Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:45]=[CH:46][CH:47]=[C:26]([F:25])[CH:27]=4)=[CH:35][CH:34]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4)cc3)c3c(N)ncnc32)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
Into a 100 mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (255 mg, 0.81 mmol, 1.20 equiv), sodium carbonate (143 g, 1.35 mol, 1998.01 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (40 mg, 0.03 mmol, 0.05 equiv). The resulting solution was stirred overnight at 80° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 260 mg (76%) of tert-butyl (3R)-3-[4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [C:1]([C:4](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:5]([O:7][CH:8]([CH3:11])[CH2:9][Cl:10])=[O:6])(=O)[CH3:2].[NH2:22]/[C:23](/[CH3:29])=[CH:24]\[C:25]([O:27][CH3:28])=[O:26]>C(O)(C)C.C(OCC)C>[CH3:29][C:23]1[NH:22][C:1]([CH3:2])=[C:4]([C:5]([O:7][CH:8]([CH3:11])[CH2:9][Cl:10])=[O:6])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:24]=1[C:25]([O:27][CH3:28])=[O:26]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)CCl
Reactant: COC(=O)/C=C(/C)N
Solvent: CCOCC
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)CCl)C1c1cccc([N+](=O)[O-])c1
Reaction time: 3.5 h
Yield: 64.1 %

Procedure:
A solution comprising 18.72 g of 1-methyl-2-chloroethyl α-acetyl-3-nitrocinnamate, prepared as described in Example 1, and 7.12 g of methyl 3-aminocrotonate in 48 ml of isopropanol was refluxed under stirring for 210 minutes. After cooling, the reaction mixture was evaporated to dryness under vacuum and the oil thus obtained was chromatographed on silica gel (200 g) using chloroform as eluent. Evaporating the fractions containing a sole product (TLC, chloroform: ethylacetate 95:5) gave a thick oil, which was dissolved in diethyl ether. The solvent was then evaporated off at 20°-25° C. to give 15.75 g of the title compound, m.p. 95°-102° C., which could be employed without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:21][C@@H:22]([C:24]3[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=3)[OH:23])[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[I-].[K+]>[CH3:36][O:35][C:33](=[O:34])[CH2:32][O:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C@@H:22]([OH:23])[CH2:21][N:19]([C:10]2[CH:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:11]=2)[CH3:20])[CH:25]=1
Reactant: COC(=O)CBr
Reactant: CN(C[C@H](O)c1cccc(O)c1)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccc([C@@H](O)CN(C)c2cnc(-c3ccccc3)c(-c3ccccc3)n2)c1
Yield: 70.5 %

Procedure:
To a solution of 0.66 g of (R)-3-{2-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-1-hydroxyethyl}phenol and 0.28 g of methyl bromoacetate in 10 ml of acetonitrile, 2 mg of potassium iodide and 0.28 g of potassium carbonate were added and the mixture was heated at reflux for 4 hours. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.55 g of the desired compound as a pale orange amorphous.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[S:24])[N:16]([CH2:25][C:26]([O:28]CC)=[O:27])[C:15]1=[O:31].Cl.S(=O)(=O)(O)O>O>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[S:24])[N:16]([CH2:25][C:26]([OH:28])=[O:27])[C:15]1=[O:31]
Reactant: CCOC(=O)Cn1c(=S)c2ccccc2n(Cc2ccc(Cl)cc2Cl)c1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cn1c(=S)c2ccccc2n(Cc2ccc(Cl)cc2Cl)c1=O
Yield: 64.3 %

