Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15](OC)=[O:16])[C:12]([CH2:19][CH3:20])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([CH:15]=[O:16])[C:12]([CH2:19][CH3:20])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-n2cc(C(=O)OC)c(CC)n2)c1
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1cccc(-n2cc(C=O)c(CC)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A solution (15 mL) of methyl 1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazole-4-carboxylate (4.4 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (35 mL) of lithium aluminum hydride (0.61 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr, the mixture was ice-cooled again, and water (1.6 mL), 1N aqueous sodium hydroxide solution (8.0 mL) and water (1.6 mL) were successively added dropwise to quench the reaction. The residue was filtered through celite, and the filtrate was concentrated under reduced pressure to give a crude product (3.5 g) of 1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazole-4-methanol as a pale-yellow oil. This was dissolved in toluene (100 mL), manganese dioxide (4.0 g) was added, and the mixture was heated under reflux with a Dean-Stark trap for 1 hr. The reaction mixture was allowed to cool to room temperature, manganese dioxide was collected by filtration, and the solvent was evaporated under reduced pressure to give the title object compound (3.4 g, 87%) as a yellow solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38]([N:45]1[CH2:50][CH2:49][O:48][CH:47]([CH2:51]Cl)[CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:38]([N:45]1[CH2:50][CH2:49][O:48][CH:47]([CH2:51][N:19]2[C:20]3[C:25](=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[CH:22][CH:21]=3)[C:17]([C:14]3[N:15]=[C:16]4[C:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:9][N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:11]4=[N:12][CH:13]=3)=[N:18]2)[CH2:46]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(Cc5ccccc5)CCO4)c4ccc(OC(F)F)cc34)nc12
Yield: 49.5 %

Procedure:
N-tert-Butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (100 mg, 188 μmol), 4-benzyl-2-(chloromethyl)morpholine (51.0 mg, 226 μmol) and cesium carbonate (184 mg, 565 mmol) in dimethylformamide (1.4 mL) were heated in a microwave at 100° C. for 45 min. The mixture was cooled, partitioned between ethyl acetate and water, and the organic phases combined and washed with water 3 times. The organic phase was dried and concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-40% ethyl acetate in hexanes) gave 2-(1-((4-benzylmorpholin-2-yl)methyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (67 mg, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25]Br)=[N:23][N:24]=2)[CH:3]=1.[CH3:27][C@@H:28]1[CH2:33][NH:32][CH2:31][C@H:30]([CH3:34])[N:29]1[CH:35]([CH3:37])[CH3:36].CCN(C(C)C)C(C)C.[I-].[Na+]>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:32]3[CH2:31][C@H:30]([CH3:34])[N:29]([CH:35]([CH3:37])[CH3:36])[C@H:28]([CH3:27])[CH2:33]3)=[N:23][N:24]=2)[CH:3]=1
Reactant: CC(C)N1[C@H](C)CNC[C@@H]1C
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CBr)o3)cc(Br)cc21
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N1[C@H](C)CN(Cc2nnc(-c3cc(Br)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@@H]1C
Temperature: 70 °C

