Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:34])([F:33])[C:7]1[N:11]2[N:12]=[C:13]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28](=O)[CH3:29])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH2:14][CH2:15][C:10]2=[N:9][N:8]=1.[C:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])[CH3:36].[O-]S([O-])(=O)=O.[Mg+2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:35]([N:38]1[CH2:43][CH2:42][N:41]([CH:28]([CH3:29])[CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]([CH:19]3[CH2:20][CH2:21][N:16]([C:13]4[CH2:14][CH2:15][C:10]5[N:11]([C:7]([C:6]([F:34])([F:33])[F:5])=[N:8][N:9]=5)[N:12]=4)[CH2:17][CH2:18]3)=[CH:32][CH:31]=2)[CH2:40][CH2:39]1)(=[O:37])[CH3:36]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(=O)COc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)N1CCN(C(C)COc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
Acetic acid (0.081 mL, 1.41 mmol) was added to 1-(4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)propan-2-one (595 mg, 1.41 mmol), N-acetylpiperazine (199 mg, 1.55 mmol) and a catalytic amount of MgSO4 in THF (5 mL). The resulting mixture was stirred at ambient temperature for 1 hour, then sodium triacetoxyborohydride (359 mg, 1.69 mmol) was added and stirring was continued for a further 16 hours. The reaction mixture was concentrated, diluted with DCM (25 mL), washed with saturated NaHCO3 (25 mL) and then filtered through a PTFE cup. The organic layer was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford racemic 6-(4-{4-[2-(4-acetylpiperazin-1-yl)propoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (199 mg, 26.4%) as a gum.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:29][C:30](=O)[CH2:31][C:32]1[NH:36][CH:35]=[N:34][N:33]=1)C>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:30](=[O:29])[CH2:31][C:32]1[NH:36][CH:35]=[N:34][N:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: CCOC(=O)Cc1nnc[nH]1
Product: COc1ccc(N2CCN(C(=O)Cc3nnc[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 19 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (4H-[1,2,4]triazol-3-yl)-acetic acid ethyl ester with heating for 15 days to afford the title compound as a yellow solid (75 mg, 19%). LC/MS (Method B) 3.17 min, [M+1]+ 462.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1>C(O)(=O)C.[Pd].[Pt](=O)=O>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][NH:12][CH2:13][CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:19]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cncc(-c2ccc(OC(F)F)cc2)c1
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1CNCC(c2ccc(OC(F)F)cc2)C1
Reaction time: 24 h

Procedure:
A solution of 8.6 g (30.9 mmol) of methyl 5-[4-(difluoromethoxy)phenyl]nicotinate in concentrated acetic acid (112 ml) was admixed with 841 mg of palladium/carbon (10% palladium) and 1.12 g of platinum(IV) oxide. This was followed by hydrogenation under a hydrogen atmosphere at standard pressure for 24 h. The reaction solution was concentrated under reduced pressure. The residue was taken up in water, acidified (pH 1) with 1 N hydrochloric acid, extracted with diethyl ether, then basified (pH>10) with saturated aqueous sodium hydrogencarbonate solution and extracted repeatedly with ethyl acetate. The combined filtrates were dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 6.6 g (74% of theory)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12](=[O:17])[CH:13]=[C:14]([CH3:16])[CH3:15])[CH:6]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+]>>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:8]([C:14]([CH3:16])([CH3:15])[CH2:13][C:12](=[O:17])[NH:11]2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(NC(=O)C=C(C)C)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: CC(=O)Nc1ccc2c(c1)NC(=O)CC2(C)C
Temperature: 100 °C

Procedure:
23.2 g. (0.1 mole) N-acetyl-3-(3,3-dimethylacryloylamino)-aniline, 92.8 g. aluminium chloride and 60 g. sodium chloride are well mixed up and heated to 100° C. for 2 hours. Thereafter, the reaction mixture is mixed with ice, briefly stirred and the crystallisate filtered off with suction. Yield 21.4 g. (92% of theory); m.p. 273°-278° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[O:25][C:26]=1[CH3:27]>>[Cl:34][C:30]1[CH:29]=[C:28]([C:24]2[O:25][C:26]([CH3:27])=[C:22]([CH2:21][N:12]3[C:13]4[C:9](=[CH:8][C:7]([CH2:6][CH:5]([O:16][CH2:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:15][CH:14]=4)[CH:10]=[CH:11]3)[N:23]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3cccc(Cl)c3)oc2C)c1)C(=O)O
Yield: 21 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(3-chloro-phenyl)-5-methyl-oxazole, the title compound was obtained in 21% yield as a yellow solid. MS: (M+H)+ 439.3.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(Cl)Cl.O>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:2]2[CH:15]=[CH:14][C:13]3[O:12][C:11]4[C:6](=[CH:7][C:8]([C:16]5[CH:17]=[N:18][CH:19]=[N:20][CH:21]=5)=[CH:9][CH:10]=4)[C@@:5]4([CH2:25][O:24][C:23]([NH2:26])=[N:22]4)[C:4]=3[CH:3]=2)[CH:28]=1
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(-c3cncnc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 100 °C

