Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH:17][C:18]([NH2:20])=[O:19])[CH2:14][CH2:15][CH3:16].[N+:21](NC1C=CC=CC=1)([O-])=[O:22].Cl>CO>[CH2:13]([N:17]([N:21]=[O:22])[C:18]([NH:20][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:19])[CH2:14][CH2:15][CH3:16]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCNC(N)=O
Reactant: O=[N+]([O-])Nc1ccccc1
Agent: Cl
Solvent: CO
Product: CCCCN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: -1 °C
Reaction time: 2 h
Yield: 669.7 %

Procedure:
A mixture of 3.6 g of D-glucose, 2.8 g of butylurea, 0.2 g of nitroaniline and 0.15 ml of a concentrated hydrochloric acid in 10 ml of methanol is heated at reflux for 20 minutes. The resulting precipitate in the amount of 3 g is separated and added with 15 ml of glacial acetic acid, 10 ml of distilled water, 1.8 g of sodium nitrite and stirred at the temperature of -1° C. for 2 hours to give 2.98 g of the product (90% of the thoretical), hydroscopic, [α]D -1° (CH3OH), Rf =0.85. Found, %: N 13.47. Calculated, % N 13.68.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C1(C)C=CC=CC=1.[OH-].[Na+].[C:16](Cl)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>O>[O:6]=[C:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:16]([O:18][CH2:19][CH:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17]
Reactant: O=C1CCCN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Into a 500 mL four neck flask were added 2-pyrrolidone (8.51 g) [mw. 85.10, 100 mmol] and toluene (170 mL), and the mixture was dissolved. Powder sodium hydroxide (4.00 g) [mw. 40.00, 100 mmol] was added thereto, Dean-Stark trap was set, and the mixture was subjected to dehydration reflux for 4 hr. After cooling to 0° C., Fmoc-Cl (25.70 g) [mw. 258.70, 99 mmol] was added at not more than 5° C., the mixture was stirred at 25° C. for 2 hr, and water (43 mL) was added to allow for partitioning. The organic layer was washed with 5 w/w aqueous potassium hydrogen sulfate solution (43 mL), and further washed twice with water (43 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Pale-yellow oil, 30.56 g, yield 99.4%, 1H-NMR (500 MHz, CDCl3, TMS) δ 1.13 (d, J=6.3 Hz, 1H), 2.04 (quin, J=7.7 Hz, 2H), 2.57 (t, J=8.2 Hz, 2H), 3.75-3.82 (m, 2H), 4.49 (d, J=7.6 Hz, 2H), 7.30-7.36 (m, 2H), 7.37-7.45 (m, 2H), 7.70-7.79 (m, 4H). 13C-NMR (125 MHz, CDCl3, CDCl3) δ 17.56, 32.87, 46.41, 46.72, 68.59, 119.97, 125.35, 127.22, 127.87, 141.31, 143.53, 151.75, 173.79.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[N+](=[CH2:31])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1>C1COCC1.CCOCC>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:31])=[O:6]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Chenodeoxycholic acid (0.5 g, 1.3 mmol) in THF (10 ml) at 0° C. was treated dropwise with freshly prepared diazomethane in ether (prepared in the usual manner from diazald) until the yellow colour persisted. After 15 minutes at 0° C. the solvent was evaporated to yield a white foam (0.55 g). The compound would not recrystallise, although gas chromatography showed the product to be 97% pure. The product was further purified by preparative silica tlc. (solvent system: EtOAc/CH2Cl2 /AcOH--10:10:1) to afford pure methyl chenodeoxycholate3 (0.42 g, 81%) as a foam: 1H NMR (60 MHz; CDCl3) δ0.65 (3H, s, 18-CH3), 0.91 (3H, s, 19-CH3), 1.85 (2H, s [exchanges on adding D2O], 3α and 7α OH's), 3.1-3.7 (1H, m, 3β-H), 3.64 (3H, s, --OMe), 3.7-3.9 (1H, m, 7β-H); IR (nujol mull) 3384 (OH's), 1740 (C=O) cm-1 ; MS: Found m/z 406.3077; C25H42O4 (M) requires 406.3083.
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:20]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:17]3=[N:18][CH:19]=2)[CH:9]=1)[C:5]([OH:7])=O)[CH3:3].[CH3:39][NH:40][CH3:41].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH3:3][N:2]([CH3:1])[CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:20]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:17]3=[N:18][CH:19]=2)[CH:9]=1)[C:5]([N:40]([CH3:41])[CH3:39])=[O:7]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)O)N(C)C)c3)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)N(C)C)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of dimethylamino-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (56 mg, 0.11 mmol), dimethylamine (2 N in THF, 0.08 mL, 0.16 mmol), and diisopropylethylamine (21 mg, 0.16 mmol) in THF (1.5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 0.16 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 560 (M+H+).
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:16][O:17][NH3+:18].[Cl-].C(N(CC)CC)C>C(O)C(C)C>[CH3:16][O:17][N:18]=[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:4][N+:5]([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])NCc1cccnc1
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: CC(C)CO
Solvent: CCN(CC)CC
Product: CON=C(C[N+](=O)[O-])NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To 3 ml of isobutyl alcohol was added 0.75 g (0.0033 mole) of 1-methylthio-1-(3-pyridylmethyl)amino-2-nitroethylene, followed by addition of 0.56 g of 0-methylhydroxylamine hydrochloride at 100-110° C. Then, a solution of 0.93 ml of triethylamine in 1 ml of isobutyl alcohol was added dropwise at the same temperature with stirring over a period of 30 minutes. After completion of dropwise addition, the reaction mixture was allowed to cool to room temperature and the solvent was distilled off. The residue was purified by silica gel column chromatography [eluents: MeOH—CHCl3 (1:3) in the first run and MeOH—CHCl3 (1:10) in the second run] to give 0.23 g of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:10])[C:4]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)=[CH:15][N:16]([CH3:18])[CH3:17]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)C(=O)Cn1ccnc1
Product: CN(C)C=C(C(=O)C(C)(C)C)n1ccnc1
Yield: 90.4 %

