]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH2:7]1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2ccc(F)cc2)c2cccc(F)c2)CC1
Yield: 89 %

Procedure:
Tert-butyl 4-(3-fluoroanilino)-1-piperidinecarboxylate 1 (20 g) was dissolved in acetonitrile (250 ml). Potassium carbonate (33.2 g) and 1-(bromomethyl)-4-fluorobenzene (11 ml) were added to the solution. The reaction mixture was heated at reflux overnight, then cooled, concentrated and the residue was taken up in dichloromethane and water. The aqueous layer was washed twice with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated. The resulting white solid was triturated in hexane and filtered off to afford tert-butyl 4-[3-fluoro(4-fluorobenzyl)anilino]-1-piperidinecarboxylate 8 (25.5 g).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][C:5]2([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][O:3]1.FC(F)(F)C(O)=O>ClCCl>[C:19]1([CH2:18][C:5]23[CH2:4][O:3][C:2](=[O:1])[N:6]2[CH2:7][CH2:8][NH:9][CH2:10]3)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OCC2(Cc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCC2(Cc3ccccc3)CNCCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.1 %

Procedure:
To 1,1-dimethylethyl tetrahydro-3-oxo-8a-(phenylmethyl)-3H-oxazolo[3,4-a]pyrazine-7(1H)-carboxylate (2.8 g, 8.6 mmol) were added dichloromethane (40 mL) and trifluoroacetic acid (9.7 g, 86 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (1.74 g, yield 88%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]([OH:15])=[O:14])=[CH:8]2.Br.[C:17](O)(=O)C>>[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]([O:15][CH3:17])=[O:14])=[CH:8]2
Reactant: CC(=O)O
Reactant: COc1cccc2cc(C(=O)O)ccc12
Agent: Br
Product: COC(=O)c1ccc2c(O)cccc2c1

