Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[C:6]=2[N:22]=1.[CH3:23][NH:24][C:25]1[N:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[N:26]=1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:30]3[CH:31]=[C:32]4[C:27](=[CH:28][CH:29]=3)[N:26]=[C:25]([NH:24][CH3:23])[N:34]=[CH:33]4)=[N:22][C:6]1=2
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Reactant: Fc1ccc(F)c(CN2CCCNc3ncc(Br)nc32)c1Cl
Product: CNc1ncc2cc(-c3cnc4c(n3)N(Cc3c(F)ccc(F)c3Cl)CCCN4)ccc2n1

Procedure:
The entitled compound can be prepared from 2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine and N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-quinazolin-2-amine as described in example 1 or 30.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:19]=4[S:20][C:3]=1[C:4]=23.[Br:26]CC[C:29]1[CH:39]=[CH:38][CH:37]=[C:31]2[C:32]([NH:34][C:35](=[O:36])[C:30]=12)=[O:33].[CH:40](N(CC)C(C)C)(C)[CH3:41]>C(Cl)(Cl)Cl>[BrH:26].[CH2:14]([N:13]([CH2:16][CH3:17])[CH2:12][CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([NH:1][CH2:40][CH2:41][N:34]3[C:35](=[O:36])[C:30]4[C:31](=[CH:37][CH:38]=[CH:39][CH:29]=4)[C:32]3=[O:33])=[C:3]3[S:20][C:19]4[CH:21]=[CH:22][C:23]([OH:25])=[CH:24][C:18]=4[C:5]([C:4]=23)=[N:6]1)[CH3:15]
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1ccc(O)cc1-2
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Solvent: ClC(Cl)Cl
Product: Br
Product: CCN(CC)CCn1nc2c3c(c(NCCN4C(=O)c5ccccc5C4=O)ccc31)Sc1ccc(O)cc1-2
Temperature: 110 °C

Procedure:
A mixture of 4.61 g of 5-amino-2-[2-(diethylamino)-ethyl]-2H-benzothiopyrano[4,3,2-cd]indazol-9-ol and 4.3 g of bromoethylphthalimide is heated at 110° C. for 16 hours, then cooled to room tempaerature. The mixture is combined with 300 ml of chloroform and 10 ml of N,N-diisopropylethylamine and heated under reflux for 2 hours, then washed with three 350-ml portions of water. The solution is evaporated to afford an oily solid which is triturated with 2-propanol. The resulting solid is collected and dried to give the title compound, mp 163°-166° C.
Reaction SMILES: O[CH2:2][C@H:3]1[N:8]([CH2:9][CH:10]([OH:22])[C:11]2[CH:20]=[CH:19][C:14]3[C:15](=[O:18])[O:16][CH2:17][C:13]=3[C:12]=2[CH3:21])[CH2:7][CH2:6][N:5]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:4]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[CH3:21][C:12]1[C:13]2[CH2:17][O:16][C:15](=[O:18])[C:14]=2[CH:19]=[CH:20][C:11]=1[CH:10]1[O:22][CH2:2][C@@H:3]2[CH2:4][N:5]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:6][CH2:7][N:8]2[CH2:9]1
Reactant: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc2c1COC2=O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: Cc1c(C2CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc2c1COC2=O
Temperature: 100 °C

Procedure:
tert-Butyl(3S)-3-(hydroxymethyl)-4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (3.3 g, 8.2 mmol) and cyanomethylene tri-n-butylphosphorane (2 equivalents) were dissolved in 45 mL benzene in a sealed and degassed tube. The mixture was heated to 100° C. for 3 h. The reaction mixture was cooled and evaporated to dryness. The residue was purified by chromatography through a 330 g Redi-sep column and eluted with 30% acetone/70% hexane mixture to yield the title compound as a cis-trans mixture. LC-MS: M+1=389.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([O-:10])=[O:9]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccccc1Br
Product: O=[N+]([O-])c1ccccc1N1CCNCC1
Temperature: 100 °C
Yield: 91.7 %