Procedure:
0.5-2 ml Microwave vial was charged with (S)-2′-bromo-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (100 mg, 0.244 mmol), pyridin-3-ylboronic acid (38.7 mg, 0.315 mmol), dichlorobis(di-t-butyl-4-dimethylaminophenylphosphine)palladium (II) (7.44 mg, 10.51 μmol) and potassium carbonate (87 mg, 0.630 mmol), dioxane (1 ml) and water (0.12 ml) were added and the vial was sealed and heated at 100° C. in the microwave oven (Biotage) for 1 hr. The mixture was diluted with DCM, filtered through Celite, concentrated and purified by flash chromatography on silica gel (12 g column, 20-100% DCM/MeOH/NH4OH in DCM) to afford (R)-2′-(pyridin-3-yl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as yellowish solid.
Reaction SMILES: C([O:8][C:9]1[CH:35]=[C:34]([Cl:36])[C:12]([CH2:13][CH:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:21][CH2:20]3)[C:15]2=[O:33])=[C:11]([Cl:37])[CH:10]=1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C1COCC1>[C:29]([Si:26]([CH3:28])([CH3:27])[O:25][C@@H:22]1[CH2:23][CH2:24][C@H:19]([N:16]2[CH2:17][CH2:18][CH:14]([CH2:13][C:12]3[C:11]([Cl:37])=[CH:10][C:9]([OH:8])=[CH:35][C:34]=3[Cl:36])[C:15]2=[O:33])[CH2:20][CH2:21]1)([CH3:31])([CH3:30])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC(Cc3c(Cl)cc(O)cc3Cl)C2=O)CC1
Reaction time: 3 h

