Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16]I)[C:12]([O:14][CH3:15])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=3)[O:28][CH:29]=2)=[CH:21][CH:20]=1.C1COCC1>CN(C=O)C.[Zn].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].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:26]=[C:27]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:34][CH:35]=3)[O:28][CH:29]=2)=[CH:23][CH:24]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Reactant: CCCCCCCOc1ccc(-c2nc(-c3ccc(Br)cc3)co2)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2nc(-c3ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc3)co2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To zinc (104 mg, 1.59 mmol) stirring in DMF (1.5 mL) was added iodine (20.2 mg, 0.08 mmol). After the color disappeared, (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (175 mg, 0.53 mmol) and further iodine (20.2 mg, 0.08 mmol) were added. After 30 min, the mixture was de-gassed by bubbling through N2 then treated with 4-(4-bromophenyl)-2-(4-(heptyloxy)phenyl)oxazole (220 mg, 0.53 mmol), Pd2dba3 (12.2 mg, 0.01 mmol) and dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (10.9 mg, 0.03 mmol) followed by THF (1 mL). The reaction mixture was heated to 50° C. for 2 h, cooled to RT and purified by column chromatography (gradient of 15-95% EA in iso-hexanes) to afford 188 mg (65%) of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(2-(4-(heptyloxy)phenyl)oxazol-4-yl)phenyl)propanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH2:27][C@H:28]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)[OH:29].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20][N:26]([CH2:27][C@@H:28]([OH:29])[C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH3:25])=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNC[C@@H](O)c1cccnc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(Cc1cc2c(s1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)C[C@@H](O)c1cccnc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 57.2 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (167 mg, 0.44 mmol), (1S)-2-(methylamino)-1-pyridin-3-ylethanol (Preparation 29) (100 mg, 0.66 mmol) and diisopropylethylamine (115 μL, 0.66 mmol) in dry DMF (8 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 7 hours at that temperature. After cooling to room temperature, the solution was diluted with water (12 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from /water (dissolved with warming 5 mL of acetonitrile, then cooled to 0° C. and then diluted with 1 mL of water, left overnight) gave the title compound (125 mg) as a white solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[S:5][C:6]2[CH:13]=[CH:12][C:11]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:10]=3[C:9](=[O:19])[C:7]=2[N:8]=1>CO.ClCCl>[Cl:3][C:4]1[S:5][C:6]2[CH:13]=[CH:12][C:11]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:10]=3[CH:9]([OH:19])[C:7]=2[N:8]=1
Reactant: O=c1c2ccc(Cl)cc2ccc2sc(Cl)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OC1c2ccc(Cl)cc2C=Cc2sc(Cl)nc21

Procedure:
Sodium borohydride (0.159 g) was added to a suspension of the product from step (vi) (1.27 g) in methanol (20 ml) and dichloromethane (5 ml) at room temperature. After 3 h the mixture was partitioned between 2N NaOH and dichloromethane. The organic phase was collected, dried, (MgSO4) and solvent evaporated to leave a colourless foam. Yield: 1.27 g Used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][N:7]=1.[CH3:38]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)C.C([O-])(=O)C.[K+].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].ClCCl>[CH3:38][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][N:7]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cnc(Cl)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cnc(C)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Temperature: 140 °C
Yield: 70.6 %