Procedure:
A heterogenous reaction mixture containing 2-bromo-nitrobenzene (2.02 g, 10.0 mmol) and piperazine (4.3 g, 50.0 mmol) was heated at 100° C. for 10 hours. The orange-red solid was extracted with ethyl acetate and washed thoroughly with 3 N NaOH solution followed by brine. The organic layer was separated and dried over Na2SO4, filtered and the solvent was removed in vacuo. The resulting red oil was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield 1-(2-nitrophenyl)-piperazine as an orange-red oil (1.90 g, 92%). It was characterized as a hydrochloride salt. Analysis calculated for C10H14N3O2Cl0.10 CHCl3: C, 47.46; H, 5.56; N, 16.44. Found: C, 47.63; H, 5.69; N, 16.42.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[CH2:9][CH:8]3[O:15][CH:7]3[CH2:6][C:5]=2[CH:4]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(O)(C)C>C1(C)C(C)=CC=CC=1>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][C@@H:7]([OH:15])[C@H:8]([N:27]1[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH3:16])[CH2:29][CH2:28]1)[CH2:9]2
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1cc2c(cc1OC)CC1OC1C2
Solvent: CC(C)O
Solvent: Cc1ccccc1C
Product: COc1cc2c(cc1OC)C[C@@H](N1CCN(c3ccccc3OC)CC1)[C@H](O)C2
Yield: 22.9 %

Procedure:
A solution of 2.94 g of 2,3-dimethoxy-6,7-epoxy-5,6,7,8-tetrahydronaphthalene, 2.9 g of 1-(o-methoxyphenyl)piperazine, and 1 ml of isopropanol in 30 ml of xylene is refluxed for 5 days. The reaction mixture is concentrated in vacuo, the residue taken up in ethyl acetate, and this is thoroughly extracted with dilute hydrochloric acid. The combined acid extracts are made basic with dilute sodium hydroxide solution, and this is thoroughly extracted with ethyl acetate. The combined ethyl acetate extracts are dried and concentrated in vacuo to an oil, which gives 1.3 g of solid on trituration with ethyl acetate. Recrystallization from ethyl acetate gives 600 mg of the title compound, melting point 172°-174° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH3:13])[CH2:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)=[O:21])=[CH:18][C:17]=1I.C(NCC)C>[Cu](I)I>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:17]1[CH:18]=[C:19]([C:20](=[O:21])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[CH:33]=[CH:34][C:16]=1[NH2:15])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(NC(=O)c2ccc(N)c(I)c2)cc1OC
Reactant: C#CCCCN(C)C(=O)OC(C)(C)C
Agent: I[Cu]I
Solvent: CCNCC
Product: COc1ccc(NC(=O)c2ccc(N)c(C#CCCCN(C)C(=O)OC(C)(C)C)c2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 500 mL round bottom flask was charged with methyl-pent-4-ynyl-carbamic acid tert-butyl ester (1.70 g, 8.62 mmol), 4-amino-N-(3,4-dimethoxyphenyl)-3-iodobenzamide (3.0 g, 7.53 mmol), copper iodide (0.225 g, 1.18 mmol), palladium tetrakistriphenylphosphine (0.93 g, 0.805 mmol), and diethylamine (258 mL) and the resulting mixture stirred at room temperature for 24 h. The resulting mixture was then concentrated in vacuo and the residue purified via flash silica gel chromatography (Analogix IF-280, SF40-400 g column, gradient 90:10-10:90 Heptane:EtOAc) to yield {5-[2-amino-5-(3,4-dimethoxy-phenylcarbamoyl)-phenyl]-pent-4-ynyl}-methyl-carbamic acid tert-butyl ester. MS (ES+) 468 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[C:23](=O)([O-])[O-].[Cs+].[Cs+].C[O:30][CH2:31][CH2:32]Br>CN(C)C=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][CH:31]([OH:30])[CH3:32])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: O=C([O-])[O-]
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: COCCBr
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Yield: 49.3 %

Procedure:
A solution of 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (45 mg, 0.15 mmol) in dimethylformamide (DMF, 1.5 mL) was successively treated with cesium carbonate (64 mg, 0.2 mmol) and 2-methoxyethyl bromide (31.3 mg, 0.23 mmol). The crude mixture was heated at 130° C. in the microwave for 30 min, then filtered off. The filtrate was evaporated down under reduced pressure and purified by preparative HPLC, yielding 27 mg of Compound 92.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[N:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cc(F)cc3c(C)c4n(c23)CCNC4=O)cn1