Procedure:
41.6 g (0.25 mol) of 3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one and 35.7 g (0.3 mol) of dimethylformamide dimethyl acetal were heated under reflux for 5 hours. The excess acetal was then distilled off. The oil which remained crystallized on cooling. 50 g (90.5% of theory) of 4,4-dimethyl-1-dimethylamino-2-(imidazol-1-yl)-pent-1-en-3-one of melting point 45°-50° C. were obtained. ##STR16##
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14](B3[O:21][C:20]([CH3:23])(C)C(C)(C)O3)=[CH:13][CH:12]=2)=[N:2]1.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[N:29]([C@H:37]2[CH2:42][CH2:41][C@H:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)[N:28]=1.C(=O)([O-])[O-:51].[Na+].[Na+]>COCCOC.O>[C:20]([OH:51])(=[O:21])[CH3:23].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:27]3[C:35]4[C:30](=[N:31][CH:32]=[N:33][C:34]=4[NH2:36])[N:29]([C@H:37]4[CH2:38][CH2:39][C@H:40]([N:43]5[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]5)[CH2:41][CH2:42]4)[N:28]=3)=[CH:15][CH:16]=2)=[N:2]1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Nc3n[nH]c4ccccc34)cc2)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(Nc5n[nH]c6ccccc56)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C

Procedure:
A mixture of N-(1H-3-indazolyl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.064 g, 0.000191 mol), trans-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.070 g, 0.000159 mol), tetrakis-(triphenylphosphine)palladium (0.011 g, 0.0000095 mol) and sodium carbonate (0.042 g, 0.000398 mol) was heated in a mixture of ethylene glycol dimethyl ether (4 mL) and water (2 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile—0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-3-[4-(1H-3-indazolylamino)phenyl]-1-[4-(4-methylpiperazino) cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.035 g, 0.000060 mol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1.O1CCCC1.O.[OH-].[Li+].Cl>O.CO>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:14]=1
Reactant: COC(=O)CCc1ccc(OCc2sc3ccccc3c2Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc(OCc2sc3ccccc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A mixture of methyl 4-[(3-chlorobenzo[b]thien-2-yl) methoxy]benzenepropanoate (1.5 g, 4.0 mmol), tetrahydrofuran (20 mL), methanol (5 mL), water (2 mL) and lithium hydroxide monohydrate (0.34 g, 8.0 mmol) was stirred overnight at room temperature. The reaction mixture was neutralized with 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to give the title compound (1.3 g, yield 94%).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH:16]([F:18])[F:17])[C:5]=2[CH2:19][O:20][CH:21]2[CH2:27][CH:26]3[N:28]([C:29]4[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=4[F:37])[CH:23]([CH2:24][CH2:25]3)[CH2:22]2)[CH2:3][CH2:2]1.[N-:38]=[N+:39]=[N-:40].[Na+].[Cl-].[NH4+]>CN(C)C(=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH:16]([F:17])[F:18])[C:5]=2[CH2:19][O:20][CH:21]2[CH2:22][CH:23]3[N:28]([C:29]4[CH:36]=[CH:35][C:32]([C:33]5[N:38]=[N:39][NH:40][N:34]=5)=[CH:31][C:30]=4[F:37])[CH:26]([CH2:25][CH2:24]3)[CH2:27]2)[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(N2C3CCC2CC(OCc2c(-c4ccccc4OC(F)F)noc2C2CC2)C3)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Fc1cc(-c2nn[nH]n2)ccc1N1C2CCC1CC(OCc1c(-c3ccccc3OC(F)F)noc1C1CC1)C2
Temperature: 120 °C
Reaction time: 8 h