Procedure:
Into 10 ml of acetic acid were dissolved 500 mg of ethyl 1-(2,4-dichlorophenyl)methyl-1,4-dihydro-2-oxo-4-thioxo-3(2H)-quinazolineacetate, and, after added 3 ml of concentrated hydrochloric acid and then 0.5 ml of concentrated sulfuric acid, the mixture was refluxed for 1 hour. After cooling by allowing to stand, the reaction mixture was poured into 200 ml of water and the deposits were collected by filtration. They were recrystallized from acetic acid to obtain 300 mg of title compound. m.p. 220°-221° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].[CH2:6](Cl)/[CH:7]=[C:8](/[CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:19])[CH3:14])\[CH3:9]>CN(C)C=O.C(OCC)(=O)C>[CH2:6]([S:5][CH2:3][CH3:4])/[CH:7]=[C:8](/[CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH3:19])[CH3:14])\[CH3:9]
Reactant: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCSC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
0.84 g of sodium hydride was added to a solution of 2.40 g of ethylmercaptan dissolved in 30 ml of N,N-dimethylformamide. Thereinto was dropped 10.00 g of phytyl chloride at 40° C. The resulting mixture was stirred at the same temperature for 3 hours. After the completion of the reaction, the resulting mixture was concentrated under reduced pressure. The residue obtained was dissolved in 30 ml of ethyl acetate. The resulting solution was washed with 1N hydrochloric acid, 3% aqueous sodium hydrogencarbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: n-hexane:ethyl acetate=9:1) to obtain 10.00 g (yield: 92%) of oily ethyl phytyl thioether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][O:20][CH:21]2[CH2:25][CH2:24][NH:23][CH2:22]2)[CH2:14][CH2:13]1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:23]2[CH2:24][CH2:25][CH:21]([O:20][CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][O:12][CH2:17][CH2:16]3)[CH2:22]2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: C1CC(OCCN2CCOCC2)CN1
Solvent: c1ccccc1
Product: COc1ccc(NC(=O)N2CCC(OCCN3CCOCC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under anhydrous conditions 2.2 g. p-methoxyphenyl isocyanate in 10 ml. of reagent grade benzene was added dropwise to a stirring solution of 3.0 g. (0.15 mole) of 3-(2-morpholinoethoxy) pyrrolidine in 40 ml. of reagent grade benzene. After the addition was complete the reaction mixture was stirred overnight at room temperature and then concentrated at reduced pressure to give the theoretical yield of crude product, which would not crystallize nor form addition salts. The crude product was chromatographed on a column of magnesium silicate to give 1.4 g. of oily product. The nuclear magnetic resonance spectrum and mass spectrum analysis agreed with the proposed structure.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][C:20]([F:24])=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH2:25]([NH:27][NH2:28])[CH3:26].CC(O)C>O>[CH2:25]([N:27]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([F:24])[CH:21]=2)[C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[N:28]1)[CH3:26]
Reactant: CCNN
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ncc(F)cc1F
Solvent: O
Solvent: CC(C)O
Product: CCn1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
A mixture of [4-(benzyloxy)phenyl](3,5-difluoropyridin-2-yl)methanone (400 mg), ethylhydrazine (369 mg) and 2-propanol (5 mL) was stirred at room temperature for 30 min, and at 90° C. for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in EtOH (40 mL) and 10% Pd—C (50% wet, 400 mg) was added. The mixture was stirred at room temperature for 1 h under H2 atmosphere, filtered and evaporated. The residue was suspended in AcOEt/IPE and collected by filtration to give the title compound (220 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[C:3]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:7][CH:8]=2)[C:3]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)Nc1c(Br)ccc2ccc(O)cc12
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1c(Br)ccc2ccc(O[Si](C)(C)C(C)(C)C)cc12
Reaction time: 18 h

Procedure:
2-Bromo-1-(tert-butoxycarbonylamino)-7-hydroxynaphthalene, as described above in Step F, (4.80 g, 14.19 mmol), tert-butyldimethylsilyl chloride (2.8 g, 18.45 mmol) and imidazole (2.2 g, 32.64 mmol) were dissolved in DMF (25 mL) and stirred for 18 hours. The mixture was poured into H2O and extracted with Et2O (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel, eluting with CH2Cl2—50% hexanes, to yield the above-titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([N:13]([CH3:34])[CH2:14][CH2:15][CH2:16][N:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:12])=[CH:5][CH:4]=1)#[N:2].[S].[CH2:36](N)[CH2:37][NH2:38]>>[NH:2]1[CH2:36][CH2:37][N:38]=[C:1]1[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([N:13]([CH3:34])[CH2:14][CH2:15][CH2:16][N:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])=[O:12])=[CH:7][CH:8]=1
Reactant: NCCN
Reactant: Cc1ccc(S(=O)(=O)N(CCCN(C)C(=O)CCc2ccc(C#N)cc2)c2ccccc2)cc1
Agent: [S]
Product: Cc1ccc(S(=O)(=O)N(CCCN(C)C(=O)CCc2ccc(C3=NCCN3)cc2)c2ccccc2)cc1