Procedure:
6-Bromo-4-[5-(bromomethyl)-1,3,4-oxadiazol-2-yl]-1-(phenylsulfonyl)-1H-indazole (200 mg, 0.441 mmol) in acetonitrile (2 ml) was treated with (2R,6S)-2,6-dimethyl-1-(1-methylethyl)piperazine (138 mg, 0.883 mmol, see J. Med. Chem., 1999, 42, 1123-1144 for literature preparation), DIPEA (0.154 ml, 0.8825 mmol) and sodium iodide (66 mg, 0.44 mmol). The reaction mixture was heated at 70° C. for 5 h. The reaction mixture was then cooled, diluted with DCM and washed with an aqueous 2M HCl solution (5 ml). The organic layer was separated using a hydrophobic frit, washed with water and the solvent removed under a stream of nitrogen to give the title compound as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:17]([CH2:18][C:19]3[O:20][C:21]([C:24](OCC)=[O:25])=[CH:22][CH:23]=3)[C:16]3[CH:29]=[CH:30][CH:31]=[CH:32][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:17]([CH2:18][C:19]3[O:20][C:21]([CH2:24][OH:25])=[CH:22][CH:23]=3)[C:16]3[CH:29]=[CH:30][CH:31]=[CH:32][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(Cn2c(N3CCCN(C(=O)OCC)CC3)nc3ccccc32)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCCN(c2nc3ccccc3n2Cc2ccc(CO)o2)CC1
Reaction time: 12 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (5 mmol) and lithium aluminum hydride (5 mmol) in tetrahydrofuran. Heat to reflux. After 12 hour, cool and carefully quench the reaction mixture with 10% aqueous ammonium chloride solution. Extract the reaction mixture with ethyl acetate. Dry the the organic layer over Na2SO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH2:9]([C:13]1([CH2:16][CH3:17])[CH2:15][NH:14]1)[CH2:10][CH2:11][CH3:12]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:15][C:13]([CH2:16][CH3:17])([NH2:14])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC1(CC)CN1
Reactant: Sc1ccccc1Br
Solvent: CO
Product: CCCCC(N)(CC)CSc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.4 %

Procedure:
To a solution of 2-bromothiophenol (13.5 g, Lancaster) in methanol (45 ml) was added dropwise 2-butyl-2-ethylaziridine (10.0 g, Synthetic Example 1(f)). The mixture was stirred at room temperature for 1 hour. Solvent was evaporated to afford the title product as a light yellow oil (25.6 g). 1H NMR consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([OH:9])[N:4]=1.[N:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N12CCN(CC1)CC2.O>CN(C)C=O.[Cl-].[Na+].O>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:18]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:19])[N:4]=1
Reactant: Oc1nccc(C(F)(F)F)n1
Reactant: O=C(Cl)N1CCOCC1
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1nccc(C(F)(F)F)n1)N1CCOCC1
Yield: 79.4 %

Procedure:
A solution of 4-trifluoromethyl-2-hydroxypyrimidine (0.49 g, 3.00 mmol), 4-morpholinecarbonyl chloride (0.45 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water and brine were added and the solution was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70→50:50)) yielding the title compound (0.66 g, 80% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[C:25]([CH:26]=O)=[CH:24][N:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:22]=2)=[CH:17][CH:16]=1.[CH2:36]([P:45](=[O:52])([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[C:25](/[CH:26]=[CH:36]/[P:45](=[O:52])([O:46][CH2:47][CH3:48])[O:49][CH2:50][CH3:51])=[CH:24][N:23]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:22]=2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)OCC
Reaction time: 15 h
Yield: 66 %

Procedure:
To a mixture of 3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.60 g), tetraethyl methylenediphosphonate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.51 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 109-110° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=[O:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]=[CH:6][C:5]3=[O:12])=[O:22])=[CH:16][CH:15]=1
Reactant: Nc1ccc2occc(=O)c2c1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc2occc(=O)c2c1
Yield: 99.1 %