Procedure:
4-(3-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)-3-fluorobenzonitrile (70 mg, 0.14 mmol) was dissolved in N,N-dimethylacetamide (2 ml), sodium azide (91 mg, 10 eq, 1.40 mmol) and ammonium chloride (75 mg, 10 eq, 1.40 mmol) were added, and the mixture was stirred at 120° C. overnight. Upon cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with brine (2×20 mL). The combined organics were separated, dried (MgSO4), and evaporated in vacuo. The product was purified by mass directed reverse phase HPLC to give a white solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20]>CN(C=O)C.CCOC(C)=O>[NH:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:11]1[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][N:6]=1
Reactant: O=Cc1n[nH]c2ccc(I)cc12
Reactant: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1ccc2[nH]nc(-c3nc4ccccc4[nH]3)c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 5-iodo-1H-indazole-3-carboxaldehyde (544 mg, 2 mmol) and 1,2-diaminobenzene (216 mg, 2 mmol) in DMF (5 mL) was add 4 Å molecular sieves. The mixture was kept at 60° C. for 2 hr, then the mixture was heated up to 80° C. overnight under air atmosphere (air balloon). The mixture was diluted with EtOAc, washed with water, dried and concentrated. The crude product was purified by flash chromatography to afford 3-(1H-benzimidazol-2-yl)-5-iodo-1H-indazole (500 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:16]([OH:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=O)=[C:5]([CH3:19])[O:4][N:3]=1.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:9]([C:29]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][C:21]=3[CH3:20])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: Cc1noc(C)c1CN1C(=O)c2ccccc2C1O
Product: Cc1noc(C)c1CN1C(=O)c2ccccc2C1c1c(C)[nH]c2ccccc12
Temperature: 180 °C

Procedure:
The product of example 22, step b) (230 mg, 0.89 mmol) was treated with 2-methyl indole (196 mg, 1.5 mmol) and heated (neat) to 180° C. for 1 h. The reaction was cooled and the sub-title product was purified by silica chromatography (EtOAc/Hex).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[C:32]([CH3:34])[CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]([N:40]6[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]6)=[C:32]([CH3:34])[CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Cc1cc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cnc1F
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cnc1N1CCN(C)CC1
Temperature: 150 °C
Yield: 30.8 %

Procedure:
Compound 436 (200 mg, 0.41 mmol) was dissolved in NMP (2 mL), N-Methyl-piperazine (82 mg, 0.82 mmol) was added in it. The reaction mixture was heated by mw at 150° C. for 90 min. The reaction mixture was concentrated in vacuo, dissolved in DCM (20 mL). And the organic layer was washed by water, dried by Na2SO4, concentrated in vacuo, and separated by prep. TLC (EtOAc/Hexanes=1:3) to give 437 (72.1 mg, yield: 31%). 1H NMR (DMSO-d6, 400 MHz): δ9.759 (s, 1H), 8.58 (s, 1H), 8.47 (t, J=11.8 Hz, 1H), 8.25 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.63-7.53 (m, 2H), 7.29-7.19 (m, 2 H), 7.08 (d, J=11.2 Hz, 2 H), 4.36 (t, J=4.8 Hz, 2 H), 4.20-4.11 (m, 2H), 3.74-3.68 (m, 2H), 3.29 (s, 6H), 2.76 (s, 3 H), 2.32 (s, 3H). LC-MS (ESI): m/z=572 [M+H]+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=2[N:9]=1.[C:26]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)#[CH:27]>>[CH:14]1([CH2:13][N:12]2[C:11]3[CH:20]=[C:21]([F:25])[C:22]([F:24])=[CH:23][C:10]=3[N:9]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:27]#[C:26][C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C#Cc1ccc(C#N)cc1
Reactant: Fc1cc2nc(-c3ccccc3Br)n(CC3CCCCC3)c2cc1F
Product: N#Cc1ccc(C#Cc2ccccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1