Procedure:
To a solution of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]pyrazin-2-yl]-3-piperidyl]carbamate (50 mg, 0.096 mmol), trimethylboroxine (36 mg, 0.29 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (8.0 mg, 0.0095 mmol) in acetonitrile 2.0 mL was added 1.00M sodium carbonate in water (0.19 mL, 0.19 mmol) and 1.00M potassium acetate in Water (0.19 mL, 0.19 mmol). The reaction mixture was heated in microwave at 140° C. for 40 min. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 80% EtOAc) to give the desired product 34 mg 70% yield. MS (ESI) m/z: 502.2.
Reaction SMILES: C[C@@H]([C@@H:9]1[C@@:13]2([CH3:30])[CH2:14][CH2:15][C:16]3[C@@:21]4([CH3:29])[CH2:22][CH2:23][C:24]([C:26]([CH3:28])([CH3:27])[CH:20]4[CH2:19][CH2:18][C:17]=3[C@:12]2([CH3:31])[CH2:11][CH2:10]1)=[O:25])CCC=C(C)C.O=[O+][O-]>C(Cl)Cl>[CH3:28][C:26]1([CH3:27])[CH:20]2[C@@:21]([CH3:29])([C:16]3[CH2:15][CH2:14][C@@:13]4([CH3:30])[C@:12]([CH3:31])([C:17]=3[CH2:18][CH2:19]2)[CH2:11][CH2:10][C@@H:9]4[C@H:21]([CH3:20])[CH2:22][CH2:23][CH:24]=[O:25])[CH2:22][CH2:23][C:24]1=[O:25]
Reactant: CC(C)=CCC[C@@H](C)[C@H]1CC[C@@]2(C)C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C(C)(C)C1CC3
Agent: O=[O+][O-]
Solvent: ClCCl
Product: C[C@H](CCC=O)[C@H]1CC[C@@]2(C)C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C(C)(C)C1CC3
Reaction time: 0.28 h

Procedure:
A solution of lanosterone (4.27 g, 9.11 mmol) in CH2Cl2 (128 mL) was placed in a three-neck round bottom flask equipped with a magnetic stir bar, thermometer, a CaCl2 drying tube and a gas inlet tube. The mixture was stirred and cooled to −50° C., at which point ozone was passed through the mixture for 17 min. The reaction mixture was then purged with argon for 20 min and then concentrated in vacuo to ca. 5 mL. After diluting the crude material with CH2Cl2 (50 mL), the organic phase was then washed twice with water (50 mL) and dried with anhydrous MgSO4. The crude product was concentrated with a rotary evaporator and purified by silica gel chromatography (step gradient of 5:1 then 3:1 hexane/EtOAc) to afford 5 as a white solid (1.578 g, 3.958 mmol, 78% based on an initial purity of 56% for the commercial lanosterol). mp 110-115° C. IR (KBr) νmax 2722, 1725, 1709 cm−1. 1H NMR (CDCl3) δ 9.77 (t, J=1.9 Hz, 1H), 2.57 (ddd, J=7.1, 11.2, 15.7 Hz, 1H), 2.5-2.3 (m, 3H), 2.10-1.18 (m, 19H), 1.11 (s, 3H), 1.09 (s, 3H), 1.06 (s, 3H), 0.90 (d, J=6.3 Hz, 3H), 0.89 (s, 3H), 0.71 (s, 3H). 13C{1H} 6 (CDCl3) δ 217.8, 203.2, 135.2, 133.2, 51.2, 50.3, 49.9, 47.4, 44.5, 41.1, 36.9, 36.1, 36.0, 34.6, 30.90, 30.87, 28.2, 28.11, 26.33, 26.2, 24.3, 21.3, 21.1, 19.4, 18.7, 18.4, 15.9. HRMS calcd for C27H43O2 (M+H)+399.3258. found 399.3258.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[CH3:8].N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].O>O1CCCC1>[CH3:7][C:4]1[C:3]([CH3:8])=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])[O:6][N:5]=1
Reactant: Cc1noc(N)c1C
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Yield: 62.8 %