Procedure:
Combine 2 g (3.6 mmol) of 3-(4-benzyloxy-2,6-dichloro-benzyl)-1-[cis-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (Preparation 71) with 150 mg Pd(OH)2 and 25 mL THF. Hydrogenate with a balloon of H2 for 3 hours. Filter the reaction through Celite®, concentrate under vacuum and purify by chromatography using CHCl3/MeOH 98/2 to recover 1.54 g (88%) of the title compound as an oil.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Br:8][C:9]1[CH:10]=[CH:11][C:12](F)=[N:13][CH:14]=1>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:13][CH:14]=1
Reactant: OCC1CC1
Reactant: Fc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc(OCC2CC2)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.49 g (6.82 mmol) cyclopropane methanol in 10 mL THF are charged with 0.42 g (11.4 mmol) NaH and the reaction mixture is stirred at r.t. for 20 min. Then 1.00 g (5.68 mmol) 5-bromo-2-fluoropyridine are added and the mixture is stirred at r.t. over night. The reaction is quenched by the addition of water and extracted with EtOAc. The organic layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo. The crude product is purified by HPLC (MeOH/H2O/FA).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1)#[CH:2].[CH2:27]([O:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33])[CH3:28].C(N(CC)CC)C>O1CCCC1.[Pd](Cl)Cl.[Cu]I>[CH2:27]([O:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](=[O:33])[C:2]#[C:1][C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([F:23])([F:25])[F:24])=[N:17]3)[CH2:10][CH2:9]2)[S:6][CH:7]=1)[CH3:28]
Reactant: C#Cc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Reactant: CCOc1ccccc1C(=O)Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccccc1C(=O)C#Cc1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
At room temperature and under an atmosphere of argon, palladium(II) chloride (5.8 mg) and copper(I) iodide were added to a solution of 1-[4-(4-ethynyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (250 mg) and 2-ethoxybenzoyl chloride in tetrahydrofuran. The mixture was stirred at room temperature for 1 minute, and triethylamine (83 mg) was then added. The reaction mixture was stirred at room temperature overnight. 5 g of silica gel were then added, and the solvent was removed under reduced pressure. The residue was purified chromatographically. This gave 1-(2-ethoxyphenyl)-3-[2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]prop-2-yn-1-one (244 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13]C)=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:15]#[N:16])=[CH:10]2)=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].O.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([OH:13])=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:15]#[N:16])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(C#N)cc2c1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2ccc(C#N)cc2c1O
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
A solution of Example 1A (1 g) in methylene chloride (100 mL) at 0° C. was treated with AlCl3, stirred for 4 h at 0° C. and at room temperature for 18 h, poured into water (200 mL) containing 6N HCl (20 mL), stirred for 1 h and diluted with methylene chloride (100 mL). The layers were separated, and the organic layer was washed with brine and dried (MgSO4) to provide 810 mg of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1I.[C:12](#[N:17])[CH2:13][CH2:14][C:15]#[CH:16].C(N(CC)CC)C.O>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:16]#[C:15][CH2:14][CH2:13][C:12]#[N:17]
Reactant: FC(F)(F)c1ccccc1I
Reactant: C#CCCC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: N#CCCC#Cc1ccccc1C(F)(F)F
Reaction time: 16 h
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, a solution of 15.0 grams (0.055 mole) of 2-trifluoromethylphenyl iodide, 4.8 grams (0.061 mole) of 4-pentynenitrile, 30.6 mL (0.22 mole) of triethylamine, 0.4 gram (0.0006 mole) of bis(triphenylphosphine)palladium(II) chloride, and 0.1 gram (0.0006 mole) of copper(II) iodide in 50 mL of acetonitrile was stirred at ambient temperature for 5 hours. After this time, gas chromatographic analysis (GC) of the reaction mixture indicated that the reaction was about 60% complete. The reaction mixture was warmed to 40°-45° C., where it was stirred for 16 hours. After this time the reaction mixture was poured into 300 mL of water, and the mixture was extracted with two 100 mL portions of diethyl ether. The combined extracts were washed with aqueous dilute hydrochloric acid and then were dried with magnesium sulfate. The mixture was filtered and concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 1:1-methylene chloride and petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 11.4 grams of 5-(2-trifluoromethylphenyl)-4-pentynenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:6][CH2:5][N:4]([C:7](=[O:16])[CH:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH3:9])[CH2:3]1.[C:18]([O:22][C:23]([N:25]1[C@@H:29]([C@H:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:27][C@H:26]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C>CN(C)C=O>[C:18]([O:22][C:23]([N:25]1[C@@H:29]([C@H:30]([OH:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:27][C@H:26]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([N:13]2[CH2:12][CH2:11][N:10]([CH:8]([CH3:9])[C:7]([N:4]3[CH2:5][CH2:6][C:2]([F:1])([F:17])[CH2:3]3)=[O:16])[CH2:15][CH2:14]2)=[O:44])=[CH:41][CH:40]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C(=O)N1CCC(F)(F)C1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)N1CCC(F)(F)C1)N1CCN(C(=O)c2ccc(C[C@@H]3CC[C@H]([C@H](O)c4ccccc4)N3C(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a stirred solution of 12 mg (0.049 mmol) of 4-(2-(3,3-Difluoropyrrolidin-1-yl)-1-methyl-2-oxoethyl)piperazine (TEA salt), and 20 mg (0.049 mmol) of 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1) in 1 mL anhydrous N,N-dimethylformamide under nitrogen atmosphere was added 0.042 mL (0.24 mmol) of N,N-diisopropylethylamine and 37 mg (0.097 mmol) of 2-(1H-7-azabezotriazole-1-yl)-1,1,3,3,-tetramethyl uranium hexafluoro phosphate methanium. The resulting reaction mixture was stirred at ambient temperature overnight. The reaction was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient) to give 23 mg of the title compound. LC/MS: (M+1)=641.2.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.Br[C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:40]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([O:49][C@@H:50]4[CH2:54][CH2:53][O:52][CH2:51]4)[CH:42]=3)=[CH:39][CH:38]=[N:37]2)=[CH:32][CH:31]=1.[N:55]1([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH4+].[Cl-]>O1CCCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:48][O:47][C:44]1[CH:45]=[CH:46][C:41]([C:40]2[N:36]([C:33]3[CH:34]=[CH:35][C:30]([N:58]4[CH2:57][CH2:56][N:55]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:60][CH2:59]4)=[CH:31][CH:32]=3)[N:37]=[CH:38][CH:39]=2)=[CH:42][C:43]=1[O:49][C@@H:50]1[CH2:54][CH2:53][O:52][CH2:51]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(-c2ccnn2-c2ccc(Br)cc2)cc1O[C@@H]1CCOC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(-c2ccnn2-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1O[C@@H]1CCOC1
Temperature: 65 °C
Yield: 33.6 %