Procedure:
The title compound was prepared in analogy to Example 72, intermediate a, from 2-(2-bromo-phenyl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole and 4-ethynyl-benzonitrile (CAS Reg. No. 3032-92-6). Off-white powder (30%). MS (Turbo Spray): m/z=452.4 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.O[C:21]1[CH:34]=CC=C(OC)[C:22]=1C(C1C=CC=CC=1)=O>>[CH:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1)([CH3:34])[CH3:22]
Reactant: O=[N+]([O-])c1oc2ccc(O)cc2c1-c1ccccc1
Reactant: COc1cccc(O)c1C(=O)c1ccccc1
Product: CC(C)Oc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
Using the procedure described in Example 3 and starting with 5-hydroxy- 2-nitro-3 -phenylbenzofuran and isopropyl iodide one obtains 5-isopropoxy-2-nitro-3-phenylbenzofuran.
Reaction SMILES: C([CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:8][CH2:7][CH2:6]1)(O)=O.[CH:26]([NH2:29])([CH3:28])[CH3:27].P(C#N)(OCC)(OCC)=[O:31].O>CN(C)C=O>[CH:26]([O:31][CH:24]([CH3:23])[CH3:19])([CH3:28])[CH3:27].[CH:26]([NH:29][CH:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH2:8][CH2:7][CH2:6]1)([CH3:28])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(=CC(=O)O)c3ccccc32)cc1
Reactant: CC(C)N
Reactant: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(C)C
Product: Cc1ccc(S(=O)(=O)N2CCCC(=CNC(C)C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 205.8 %

Procedure:
To a solution of 5-carboxymethylidene-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (3.0 g) and isopropylamine (2.5 g) in dimethylformamide (30 ml) is added diethyl cyanophosphate (2.1 g), and the mixture is stirred at room temperature for 30 minutes. To the mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, concentrated, and the precipitated crystals are recrystallized from chloroform--diisopropyl ether to give 5-isopropylaminomethylidene-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (trans-compound) (3.2 g).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([N:25]([CH:34]([CH3:36])[CH3:35])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:24]>CN(C=O)C>[CH:34]([N:25]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:23](=[O:24])[CH2:22][NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:35])[CH3:36]
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)cc1
Yield: 60.7 %

Procedure:
To a solution of N-phenyl-benzene-1,2-diamine(3.08 g) in DMF (35 mL) was added potassium carbonate (2.31 g) and 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (4.79 g) and stirred 18h at ambient temperature. The solvent was evaporated in vacuo and the resultant oil was dissolved in ethyl acetate(250 mL), washed with 1N HCl (4×100 mL), dried over sodium sulfate, filtered, and concentrated to a brown oil. The oil was subjected to flash chromatogaraphy on silica gel (70 g) eluted with ethyl acetate/hexanes (1:4, 1L). Fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound as a tan foam (3.95 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CCCCCC.C([Li])CCC.[CH3:33][C:34]([CH3:40])=[C:35]1[CH:39]=[CH:38][CH:37]=[CH:36]1>C1COCC1.O>[CH:35]1([C:34]([C:11]2[C:10]3[CH2:9][C:8]4[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=4)[C:15]=3[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=2)([CH3:40])[CH3:33])[CH:39]=[CH:38][CH:37]=[CH:36]1
Reactant: CC(C)=C1C=CC=C1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C(C)(C)C3C=CC=C3)c1C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 3.0 g(10.8 mmol) of 3,6-di-tert-butylfluorene in 40 ml of THF, 7.0 ml (11.3 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 6 hours. From the reaction mixture, the solvent was removed under reduced pressure, and the residue was washed with pentane and dried to obtain a white solid. To a solution of the solid in 30 ml of THF, a solution of 1.4 g (13.2 mmol) of 6,6-dimethylfulvene in 30 ml of THF was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring for 5 hours. Then, 30 ml of water was added. The organic phase extracted with diethyl ether and separated was dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a solid. The solid was recrystallized from methanol to obtain 2.9 g of a slightly yellow solid. The analyzed values are given below.