Procedure:
Analogously to 13b), 3-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methyl-N-{3-[phenyl(toluene-4-sulphonyl)amino]propyl}propionamide was prepared from 1.82 g (3.83 mmol) of 3-(4-cyanophenyl)-N-methyl-N-{3-[phenyl(toluene-4-sulphonyl)amino]propyl}propionamide, 122 mg (3.83 mmol) of sulphur and 7 ml of ethylenediamine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1>>[O:9]1[CH2:10][CH:11]=[C:12]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:14]1
Reactant: O=C1CCOCC1
Reactant: C#Cc1ccccn1
Product: C(#Cc1ccccn1)C1=CCOCC1

Procedure:
Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), tetrahydro-4H-pyran-4-one (6.0 mmol, 600 mg); yields 2-(3,6-dihydro-2H-pyran-4-ylethynyl)pyridine as a transparent oil (200 mg, 18% overall yield). 1H NMR (CDCl3, 300 MHz) Δ8.57 (m, 1H), 7.63 (m, 1H), 7.44 (m, 1H), 7.21 (m, 1H), 6.29 (m, 1H), 4.25 (m, 2H) 3.81 (m, 2H), 2.36 (m, 2H). MS (EI ionization) 185 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[Br:11]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[CH2:8][C:9]#[N:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CCc1ccccc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCc1cc(Br)ccc1N
Temperature: 0 °C
Yield: 53.2 %

Procedure:
To a cooled solution of (2-aminophenyl)acetonitrile (13 g, 98 mmol) in dimethylformamide (150 mL) at 0° C., was added N-bromosuccinimide (19.3 g, 108 mmol) in portions for 30 minutes and maintained at 0° C. for 1 hour. The mixture was diluted with ethyl acetate (300 mL) and washed with water (3×100 mL) and saturated sodium chloride (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained crude product was purified by column chromatography (100-200 mesh silica gel) using 10% ethyl acetate in petroleum ether as eluent to afford (2-amino-5-bromophenyl)acetonitrile (11 g, 53%) as solid. 1HNMR (CDCl3) δ 7.35 (s, 1H), 7.25 (d, 1H), 6.65 (d, 1H), 3.7 (br, 2H), 3.52 (s, 2H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)N.[CH2:12]1[CH2:19][C:17](=O)[C:15](=[O:16])[CH2:14][CH2:13]1>CO.CC(O)=O.Cl>[O:16]=[C:15]1[C:14]2[NH:2][C:4]3[C:11](=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=3)[C:13]=2[CH2:12][CH2:19][CH2:17]1
Reactant: N#Cc1ccc(NN)cc1
Reactant: O=C1CCCCC1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc2[nH]c3c(c2c1)CCCC3=O
Temperature: 60 °C
Reaction time: 12 h
Yield: 89.2 %