Procedure:
Into a 1-neck round-bottom flask was added 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (4.74 mg, 0.0120 mmol), 1-(4-bromophenyl)-5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazole (50.0 mg, 0.120 mmol), tert-butyl 1-piperazinecarboxylate (26.9 mg, 0.144 mmol) and tris(dibenzylideneacetone) dipalladium(0) (11.0 mg, 0.0120 mmol). The reaction was placed under an atmosphere of argon, 0.4 mL of 1.00 M lithium bis(trimethylsilyl)amide in tetrahydrofuran was added and the mixture was heated to 65° C. for 16 hours. After cooling to room temperature, 30 mL of saturated aqueous NH4Cl solution was added and the aqueous layer was extracted with 30 mL ethyl acetate. The separated organic layer was dried over sodium sulfate, filtered, and approximately 1 g silica gel was added and the mixture was evaporated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 20% ethyl acetate in hexanes to yield tert-butyl 4-[4-(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)phenyl]piperazine-1-carboxylate (21 mg, 34%) as a yellow oil. LC/MS (EI) tR 4.62 (Method C), m/z 521.3 (M++1). 1H NMR (CDCl3 300 MHz) δ 1.5 (s, 9H); 1.9 (m, 2H); 3.1 (m, 4H); 3.6 (m, 4H); 3.7-3.9 (m, 4H); 3.9 (s, 3H); 4.6 (m, 1H); 6.4 (s, 1 h); 6.6 (s, 1H); 6.9-7.1 (m, 4H); 7.2 (d, 2H); 7.6 (S, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]3[CH2:14][CH:13]3[C:15]3[CH:16]=[C:17]([O:21]C)[CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(S)C.Cl>C(Cl)Cl.C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]3[CH2:14][CH:13]3[C:15]3[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1cccc(C2CC2c2ccc3ccc(Cl)cc3n2)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCS
Product: Oc1cccc(C2CC2c2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C

Procedure:
To the cyclopropylanisole (from Step 2) (1.478 g, 4.77 mmoles) in 20 mL CH2Cl2 at -10° C. was added AlCl3 (1.915 g, 3 eg.) and ethanethiol (1.2 mL, 3.3 eg.). The temperature was raised to 0° C. for 2 hours. Then 10% HCl and THF: EtOAc (1:1) were added and the mixture was stirred and heated until the resulting gum was solubilized. After separation of the phases and extractions with THF:EtOAc (1:1), flash chromatography using 5% EtOAc in toluene yielded the title phenol.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:8][CH:7]=1)=O)C.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[OH:3][CH2:4][C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cn2c(NC3CCN(C(=O)OCC)CC3)nc3ccccc32)o1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(CO)o2)CC1
Temperature: 0 °C

Procedure:
Combine (1-(5-ethyoxycarbonylfur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine (2.7 mmol) and tetrahydrofuran (10 mL). Add a solution of lithium aluminum hydride (5.4 mL, 1.0M in tetrahydrofuran, 5.4 mmol). After 18 hours pour the reaction mixture into a beaker, dilute with dichloromethane, and cool to 0° C. With stirring add portionwise, Na2SO4.10 H2O until the evolution of gas ceases. Add dichloromethane to about double the volume, add celite, stir to form a thick slurry, and filter. Evaporate the filtrate in vacuo to give (1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([Br:15])[CH:3]=1.C([Li])CCC.CCCCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH:30]([C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([Br:15])[CH:3]=1)=[O:31]
Reactant: Brc1cc(Br)c2c(c1)oc1ccccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cc(Br)cc2oc3ccccc3c12
Temperature: -50 °C

Procedure:
To a stirred solution of the 1,3-dibromobenzofuran 11 (10 g, 30.9 mmol) in anhydrous THF (250 mL) at -78° C. under nitrogen was added a 2.5M butyllithium in hexane solution (13.6 mL, 33.9 mmol). The resulting red solution was warmed to -50° C. and held there for 10 min. before anhydrous DMF (2.6 mL, 33.9 mmol) was added dropwise. The resulting rust colored solution was stirred an additional 20 min. at -50° to -40° C. before being quenched with saturated ammonium chloride solution (25 mL). The THF was removed under vacuum and the residue was dissolved in ethyl acetate (EtOAc) and washed sequentially with water, saturated aqueous ammonium chloride solution, water and brine. The organic solution was then dried with magnesium sulfate and decolorized with Norite. The mixture was then filtered and concentrated under vacuum. The residue was triturated with ether/hexane to provide 4.0 g of pale yellow flakes of dibenzofuran 35. The mother liquor was then chromatographed (silica gel, 30% EtOAc in hexanes) to provide an additional 2.1 g of dibenzofuran 35 (total yield: 73%).
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.[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:33]5[CH:32]=[N:31][CH:30]=[C:29]([O:28][CH2:27][CH2:26][O:25][CH3:24])[CH:34]=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: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COCCOc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: COCCOc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

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 3-(2-methoxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 59.1.1) to give the title compound as a white solid. (HPLC: tR 2.17 min (Method A); M+H=445 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.35-8.27 (m, 2H), 8.18-8.08 (m, 2H), 8.04-7.97 (m, 1H), 7.61-7.56 (m, 1H), 7.44-7.38 (m, 1H), 4.25 (t, 2H), 3.89 (s, 3H), 3.71 (t, 2H), 3.57 (s, 3H), 3.31 (s, 3H), 1.96 (s, 3H))