Procedure:
The title compound, off-white solid (67 mg, 82%), MS (ISP) m/z=326.4 [(M+H)+], mp 226° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 6-methoxy-pyridin-3-ylboronic acid (49.7 mg, 0.325 mmol).
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C>CO.O>[OH:6][CH2:7][CH2:8][C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)OCCc1oc(C)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(-c2ccccc2)c(CCO)o1
Reaction time: 0.5 h

Procedure:
2N Sodium hydroxide (40 ml) was added to a solution of 5-(2-acetoxyethyl)-2-methyl-4-phenyloxazole (16.6 g) in methanol (40 ml) and the mixture was stirred for 30 minutes, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue wwas purified by silica gel chromatography (silica gel: 190 g, eluent: isopropyl ether) to give an oil of 5-(2-hydroxyethyl)-2-methyl-4-phenyloxazole, yield 11.7 g (84.8%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1C(O)=O.C([N:17](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CC(O)(C)C.Cl[Cu]>[F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[NH2:17]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1F
Agent: Cl[Cu]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: Nc1ccc(C(F)(F)F)cc1F
Temperature: 50 °C
Yield: 57.9 %

Procedure:
To the solution of 2-fluoro-4-(trifluoromethyl)benzoic acid (1 kg, 4.805 mol, 1.00 equivalent “eq.”) and CuCl (14.26 g, 0.144 mol, 0.03 eq.) in t-BuOH (11.7 L) was added triethylamine (TEA, 533.8 g, 5.286 mol, 1.10 eq.) dropwise at room temperature (rt). Then the solution was heated to 50° C. and diphenylphosphoryl azide (DPPA, 1393 g, 5.045 mol, 1.05 eq.) was added dropwise to the solution at 50-60° C. After heating at 80-85° C. overnight the solution was concentrated under vacuum. The residual was dissolved in H2O and filtered. The filtrate was extracted with ethyl acetate. The organic layers was dried with Na2SO4, filtered and concentrated under vacuum. The residual was dissolved in tent-Butyl methyl ether (TBME) and HCl (gas) was bubbled in for 2 hours. The filtrate was collected and dissolved in water and basified with 2 M NaOH. The solution was extracted with TBME. The organic layers were dried and concentrated under vacuum to give 2-fluoro-4-(trifluoromethyl)aniline (498 g, 58%) as a red oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([O:17][CH3:18])=[C:12]([F:19])[CH:11]=2)=O)[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)S(O)(=O)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH:7]=1)[CH2:8][C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][CH3:18])=[C:12]([F:19])[CH:11]=1
Reactant: COc1c(F)cc(C(=O)c2cc(Br)ccc2Cl)cc1F
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1c(F)cc(Cc2cc(Br)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of (5-bromo-2-chlorophenyl)(3,5-difluoro-4-methoxy-phenyl)methanone (629 mg, 1.7 mmol) in trifluoroacetic acid (6 mL) was added triethylsilane (1.1 mL, 6.9 mmol), and the mixture was stirred for 10 minutes at 25° C. Trifluoromethane-sulfonic acid (50 μL) was added, and the reaction was briefly boiled. The mixture was stirred overnight at 25° C. before the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and was washed with saturated sodium carbonate and brine, dried over sodium sulfate, and concentrated to give a crude product. 573 mg of pure product was obtained by column chromatography (94.8% yield).
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH2:20][C:21]4[CH:26]=[CH:25][C:24](F)=[CH:23][C:22]=4F)[CH:19]=3)[C:6](=[O:29])[N:5]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:4]=2[N:3]=1.[Cl:35]C1C=CC=CC=1CBr.N1CCOCC1>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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:35])[CH:19]=3)[C:6](=[O:29])[N:5]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:4]=2[N:3]=1
Reactant: Clc1ccccc1CBr
Reactant: CCCCCn1c(=O)n(CCCc2cnn(Cc3ccc(F)cc3F)c2)c(=O)c2[nH]c(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Product: CCCCCn1c(=O)n(CCCc2cnn(Cc3ccccc3Cl)c2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 5.5 h