Procedure:
To the slurry of 6-aminochromone (3.0 g, 18.6 mmol) stirred and heated to 80° C. in toluene (200 mL) was added 4-chlorophenyl isocyanate (3.2 g, 20.5 mmol) and the mixture was refluxed for 18 hrs. The reaction mixture was cooled and the precipitate was filtered and washed with methanol. The residue was dried in vacuo to afford a yellow powder (5.8 g, 99%) of 1-(4-chloro-phenyl)-3-(4-oxo-4H-chromen-6-yl)-urea. LCMS m/z (%)=315 (M+H, 35Cl 100), 317 (M+H37Cl 32.2) 1H NMR (400 MHz, DMSO-d6) δ: 9.098 (bs, 1H), 8.94 (bs, 1H), 8.28-8.30 (d, J=5.99 Hz, 1H), 8.20-8.21 (d, J=2.69 Hz, 1H), 7.81-7.84 (dd, J=9.0, 2.75 Hz, 1H), 7.62-7.64 (d, J=9.07 Hz, 1H), 7.52-7.55 (dd, J=6.84, 2.16 Hz, 2H), 7.35-7.37 (dd, J=6.85, 2.11 Hz, 2H), 6.33-6.34 (d, J=5.98 Hz, 1H).
Reaction SMILES: C(S([O:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:39])([CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@H:20]([CH2:24][O:25][C:26]3[C:35]4[C:34]([NH2:36])=[N:33][S:32](=[O:38])(=[O:37])[NH:31][C:30]=4[CH:29]=[CH:28][CH:27]=3)[CH2:19]2)=[O:17])[CH3:14])[CH:10]=[CH:9][C:8]=1[O:40][CH3:41])(=O)=O)C.[OH-].[Na+].Cl>CCO>[NH2:36][C:34]1[C:35]2[C:26]([O:25][CH2:24][C@H:20]3[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][C:13]([C:11]4[CH:10]=[CH:9][C:8]([O:40][CH3:41])=[C:7]([OH:6])[CH:12]=4)([CH3:39])[CH3:14])[CH2:19]3)=[CH:27][CH:28]=[CH:29][C:30]=2[NH:31][S:32](=[O:38])(=[O:37])[N:33]=1
Reactant: CCS(=O)(=O)Oc1cc(C(C)(C)CC(=O)N2CCC[C@H](COc3cccc4c3C(N)=NS(=O)(=O)N4)C2)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(C)(C)CC(=O)N2CCC[C@H](COc3cccc4c3C(N)=NS(=O)(=O)N4)C2)cc1O
Temperature: 85 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
To a solution of (S)-5-(4-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-2-methyl-4-oxobutan-2-yl)-2-methoxyphenyl methanesulfonate (200 mg, 0.34 mmol) (Example 50) in EtOH (20 mL) was added 2N aqueous NaOH (0.34 mL). The reaction mixture was stirred at 85° C. for 3 hours, cooled to 0° C. and neutralized 2N HCl. The solution was concentrated under reduced pressure and purified by preparative HPLC (10-90% acetonitrile in water) to give the title compound (78 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 1.17-1.32 (m, 8H), 1.43-1.64 (m, 2H), 1.74-1.8 (m, 1H), 2.52-2.67 (m, 2H), 2.77-2.83 (m, 0.5H), 3.51-3.54 (m, 0.5H), 3.65-3.68 (m, 4H), 3.73-3.84 (m, 2H), 4.1-4.18 (m, 1H), 5.9-5.94 (m, 1H), 6.15-6.19 (m, 1H), 6.5 (brs, 1H), 6.66-6.78 (m, 3H), 6.89-6.95 (m, 1H), 8.71 (s, 1H). MS 517 (MH+).
Reaction SMILES: I[C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH:32]=[C:31]([S:36]([O-:38])=[O:37])[CH:30]=[CH:29]3)=[CH:22][CH:21]=1.[Na+]>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH:32]=[C:31]([S:36]([C:2]2[C:10]4[N:9]=[CH:8][N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=4[CH:5]=[CH:4][CH:3]=2)(=[O:38])=[O:37])[CH:30]=[CH:29]3)=[CH:22][CH:21]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: C[Si](C)(C)CCOCn1cnc2c(I)cccc21
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cnc2c(S(=O)(=O)c3ccc4cc(-c5ccc(F)cc5)ccc4c3)cccc21
Yield: 39.7 %