Procedure:
4-Hydrazinylbenzonitrile hydrochloride (3 g, 17.6 mmol) dissolved in MeOH (30 mL), was heated to 60° C., and 1,2-cyclo hexadione (1.98 g, 17.6 mmol) in AcOH (30 mL) and HCl (12 mL) were added while maintaining the temperature at 60° C. The reaction mixture was stirred at 60° C. for 12 h and then cooled to room temperature. The volatiles were removed in vacuo and the residue was diluted with water, neutralized with saturated NaHCO3 solution and extracted with EtOAc (2×40 mL). The combined organic extracts were concentrated under reduced pressure to give the crude product which was purified by silica gel chromatography [EtOAc-hexane (1:3) as eluant] to provide the title compound (3.3 g, 89%). 1H NMR (200 MHz, CDCl3, δ in ppm) 8.80 (bs, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.45 (dd, J=12.0, 2.0 Hz, 1H), 7.30 (d, J=12.5 Hz, 1H), 2.90 (t, J=9.0 Hz, 2H), 2.62 (t, J=9.0 Hz, 2H), 2.25 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[C:32]([CH:41]=O)[CH:31]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[C:32]([CH2:41][NH:17][CH2:16][CH2:15][N:12]4[CH2:13][CH2:14][N:9]([C:3]5[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=5[CH3:1])[CH2:10][CH2:11]4)[CH:31]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Reactant: O=Cc1cc(-c2ccc(C3CCCCC3)cc2)n(-c2ccccc2)n1
Product: Cc1ccc(N2CCN(CCNCc3cc(-c4ccc(C5CCCCC5)cc4)n(-c4ccccc4)n3)CC2)c(C)c1
Yield: 52.8 %

Procedure:
Compound 34 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 5-(4-cyclohexyl phenyl)-1-phenyl pyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1.[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[CH:14]=[CH:15][C:16]=1[NH2:17]
Reactant: [H][H]
Reactant: COc1cc(OC2CCN(C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(OC2CCN(C)CC2)ccc1N
Reaction time: 8 h

Procedure:
To a solution of 4-(3-Methoxy-4-nitro-phenoxy)-1-methyl-piperidine (3.0 g, 11.3 mmol) in ethanol (50 mL), 5% palladium on carbon (300 mg) is added under a nitrogen atmosphere. The reaction vessel is fitted with a balloon adapter and charged with hydrogen and evacuated three times until the reaction is under a hydrogen atmosphere. The reaction is allowed to stir overnight. The reaction mixture is filtered through a pad of Celite and washed with methanol. The filtrate is concentrated in vacuo to afford 2-Methoxy-4-(1-methyl-piperidin-4-yloxy)-phenylamine in quantitative yield (2.7 g).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:27]=[CH:26][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH:19]6[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]6)[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:33]=[N:32]1
Reactant: CN1CCC(n2ncnc2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)CC1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CN1CCC(n2ncnc2-c2nc3c(s2)CCOc2cc(-c4cnn(CC(C)(C)O)c4)ccc2-3)CC1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(1-methyl-piperidin-4-yl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 380. MS (ESI+) 506.2. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.44 (dd, J=8.3, 1.8, 1H), 7.32 (d, J=1.7, 1H), 5.47-5.35 (m, 1H), 4.72 (s, 1H), 4.39 (t, J=4.9, 2H), 4.04 (s, 2H), 3.45 (t, J=5.0, 2H), 3.05-2.95 (m, 2H), 2.28 (s, 3H), 2.22-1.98 (m, 6H), 1.10 (s, 6H)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[S:15]1[CH:19]=[C:18]([C:20]2[C:29]3[N:28]=[CH:27][CH:26]=[N:25][C:24]=3[C:23]([C:30](O)=[O:31])=[CH:22][CH:21]=2)[C:17]2[CH:33]=[CH:34][CH:35]=[CH:36][C:16]1=2>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:30]([C:23]3[C:24]4[N:25]=[CH:26][CH:27]=[N:28][C:29]=4[C:20]([C:18]4[C:17]5[CH:33]=[CH:34][CH:35]=[CH:36][C:16]=5[S:15][CH:19]=4)=[CH:21][CH:22]=3)=[O:31])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: O=C(O)c1ccc(-c2csc3ccccc23)c2nccnc12
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ccc(NC(=O)c3ccc(-c4csc5ccccc45)c4nccnc34)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 20 h at rt, using 6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described in Example 33 but using N-methyl-piperazine in Step 33.2) and 8-benzo[b]thiophen-3-yl-quinoxaline-5-carboxylic acid (Example 59). Title compound: ESI-MS: 481.0 [M+H]+; tR=3.81 min (System 1); TLC: Rf=0.40 (DCM/MeOH, 9:1).
Reaction SMILES: [Al](C)(C)C.C(O[C:8]([C:10]1[C:15]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=1)=[O:9])C.[C:24]([SiH2:28][O:29][C:30]([CH3:38])([CH3:37])[C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([SiH2:28][O:29][C:30]([CH3:38])([CH3:37])[C:31]1[N:32]=[C:33]([NH:36][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:22]=[N:21][CH:20]=[N:19][CH:18]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:34][CH:35]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cncnc1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1csc(N)n1
Agent: C[Al](C)C
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2nc(C(C)(C)O[SiH2]C(C)(C)C)cs2)n1