Procedure:
Prepared by the method for 8-chloro-1-(3-{1-[(2,4-difluorophenyl)methyl]-1H-pyrazol-4-yl}propyl)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione, Example 6 but from 2-chlorobenzyl bromide (164 mg, 0.8 mmol). However, in order to complete the deprotection step further tetrakis(triphenylphosphine)palladium(0) (40 mg) and morpholine (0.15 ml) were added and stirring continued for a further 5.5 h. Purification by aminopropyl SPE as above afforded the title compound as a solid (42 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][C:17]#[N:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:21]>O1CCCC1>[ClH:21].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([CH3:20])([CH3:19])[CH2:16][C:17]#[N:18])[CH2:10][CH2:9]1
Reactant: CC(C)(CC#N)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(CC#N)CC1CCNCC1
Reaction time: 2 h

Procedure:
To a solution of 6.7 g of 4-[1-(tert-butoxycarbonyl)-piperidin-4-yl]-3,3-dimethylbutyronitrile in 50 ml of tetrahydrofuran was added at room temperature 20 ml of conc. hydrochloric acid and the resulting mixture was stirred for 2 hours. Then the reaction mixture was concentrated under reduced pressure to thereby give crude 4-(piperidin-4-yl)-3,3-dimethylbutyronitrile hydrochloride. This crude product was dissolved in 100 ml of dichloromethane. After adding 10.5 g of anhydrous potassium carbonate and 3.3 ml of benzyl bromide, the reaction mixture was reacted at room temperature for 12 hours. After adding water, the reaction mixture was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 4.7 g of the title compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C([O-])([O-])=O.[K+].[K+].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29](C3C=CC(Cl)=CC=3Cl)=[CH:28][N:27]3[C:38]([CH2:41][C:42]4[CH:43]=[N:44][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:46][CH:47]=4)=[N:39][N:40]=[C:26]3[CH:25]=2)=[CH:20][CH:19]=1.O1CCO[CH2:54][CH2:53]1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:29]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:28][N:27]3[C:38]([CH2:41][C:42]4[C:43]([CH2:53][CH3:54])=[N:44][C:45]([C:48]([F:49])([F:51])[F:50])=[CH:46][CH:47]=4)=[N:39][N:40]=[C:26]3[CH:25]=2)=[CH:22][CH:23]=1
Reactant: C1COCCO1
Reactant: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)cn23)cn1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3F)cn12
Yield: 55 %

Procedure:
The title compound (5.5 mg, 55%) as a white powder was prepared from 6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethylpyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.020 mmol), 2-fluorophenylboronic acid (5.5 mg, 0.039 mmol), K2CO3 (8.2 mg, 0.059 mmol) and Pd(PPh3)4 (2.8 mg, 0.002 mmol) in 1,4-dioxane (0.28 mL) and H2O (0.09 mL) by the procedures analogous to those described for 7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56). LC/MS (method B): retention time=Time: 1.86, [M+H]+=497.3.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:14][CH2:15][O:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([C:24]2[NH:33][C:32](=[O:34])[C:31]3[C:26](=[CH:27][C:28]([O:37][CH3:38])=[CH:29][C:30]=3[O:35][CH3:36])[N:25]=2)=[CH:19][C:18]=1[CH3:39].O>CN(C)C=O>[CH3:36][O:35][C:30]1[CH:29]=[C:28]([O:37][CH3:38])[CH:27]=[C:26]2[C:31]=1[C:32](=[O:34])[NH:33][C:24]([C:20]1[CH:21]=[C:22]([CH3:23])[C:17]([O:16][CH2:15][CH2:14][N:6]3[C:7](=[O:9])[CH2:8][N:4]([CH:1]([CH3:3])[CH3:2])[C:5]3=[O:10])=[C:18]([CH3:39])[CH:19]=1)=[N:25]2
Reactant: CC(C)N1CC(=O)NC1=O
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4C(=O)CN(C(C)C)C4=O)c(C)c3)nc2c1
Reaction time: 0.17 h