Procedure:
Prepared according to the method of Example 6 Step 4 using 4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.46 g, 1.23 mmol) and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (0.42 g, 1.36 mmol), to give the title compound as a colourless solid (260 mg, 39%). 1H NMR (500 MHz, CDCl3): δ 8.92 (1H, s), 8.21 (1H, dd, J=1.4, 8.6 Hz), 8.16 (1H, d, J=7.7 Hz), 8.07 (2H, d, J=9.9 Hz), 7.96 (1H, s), 7.91 (1H, d, J=8.7 Hz), 7.77 (2H, d, J=7.3 Hz), 7.64 (2H, dd, J=5.3, 8.5 Hz), 7.47 (1H, t, J=7.9 Hz), 7.17 (2H, t, J=8.6 Hz), 5.51 (2H, s), 4.12 (2H, q, J=7.1 Hz), 3.47 (2H, t, J=8.1 Hz), 2.04 (3H, s), 1.26 (3H, t, J=7.1 Hz), 0.86 (2H, t, J=8.1 Hz), −0.08 (9H, s); m/z (ES+) 534 [MH+].
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:14])[N:6]([CH:11]3[CH2:13][CH2:12]3)[N:7]=2)[CH:3]=1.[F:15][C:16]1[CH:30]=[CH:29][C:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][NH:25][C:24](=[O:28])[CH:23]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC.N>CS(C)=O.[Cu]I>[CH:11]1([N:6]2[C:5]([CH3:14])=[C:4]3[C:8]([CH:9]=[CH:10][C:2]([N:25]4[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]5[CH:29]=[CH:30][C:16]([F:15])=[CH:17][CH:18]=5)=[CH:23][C:24]4=[O:28])=[CH:3]3)=[N:7]2)[CH2:13][CH2:12]1
Reactant: Cc1c2cc(Br)ccc2nn1C1CC1
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: Cc1c2cc(-n3ccc(OCc4ccc(F)cc4)cc3=O)ccc2nn1C1CC1
Temperature: 150 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a suspension of 5-bromo-2-cyclopropyl-3-methyl-2H-indazole (2.0 g), 4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one (1.7 g) and potassium carbonate (3.3 g) in DMSO (20 ml) were added copper(I) iodide (1.5 g) and N,N′-dimethylethylenediamine (0.7 g), and the mixture was stirred at 150° C. for 3 hr. The reaction mixture was added to 28% aqueous ammonia, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate to give the title compound (2.17 g).
Reaction SMILES: [CH2:1]([CH:7]([C:12](=[O:33])[CH2:13][CH:14]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)C.[BH4-].[Na+]>C1COCC1>[CH2:1]([CH:7]([CH:12]([OH:33])[CH2:13][CH:14]([O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:8]([O:10][CH3:11])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCC(CC(=O)C(CCCCCC)C(=O)OC)OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(CC(O)C(CCCCCC)C(=O)OC)OC1CCCCO1
Temperature: -5 °C
Yield: 98.9 %

Procedure:
7.76 g of methyl 2-hexyl-3-oxo -5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate are dissolved in 500 ml of THF while gassing with argon, treated with 20 ml of ethanol and cooled to -5° C. 5.3 g of NaBH4 are added portionwise while stirring in such a manner that the temperature does not exceed 0° C. After stirring for 3 hours the excess sodium borohydride is filtered off, the reaction mixture is hydrolyzed (to pH 6) with 2N hydrochloric acid in the cold and the solvent is evaporated off. The residue is extracted with ether and the ethereal phase is dried and evaporated. There are obtained 7.71 g of methyl 2-hexyl-3-hydroxy-5-[(tetrahydro-2H-pyran-2-yl)oxy]hexadecanoate.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-])=[O:15])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[C:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:18])[N:32]([CH2:31][CH2:30][CH2:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: NCCCc1ccccc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(CCCc1ccccc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 3-phenylpropylamine(0.19 mL, 1.4 mmol). Purification using silica gel, eluting with 9:1 CH2Cl2 /acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 114 as a white solid (m.p. 222-223° C.).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Si:16]([CH2:19]Cl)([CH3:18])[CH3:17])=[O:5])[CH3:2].[Na+].[I-:24]>C(#N)C.CCOCC>[CH2:1]([N:3]([CH2:21][CH3:22])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Si:16]([CH2:19][I:24])([CH3:18])[CH3:17])=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)c1c([Si](C)(C)CCl)ccc2ccccc12
Reactant: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CCN(CC)C(=O)c1c([Si](C)(C)CI)ccc2ccccc12
Yield: 98 %

