Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[CH2:42][CH2:41][P:40]([CH3:44])(=[O:43])[CH2:39][CH2:38]3)[CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[CH2:42][CH2:41][P:40]([CH3:44])(=[O:43])[CH2:39][CH2:38]4)[CH2:33][CH2:32]3)=[CH:30][C:24]=2[O:23][CH3:22])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Reactant: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1N
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH:8]=O)=[CH:2]1.[CH2:10]([NH2:13])[CH:11]=[CH2:12].C(O)(=O)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:10]([NH:13][CH2:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[CH:11]=[CH2:12]
Reactant: O=CCCc1ccoc1
Reactant: C=CCN
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCNCCCc1ccoc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the above crude 3-(3-furyl)propanal, 7.94 ml (106 mmol) of allylamine and 2.54 ml (42.3 mmol) of acetic acid in 100 ml of methanol, 1.33 g (21.2 mmol) of sodium cyanoborohydride was added at room temperature, followed by stirring at room temperature for 1 day. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1.CC1(C)OB([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)OC1(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:3]2[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:9][N:8]([CH3:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccccc2)OC1(C)C
Reactant: Cn1cc(I)c2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccccc2)c2c(Cl)ncnc21
Temperature: 70 °C
Yield: 47.9 %

Procedure:
A stirred suspension of 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (3.31 g, 11.3 mmol), tetramethyl-2-phenyl-1,3,2-dioxaborolane (2.76 g, 13.53 mmol) and sodium carbonate (3.59 g, 33.8 mmol) in 1,4-dioxane (90 ml) and water (18.0 ml) was degassed by bubbling N2 through it for 10 min. 1,1′-Bis(diphenylphosphino)ferrocenedichloro palladium(II) dichloromethane complex (0.921 g, 1.13 mmol) was then added and the reaction mixture degassed with N2 again for 10 min before heating at 70° C. for 2 h. The solvent was removed in vacuo and the residue partitioned between saturated sodium hydrogen carbonate (90 ml) and dichloromethane (90 ml). The layers were separated and the aqueous phase extracted with dichloromethane (3×45 ml). The combined organic phases were dried (phase separator cartridge) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (gradient 0-50% ethyl acetate in cyclohexane) to afford the title compound (1.32 g, 48%). LCMS RT=1.26 min, [M(35Cl)+H]+=244.1, [M(37Cl)+H]+=246.1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]=[C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-Nitro-1-tetralone (1.00 g, 5.23 mmol) was dissolved in dry THF (5 mL) and added to a solution of methyltriphenylphosphonium bromide (2.00 g, 5.60 mmol) and n-butyllithlum (2.5M in hexanes, 2.2 mL, 5.5 mmol) in THF (10 mL) cooled by an ice water bath. The mixture was allowed to warm to room temperature and stirred overnight. It was poured into ice water 45 mL) and extracted with EtOAc (3×20 mL). The extract was washed with NaCl solution, dried (MgSO4), filtered and concentrated to give a black solid (1.504 g). It was dissolved in CHCl3 and flash chromatographed over silica gel (65 g) eluting with EtOAc/hexane (1:20) to afford a white solid (263 mg, 27% yield): mp 45°-470° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[SH:12].[BH4-].[Na+].C([O-])(=O)C.[Na+].Br[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:22](OC)=[O:23]>C(O)C.C(O)(=O)C>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH:21]2[S:12][C:3]3[CH:4]=[CH:5][C:6]4[C:11]([C:2]=3[NH:1][C:22]2=[O:23])=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:27][CH:28]=1
Reactant: Nc1c(S)ccc2ccccc12
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Nc2c(ccc3ccccc23)SC1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of 1-amino-2-naphthalenethiol (27.81 g) in ethanol (500 ml) is added sodium borohydride (11.35 g) at room temperature. The mixture is stirred for 20 minutes, and thereto is added dropwise acetic acid (200 ml) and is further added sodium acetate (24.6 g). To the mixture is further added dropwise methyl α-bromo-4-chlorophenylacetate (46.8 g), and the mixture is sitrred at room temperature under argon overnight. The reaction mixture is poured into ice water and the resulting precipitate is separated by filtration, washed, dried and recrystallized from tetrahydrofuran-n-hexane to give 3-(4-chlorophenyl)-1H-naphtho-[2,1-b][1,4]thiazin-2(3H)-one (44.45 g, yield 82.6%) as crystals.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[H-].[Na+].CC1C=CC(S(O[CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=O)=O)=CC=1>O1CCCC1>[F:3][C:2]([F:5])([F:4])[CH2:1][O:6][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOCc2ccccc2)cc1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)COCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 62.6 %