Procedure:
To a solution of 1-isopropyl-imidazolidine-2,4-dione (0.10 g, 0.70 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in mineral oil, 31 mg, 0.77 mmol) and the reaction mixture was stirred for 10 minutes. Then, 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.32 g, 0.73 mmol) was added. The reaction mixture was stirred at 55° C. for 16 hours, then poured into water (100 mL). The solid was filtered and dried. The crude compound was purified by column chromatography (silica gel 230-400 mesh; eluting with 2:1 ethyl acetate and dichloromethane) to give the title compound as a white solid. Yield: 0.09 g (26.0%). MP 219-221° C. 1H NMR (400 MHz, DMSO): δ 9.64 (s, 1H), 7.69 (s, 2H), 6.82 (d, J=2.4 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 4.42 (m, 1H), 4.02 (m, 2H), 3.98 (m, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.85 (s, 2H), 2.32 (s, 6H) 1.22 (d, J=6.4 Hz, 6H). MS (ES+) m/z: 495.16 (M+1).
Reaction SMILES: [C:1]1([C:7](=[CH2:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>O1CCCC1.CN(C)C(=N)N(C)C>[N:14]1([CH2:13][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1c[nH]cn1
Reactant: C=C(C(=O)OCC)c1ccccc1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(Cn1ccnc1)c1ccccc1
Yield: 81.9 %

Procedure:
A solution of ethyl 2-phenylprop-2-enoate (160 g, 0.45 mol), imidazole (36.7 g 0.54 mol) and tetramethylguanidine (2 g, 0.017 mol) in dry tetrahydrofuran (1 L) was heated at reflux temperature for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in dilute hydrochloric acid. The resulting aqueous solution was washed with ether, basified with dilute aqueous sodium hydroxide and extracted with chloroform. The organic phase was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield ethyl 3-(imidazol-1-yl)-2-phenylpropanoate (90 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:17](C(OCC)=O)(C(OCC)=O)[C:18]([O:20]CC)=[O:19])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[NH3:9].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCc2nc(C(C)(C)C)n(Cc3ccc(Cl)cc3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CC(=O)O)CC2
Product: N
Yield: 174.8 %

Procedure:
Intermediate 35 (496 mg) was dissolved in ethanol (5 ml) and the resulting soln. was treated with sodium hydroxide, 2M aq (3 ml). The resulting suspension was heated to reflux for 4 hr. The reaction mixture was allowed to cool and concentrated in vacuo. The crude residue was taken up in acetic acid (10.00 ml) and heated to reflux for 1 hr. Reaction mixture concentrated in vacuo. The residue was purified by reverse phase chromatography using acetonitrile water with an ammonium carbonate modifier gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (304 mg) as a white solid. LC/MS MH+ 347, Rt 1.93 min (5 minute run).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9](=[O:11])[CH3:10])[CH:5]=1.[C:12]([Mg]Br)#[CH:13]>C1COCC1>[CH3:1][O:2][CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])([C:12]#[CH:13])[CH3:10])[CH:5]=1
Reactant: COCc1cc(C(C)=O)no1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cc(COC)on1
Reaction time: 1.5 h

Procedure:
To a solution of 1-[5-(methoxymethyl)isoxazol-3-yl]ethanone (220 mg, 1.42 mmol) in dry THF (4 mL) at 0° C. under an atmosphere of nitrogen, was introduced ethynylmagnesium bromide (4.4 mL of a 0.5M solution in THF, 2.20 mmol) dropwise over 5 min. After 1.5 hr at this temperature, the reaction was carefully quenched with water (0.2 mL) and the resulting suspension concentrated in vacuo. The residual syrup was slurried in water (5 mL) and the pH adjusted to 2 with 5M aqueous hydrochloric acid for 5 min., then saturated sodium bicarbonate solution introduced until the pH was ˜7.5. Following extraction of the basic aqueous solution with EtOAc (2×100 ml), the combined EtOAc extracts were dried (Na2SO4), filtered and the filtrate concentrated in vacuo to furnish the crude title compound as a pale brown oil: 1H NMR (500 MHz, CDCl3) delta 1.89 (3H, s), 2.66 (1H, s), 3.02 (1H, br. s), 3.45 (3H, s), 4.55 (2H, s), 6.39 (1H, s); LC-MS: m/z=+181.95 (M+H)+.