Procedure:
The Al(Me)3-catalyzed reaction of 6-Methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester and 4-(tert-Butyl-dimethyl-silanyloxymethyl)-thiazol-2-ylamine (CAS [752241-92-2]; WO2004076420) in accordance with the general method of Example 78, step 2 yielded the title compound as an off-white solid, MS (ISP): m/e=457.3 (M+H+).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.BrC1C=C2C(=CC=1)C(C)(C)C[CH:37]=[C:36]2[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:51]([CH3:54])([CH3:53])[CH3:52]>>[C:51]([C:46]1[CH:47]=[CH:48][C:49]([C:36]2[C:45]3[CH:50]=[C:49](/[C:27](/[Si:28]([CH3:29])([CH3:30])[CH3:31])=[CH:26]/[C:23]4[CH:22]=[CH:21][C:20]([CH2:19][OH:18])=[CH:25][CH:24]=4)[CH:48]=[CH:47][C:46]=3[C:51]([CH3:53])([CH3:52])[CH2:54][CH:37]=2)=[CH:50][CH:45]=1)([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)[Si](OCc1ccc(C#C[Si](C)(C)C)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1ccccc1C1=CCC(C)(C)c2ccc(Br)cc21
Product: CC(C)(C)c1ccc(C2=CCC(C)(C)c3ccc(/C(=C/c4ccc(CO)cc4)[Si](C)(C)C)cc32)cc1

Procedure:
Following General Procedure A, 4-[(trimethylsilyl)ethynyl]benzyl tert-butyldiphenylsilyl ether and 6-bromo-4-(tert-butylphenyl)-1,1-dimethyl-1,2-dihydronaphthalene (which can be prepared by the procedure described in Klein, et al., U.S. Pat. No. 5,952,345) were coupled to give the title compound (Compound 29). PNMR (300 MHz, CDCl3): δ0.0 (s, 9 H), 1.48 (s, 6 H), 1.51 (s, 9 H), 2.49 (d, J=4.8 Hz, 2 H), 4.82 (d, J=4.8 Hz, 2 H), 6.13 (t, J=4.8 Hz, 1 H), 7.00 (d, J=1.7 Hz, 1 H), 7.22 (dd, J=1.7, 7.9 Hz, 1 H), 7.30-7.50 (m, 8 H), 7.55 (d, J=8.8 Hz, H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:21]1[CH2:25][CH2:24][N:23]([C@@H:26]([CH3:35])[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[C:22]1=[O:36])[CH2:16][C:17]([O:19]C)=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[OH-].[Li+].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:21]1[CH2:25][CH2:24][N:23]([C@@H:26]([CH3:35])[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:28])[C:22]1=[O:36])[CH2:16][C:17]([OH:19])=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: COC(=O)CN([C@H]1CCN([C@@H](C)C(=O)N2CCOCC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N(CC(=O)O)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Yield: 61.6 %

Procedure:
To a solution of methyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate (0.010 g) in THF (2 ml) was added lithium hydroxide (0.003 g) in water (2 ml), and the resultant solution stirred for 16 h. The mixture was acidified to pH5 using hydrochloric acid (2N), and then concentrated under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.006 g) as a white solid.