Procedure:
To a stirred solution of trifluoroethanol (0.1 g) and sodium hydride (60% dispersion in mineral oil; (0.05 g) in tetrahydrofuran (10 ml) was added the product of step (b) (0.5 g) and the reaction stirred for 24 hours at 20° C. The reaction was quenched by the addition of methanol (5 ml) and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried and the solvent removed in vacuo. Purification by column chromatography on silica gel (Biotage), eluting with 50% ethyl acetate in cyclohexane gave the title compound (0.27 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2C=C)=[C:4]([CH:25]=[CH2:26])[N:3]=1>CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.ClCCCl>[NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]2[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[CH:26]=[CH:25][C:4]=2[N:3]=1
Reactant: C=Cc1cc(OC)ccc1-c1nc(Cc2ccccc2)c(N)nc1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: COc1ccc2c(ccc3nc(N)c(Cc4ccccc4)nc32)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 25.4 %

Procedure:
Under an argon atmosphere, to a solution of Hoveyda-Grubbs second generation catalyst (84.5 mg, 135 μmol) in 1,2-dichloroethane (100 mL) was added 2-amino-3-benzyl-5-(4-methoxy-2-vinylphenyl)-6-vinylpyrazine (9) (585 mg, 1.70 mmol) at room temperature. The mixture was then heated to 90° C. and stirred overnight (17 hours). After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=3/1-2/1) to give 3-amino-2-benzyl-8-methoxybenzo[f]quinoxaline (12) as a white solid (136 mg, 431 μmol, 25.3%). TLC Rf=0.64 (n-hexane/ethyl acetate=1/1); 1HNMR (500 MHz, CDCl3) δ 3.98 (s, 3H), 4.39 (s, 2H), 4.63 (s, 2H), 7.21-7.38 (m, 7H), 7.63 (d, 1H, J=9.0 Hz), 7.85 (d, 1H, J=9.0 Hz), 9.00 (d, 1H, J=9.0 Hz); 13C NMR (126 MHz, CDCl3) δ 41.8, 55.4, 107.5, 118.1, 124.9, 125.5, 125.8, 127.2, 128.7 (2C), 129.1 (2C), 130.1, 132.7, 134.6, 136.6, 138.9, 143.1, 151.2, 158.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[CH:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:18][NH:19][CH:10]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1cccs1)c1ccc(Br)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Brc1ccc(C2=CC(c3cccs3)NN2)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
1-(4-Bromophenyl)-3-(2-thienyl)-2-propen-1-one (3.0 g, 10.2 mmol) and hydrazine hydrate (1.0 g, 20 mmol) were added to ethanol (30 ml) and heated under reflux for 3 hours. After the mixture was allowed to cool to room temperature, the solvent was distilled off to obtain 3.0 g (98%) of the desired 3-(4-bromophenyl)-5-(2-thienyl)-pyrazoline in the form of a resinous material.
Reaction SMILES: [NH:1]([C:3]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=2[N:4]=1)[NH2:2].[C:13]([CH:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[C:17](OCC)=[O:18])(=O)[CH3:14]>>[CH3:14][C:13]1[C:16]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[C:17]([OH:18])[N:1]([C:3]2[NH:7][C:6]3[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:5]=3[N:4]=2)[N:2]=1
Reactant: Cc1ccc2[nH]c(NN)nc2c1
Reactant: CCOC(=O)C(Cc1ccc(-c2ccccc2)cc1)C(C)=O
Product: Cc1ccc2[nH]c(-n3nc(C)c(Cc4ccc(-c5ccccc5)cc4)c3O)nc2c1