Procedure:
To a solution of 5-amino-3,4-dimethylisoxazole (1.00 g, 8.92 mmol) and pyridine (0.873 ml, 10.7 mmol) in tetrahydrofuran (30 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.48 ml, 10.7 mmol), and the mixture was stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 1.61 g (62.9%) of the desired product as an oil.
Reaction SMILES: C(OC([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:35]=[CH:34][C:33]4[C:32]5[C:27](=[CH:28][C:29]([Br:36])=[CH:30][CH:31]=5)[C:26]([F:38])([F:37])[C:25]=4[CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.Br.CCN(C(C)C)C(C)C.[CH3:49][O:50][C:51]([NH:53][CH:54]([CH:58]([CH3:60])[CH3:59])[C:55](O)=[O:56])=[O:52].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CC(O)=O.CN(C=O)C.CCOC(C)=O>[CH3:49][O:50][C:51](=[O:52])[NH:53][CH:54]([C:55]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:35]=[CH:34][C:33]4[C:32]5[C:27](=[CH:28][C:29]([Br:36])=[CH:30][CH:31]=5)[C:26]([F:37])([F:38])[C:25]=4[CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:14][CH2:15]2)[CH2:12]1)=[O:56])[CH:58]([CH3:60])[CH3:59]
Reactant: O=C(OCc1ccccc1)N1CC2(CC2)CC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(Br)ccc2-3)[nH]1
Reactant: COC(=O)NC(C(=O)O)C(C)C
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(Br)ccc2-3)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.1 %

Procedure:
6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester 610 (800 mg, 1.38 mmol) was dissolved in methylene chloride (15 mL) and HBr in AcOH (37%, 2 mL) was added and stirring at room temperature was continued. After 180 minutes, the suspension was diluted with hexanes and the solid was collected via filtration and was washed with hexanes and subjected to vacuum. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (4.0 mL) and DIEA (356 mg, 2.76 mmol) was added. A solution of 2-(L)-Methoxycarbonylamino-3-methyl-butyric acid 611 (242 mg, 1.38 mmol), HATU (524 mg, 1.38 mmol) and DIEA (178 mg, 1.38 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 50 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by silica gel chromatography (eluent:EtOAc/hexanes) to yield the slightly impure compound 612 (878 mg). LCMS-ESI+: calc'd for C29H29BrF2N4O3: 599.5 (M+). Found: 598.5/600.5 (M+H+).
Reaction SMILES: Cl.BrC1SC2=NC(N)=CN2C=1.C(OC(N[C@@H](C1C=CC=CC=1)C(N1CCC[C@H]1C(O)=O)=O)=O)(C)(C)C.[C:37]([O:41][C:42](=[O:70])[NH:43][C@@H:44]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@@H:48]1[C:52](=[O:63])[NH:53][C:54]1[N:55]=[C:56]2[N:60]([CH:61]=1)[CH:59]=[C:58]([Br:62])[S:57]2)=[O:46])([CH3:40])([CH3:39])[CH3:38]>>[C:37]([O:41][C:42](=[O:70])[NH:43][C@@H:44]([C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1)[C:45]([N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52](=[O:63])[NH:53][C:54]1[N:55]=[C:56]2[N:60]([CH:61]=1)[CH:59]=[C:58]([Br:62])[S:57]2)=[O:46])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Agent: Cl
Agent: Nc1cn2cc(Br)sc2n1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 23 was synthesized from compound 11 (0.471 mmol) and compound 22 (0.707 mmol), following the procedure as described for compound 12a. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate before washing sequentially with Na2CO3, HCl (0.5N), and brine. The organic layers were dried, filtered, and concentrated under reduced pressure. The crude was purified by chromatography on a silica gel column to give compound 23 as a yellow solid in 45% yield. MS (ESI, EI+) m/z=548.07-550.02 (MH+).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:2].ClCC=CC1C=CC=CC=1.C(N(CC)CC)C.[F:28][C:29]([F:48])([C:33]([F:47])([F:46])[C:34]([F:45])([F:44])[C:35]([F:43])([F:42])[C:36]([F:41])([F:40])[CH:37]([F:39])[F:38])[C:30](Cl)=[O:31]>C(C1C=CC=C(C(C)(C)C)C=1O)(C)(C)C.C(#N)C>[CH:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:30](=[O:31])[C:29]([F:28])([F:48])[C:33]([F:46])([F:47])[C:34]([F:44])([F:45])[C:35]([F:42])([F:43])[C:36]([F:40])([F:41])[CH:37]([F:38])[F:39])=[CH2:2]
Reactant: C=CNCc1ccccc1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: ClCC=Cc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CN(Cc1ccccc1)C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 0 °C
Yield: 65.1 %