Procedure:
A solution of this naphthalenecarboxamide (1.0 g, 3.0 mmol) and NaI (13.5 g, 90 mmol) in acetonitrile (90 mL) was refluxed overnight, then was diluted with ether and filtered through celite to remove most of the salts. The filtrate was then concentrated and eluted through a plug of silica gel with ethyl acetate. Concentration of the ethyl acetate afforded 1.25 g of the desired compound as a yellow oil, a 98% yield.
Reaction SMILES: NC1C=C(Cl)C(C)=CC=1NC(C1C([N+]([O-])=O)=CNN=1)=O.[NH:21]1[C:32]2[C:24](=[CH:25][C:26]3[CH2:27][CH2:28][CH2:29][C:30]=3[CH:31]=2)[N:23]=[C:22]1[C:33]1[C:37]([NH2:38])=[CH:36][N:35]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[N:34]=1.C(N(CC)CC)C.[CH3:52][N:53]1[CH2:58][CH2:57][N:56]([C:59](Cl)=[O:60])[CH2:55][CH2:54]1.[Cl-].[Na+].O.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[NH:23]1[C:24]2[C:32](=[CH:31][C:30]3[CH2:29][CH2:28][CH2:27][C:26]=3[CH:25]=2)[N:21]=[C:22]1[C:33]1[C:37]([NH:38][C:59]([N:56]2[CH2:57][CH2:58][N:53]([CH3:52])[CH2:54][CH2:55]2)=[O:60])=[CH:36][N:35]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][O:40]2)[N:34]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: Nc1cn(C2CCCCO2)nc1-c1nc2cc3c(cc2[nH]1)CCC3
Agent: Cc1cc(NC(=O)c2n[nH]cc2[N+](=O)[O-])c(N)cc1Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)Nc2cn(C3CCCCO3)nc2-c2nc3cc4c(cc3[nH]2)CCC4)CC1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
By proceeding in a similar manner to Reference Example 48(a) above but (i) treating a solution of 3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine [302 mg, Reference Example 49(d)] and triethylamine (0.94 g, 10 eq) in tetrahydrofuran (10 mL) with 4-methylpiperazine-1-carbonyl chloride (930 mg, 4.67 mmol), (ii) stirring the mixture at 45° C. for 4 hours, then at 55° C. for 1 hour, (iii) treating the cooled reaction mixture with aqueous sodium bicarbonate (200 mL) and extracting this mixture three times with ethyl acetate (100 mL), and (iv) evaporating the combined extracts and chromatographing the residue on silica gel (ethyl acetate/gradient 5-20% methanol) there was prepared 4-methylpiperazine-1-carboxylic acid [3-(1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide (189 mg) as a purple solid. LC-MS (Method F): RT=2.28 minutes, 450 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.C([O-])([O-])=O.[K+].[K+].ClC1C=CC(C2C(C3C=CC(Cl)=CC=3Cl)=CN3C(CC4C=NC(C(F)(F)F)=CC=4)=NN=C3C=2)=CC=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:3]2[C:2]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH3:30])=[CH:7][N:6]3[C:8]([CH2:11][C:12]4[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)=[CH:28][CH:27]=1
Reactant: COc1ccccc1B(O)O
Reactant: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)cn23)cn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1-c1cn2c(Cc3ccc(C(F)(F)F)nc3C)nnc2cc1-c1ccc(Cl)cc1
Yield: 75.7 %

Procedure:
The title compound (7.7 mg, 75%) as a white powder was prepared from 6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.020 mmol), 2-methoxyphenylboronic acid (6.0 mg, 0.039 mmol), K2CO3 (8.2 mg, 0.059 mmol) and Pd(PPh3)4 (2.8mg, 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 56E). LC/MS (method B): retention time=1.87 min, [M+H]+=509.3.