Procedure:
5-Methoxy-2-naphthoic acid (49 7 g; 0 246 mol, J Med Chem 1993, 36, 2485) in glacial acetic acid (450 ml) and in 48% strength aqueous hydrobromic acid solution (450 ml) is heated to reflux for 15 h After cooling, the reaction mixture is concentrated in vacuo and is extracted with dichloromethane after addition to water The organic phase is washed with water, dried over MgSO4 and concentrated in vacuo. The residue is dissolved in MeOH (1.6 l) The solution is saturated with hydrogen chloride (about 1 h), the reaction mixture heating to reflux temperature. The solvent is then stripped off in vacuo, the residue is taken up in ethyl acetate, and the mixture is washed with satd NaCl solution, dried (MgSO4) and concentrated in vacuo. The residue is chromatographed on silica gel using dichloromethane:ethyl acetate (20:1). The product thus obtained is stirred with dichloromethane/petroleum ether, filtered off with suction and dried in vacuo.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19]>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:23]2[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: Nc1ncc(-c2ccc(C=O)cc2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 4-formylbenzene-boronic acid gives “A75”; method 1: HPLC/MS: 1.29 min, [M+H]=319;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:7]=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[OH:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=3)[CH:7]=2)=[CH:23][CH:22]=1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1ccccc1
Reactant: OB(O)c1ccc(O)cc1
Product: O=C(Nc1nc2ccc(-c3ccc(O)cc3)cn2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for example 56 but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B5), 150 mg; 0.47 mmol; 1.0 eq.) and 4-hydroxyphenylboronic acid (131 mg; 0.95 mmol; 2.0 eq.) as a white solid (15 mg, 9%). HPLC, Rt: 2.60 min. (purity 97.2%). LC/MS, M+(ESI): 331.1, M−(ESI): 329.1.
Reaction SMILES: [CH3:1][C:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][N:3]=1.[O:26]1CCOCC1>C(#N)C>[CH:1]([C:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[CH:17]=2)=[N:4][N:3]=1)=[O:26]
Reactant: CC1=NN=C(c2ccc([N+](=O)[O-])c(C)c2)c2cc3c(cc2C1)OCO3
Reactant: C1COCCO1
Solvent: CC#N
Product: Cc1cc(C2=NN=C(C=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of 3.37 g (10.0 millimoles) of 8-methyl-5-(4-nitro-3-methyl-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine, 1.66 g (10.5 millimoles) of selen(IV)oxide and 100 ml of dioxane is stirred on an oil-bath at 80° C. for 3 hours. The solution is filtered on a hot coal-bed washed with 50 ml of hot dioxane and evaporated in vacuo. The crude product obtained is treated with 20 ml of acetonitrile. Thus 2.42 g of the desired compound are obtained, yield 69%, mp.: 188–191° C.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([Cl:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][C:15]=4[CH3:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=CC(CC3C(OC)=NC4C(C=3Cl)=CC(Br)=CC=4C)=CC=2)C=CC=N1.[CH3:54][N:55]1[C:59]([C:60]([C:62]2[CH:63]=[N:64][C:65]([C:68]([F:71])([F:70])[F:69])=[CH:66][CH:67]=2)=[O:61])=[CH:58][N:57]=[CH:56]1.[Li]CCCC.C(=O)=O>>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([Cl:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:60]([C:59]3[N:55]([CH3:54])[CH:56]=[N:57][CH:58]=3)([C:62]3[CH:63]=[N:64][C:65]([C:68]([F:70])([F:69])[F:71])=[CH:66][CH:67]=3)[OH:61])=[CH:16][C:15]=4[CH3:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Reactant: Cn1cncc1C(=O)c1ccc(C(F)(F)F)nc1
Agent: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Product: Cc1cc(C(O)(c2ccc(C(F)(F)F)nc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloro-8-methylquinoline (393 mg, 0.880 mmol, Intermediate 19: step a) and (1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanone (224 mg, 0.880 mmol, Intermediate 36: step c) in dry degassed THF (16 mL, THF was degassed with nitrogen for 1 h) was cooled to −78° C. and n-BuLi (1.6 M in hexane, 0.5 mL, 0.8 mmol) was added over 1.5 minutes. Stirring was continued at −78° C. for 10 minutes and the dry ice bath was replaced with an ice water bath. Stirring was continued for 1 hour after which the reaction mixture was quenched with saturated aqueous NH4Cl solution. EtOAc was added and the layers were separated and the aqueous mixture again extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification using flash column chromatography (5% MeOH in dichloromethane) yielded the substantially pure title compound. MS (ESI) 623.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[CH:21]=[C:22]([C:30]([O:32][CH3:33])=[O:31])[CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:19][C:20]3[CH:21]=[C:22]([C:30]([O:32][CH3:33])=[O:31])[CH:23]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:25]=3)=[O:18])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)cc(C(=O)OC)c1
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Intermediate 11) (0.4 g, 1.3 mmol), dimethyl 5-amino-1,3-benzenedicarboxylate (0.29 g, 1 eq), HATU (0.69 g, 1.3 eq) and DIPEA (0.34 mL, 1.3 eq) in DMF (10 mL) was stirred at 45° C. for 24 hours. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate and concentrated. The title compound was obtained as a white solid (650 mg, 95%) after recrystallisation from acetonitrile. LC/MS: m/z 477 (M+H)+, Rt: 3.81 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[N:20]1([C:26]2[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([C:26]2[N:31]=[CH:30][C:29]([NH:32][C:13]([C:11]3[N:12]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[O:9][C:10]=3[C:16]([F:19])([F:18])[F:17])=[O:15])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=C(O)c1nc(-c2ccccc2Cl)oc1C(F)(F)F
Reactant: Nc1ccc(N2CCOCC2)nc1
Product: O=C(Nc1ccc(N2CCOCC2)nc1)c1nc(-c2ccccc2Cl)oc1C(F)(F)F

Procedure:
With a procedure similar to example 16 above, 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C20H16ClF3N4O3 (m/e) 452, obsd 453 (M+H).