Procedure:
300 ml of acetonitrile, 33.9 g (0.3 mol) of vinylbenzylamine (synthesized by the method described in "Kobunshi Gakkai Yokoshu", vol. 26, page 834 (G3 C-07) (1977) from chloromethylstyrene (meta:para=about 6:4); p.b.: 82° C./1.5 mm Hg), 30.3 g (0.3 mol) of triethylamine, and 0.5 g of 2,6-di-t-butylphenol were charged into a 500-ml three-necked flask equipped with a stirrer, and a calcium chloride tube, and the mixture was then cooled with ice water. 109.5 g (0.3 mol) of the 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-n-heptanoic acid chloride synthesized in Synthesis Example 1 was added dropwise, with stirring and ice-cooling. Next, the mixture was stirred for 1 hour at room temperature, and the deposited triethylamine hydrochloride was filtered off. The filtrate was distilled under reduced pressure to remove the acetonitrile, 200 ml of ethyl acetate was added to the remainder to be dissolved, and white insolubles were filtered off. The filtrate was distilled under reduced pressure to be condensed, and 300 ml of n-hexane was added to the remainder, followed by cooling. The deposited white crystals were filtered and dried in vacuo at room temperature, thus producing 90.1 g (yield: 65.2%; m.p.: 53° to 57° C.) of 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-n-heptanoic acid vinylbenzylamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([N+:25]([O-])=O)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.ClCCl>C1COCC1.C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH2:25])=[CH:17][N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncc([N+](=O)[O-])c3ccccc23)CC1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncc(N)c3ccccc23)CC1
Yield: 98.4 %

Procedure:
To a slurry of 4-(4-nitro-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (33.5 g, 89.7 mmol) in THF (300 mL) and ethanol (300 mL) add 10% Pd/C (1.80 g, 1.69 mmol) as a slurry in ethanol (25 mL). Place the mixture in a Parr shaker under hydrogen atmosphere (25-40 psi) at room temperature for 8 hours. Filter the mixture through a pad of diatomaceous earth and wash with ethanol until the filtrate is colorless. Concentrate the filtrate under reduced pressure to give dark oil. Subject residue to silica gel chromatography eluting with 1% then 2.5% MeOH/dichloromethane to afford the title compound (30.3 g, 98% yield) as an orange glass. (ES+): m/z 344 (M++H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]([C:10](=[O:12])[NH2:11])=[N:5]1.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>COCCO>[F:14][C:2]([F:1])([F:13])[CH2:3][N:4]1[C:8](=[O:9])[C:7](=[CH:20][C:19]2[CH:22]=[CH:23][C:16]([OH:15])=[CH:17][CH:18]=2)[C:6]([C:10](=[O:12])[NH2:11])=[N:5]1
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)C1=NN(CC(F)(F)F)C(=O)C1
Solvent: COCCO
Product: NC(=O)C1=NN(CC(F)(F)F)C(=O)C1=Cc1ccc(O)cc1

Procedure:
0.1 mole of 1-trifluoroethyl-3-carbamoyl-2-pyrazolin-5-one and 0.1 mole of p-hydroxybenzaldehyde were stirred for 1 hour in 150 ml of boiling ethylene glycol monomethyl ether. The solvent was distilled off under reduced pressure and the yellow dye was crystallized from methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:28]1([CH2:34][CH2:35][NH2:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1.CN(C=O)C>[N:28]1([CH2:34][CH2:35][NH:36][C:24]([C:23]2[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=2/[CH:18]=[C:10]2\[C:11](=[O:17])[NH:12][C:13]3[C:9]\2=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=3)=[O:25])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Reactant: NCCN1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCCN2CCCCC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Yield: 69.5 %

Procedure:
2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (90.5 mg) was coupled with 2-piperidin-1-yl-ethylamine (48 mg, 1.5 eq.), HOBt (1 eq.), EDC (1.5 eq.) and TEA (3 drops) in THF (2 mL), DMF (0.3 mL) at rt for overnight to give 82 mg (70%) of the titled compound as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[NH:18][C:17](=[O:24])/[C:16]/2=[CH:25]\[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([OH:35])[CH:29]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19](=[O:23])[NH:18][C:17](=[O:24])/[C:16]/2=[CH:25]\[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][CH2:3][CH2:4][CH3:5])=[C:30]([OH:35])[CH:29]=1
Reactant: CCCCBr
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Temperature: 25 °C
Yield: 37.1 %

Procedure:
To a solution of 1-bromobutane (30.4 μl, 0.28 mmol) and tetrabutylammonium iodide (104 mg, 0.283 mmol) in anhydrous N,N-dimethylformamide (2 ML) is added potassium carbonate (207 mg, 1.5 mmol). The mixture stirred at room temperature and (4Z)-6-bromo-4-{[(3,4-dihydroxybenzyl)amino]methylene} isoquinoline-1,3(2H,4H)-dione (100 mg, 0.26 mmol) is added. After the mixture is stirred at 65° C. for 30 min, the resulting mixture is concentrated and the residue is then partitioned between water (20 ml) and ethyl acetate (20 ml). The organic layer is then dried and purified by high performance liquid chromatography to give 43 mg of a white solid. MS (ESI) m/z 444.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13]([O:15][C:16](=[O:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:35])[CH2:17][C:18]1[CH:19]=[C:20]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[CH:4]=[O:5])[C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH3:14]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Br
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc([N+](=O)[O-])cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-bromo-5-nitro-benzaldehyde and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[CH:56][CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42](B2OC(C)(C)C(C)(C)O2)[C:41]([CH3:54])=[N:40]1.C(=O)([O-])[O-].[Na+].[Na+]>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].C1(C)C=CC=CC=1.C(O)C.O>[F:34][C:35]1[CH:36]=[C:37]([CH:55]=[CH:56][CH:57]=1)[CH2:38][N:39]1[C:43]([CH3:44])=[C:42]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:3]=2)[C:41]([CH3:54])=[N:40]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C)CC5)cc4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C)CC5)cc4)cnc32)cc1
Yield: 115.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 3-iodo-5-(4-(4-methylpiperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (intermediate 48) (200 mg, 0.349 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (231 mg, 0.699 mmol) in sodium carbonate (111 mg, 1.048 mmol), PdCl2(dppf) (12.7 mg, 0.017 mmol), Toluene/ethanol/water (20/10/2 ml) to afford 262 mg of the crude titled compound. MS: m/z=649 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])[C:6]=2[CH:18]=1.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](B(O)O)=[CH:30][CH:29]=[N:28]2)=[CH:23][CH:22]=1>>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[N:7]1[C:6]2[CH:18]=[C:2]([C:31]3[N:27]([C:24]4[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:35])[F:36])=[CH:26][CH:25]=4)[N:28]=[CH:29][CH:30]=3)[CH:3]=[CH:4][C:5]=2[N:9]=[CH:8]1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)c(F)c1
Reactant: OB(O)c1ccnn1-c1ccc(C(F)(F)F)cc1
Product: Fc1ccc(-n2cnc3ccc(-c4ccnn4-c4ccc(C(F)(F)F)cc4)cc32)c(F)c1

Procedure:
The title compound, off-white solid (48 mg, 34%), MS (ISP) m/z=441.4 [(M+H)+], mp 129° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(2,4-difluoro-phenyl)-1H-benzo[d]imidazole (intermediate K) (100 mg, 324 μmol) and 1-(4-trifluoromethyl-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate C) (91.1 mg, 356 μmol).