Procedure:
Using 2-hydrazino-5-methyl-1H-benzimidazole (4) obtained in Example 1, step 3 and ethyl 2-acetyl-3-(4-phenylphenyl)propanoate (33), and by a method similar to that in Example 1, step 4, 3-methyl-1-(5-methyl-1H-benzimidazol-2-yl)-4-[(4-phenylphenyl)methyl]-1H-pyrazol-5-ol (34) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][CH:19]=1)[CH:6]=[CH:7][CH:8]=O.[O:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].N1CCCCC1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][CH:19]=1)[CH:6]=[CH:7][CH:8]=[C:30]1[O:26][C:27](=[O:32])[NH:28][C:29]1=[O:31]
Reactant: O=C1COC(=O)N1
Reactant: COc1cc(C=CC=O)ccc1OCc1coc(-c2ccccc2)n1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1cc(C=CC=C2OC(=O)NC2=O)ccc1OCc1coc(-c2ccccc2)n1
Reaction time: 72 h
Yield: 42.3 %

Procedure:
A mixture of 3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamaldehyde (5.5 g), 2,4-oxazolidinedione (6.7 g), piperidine (1.4 g) and acetic acid (120 ml) was stirred for three days under reflux. The reaction mixture was cooled, and resulting crystalline precipitate was collected by filtration, which was washed with water, ethanol and isopropyl ether, successively to give 5-[3-methoxy-4-(2-phenyl-4-oxazolylmethoxy)cinnamylidene]-2,4-oxazolidinedione (2.9 g, 43%), which was recrystallized from chloroform-methanol to afford yellow needles, m.p.227-228° C.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:49]([O:50]CC2C=CC=CC=2)[C@H:48]([O:58][C@@H:59]2[O:88][C@H:87]([CH3:89])[C@@H:78]([O:79]CC3C=CC=CC=3)[C@H:69]([O:70]CC3C=CC=CC=3)[C@H:60]2[O:61]CC2C=CC=CC=2)[C@@H:47]([CH2:90][O:91]CC2C=CC=CC=2)[O:46][C@@H:10]1[O:11][C@@H:12]1[C@@H:19]2[C@@H:15]([N:16](C(OCC3C=CC=CC=3)=O)[O:17][CH2:18]2)[C@H:14]([O:30]CC2C=CC=CC=2)[C@@H:13]1[O:38]CC1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.Cl>CO.[OH-].[Pd+2].[OH-].[C]>[C@@H:59]1([O:58][C@@H:48]2[C@@H:47]([CH2:90][OH:91])[O:46][C@H:10]([O:11][C@@H:12]3[C@@H:19]([CH2:18][OH:17])[C@@H:15]([NH2:16])[C@H:14]([OH:30])[C@H:13]3[OH:38])[C@H:9]([OH:8])[C@H:49]2[OH:50])[O:88][C@H:87]([CH3:89])[C@@H:78]([OH:79])[C@H:69]([OH:70])[C@H:60]1[OH:61]
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H](O[C@@H]3[C@H]4CON(C(=O)OCc5ccccc5)[C@H]4[C@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)O[C@@H]2COCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](N)[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
The compound (115 mg, 86.8 μmol) synthesized in Example 15 (15a) was dissolved in methanol (20 mL) and ethyl acetate (1 mL) and hydrochloric acid (10 μL) and 20% palladium hydroxide-carbon (115 mg) were added thereto, followed by stirring of the mixture at room temperature under a hydrogen atmosphere for 4 hours. After celite filtration, the solvent was distilled off under reduced pressure and the residue was purified by ion exchange resin (Dowex 50w×8) column (water—5% ammonia water). Further, it was purified using silica gel flash column chromatography (ethyl acetate:methanol:water, 1:1:1, V/V) to obtain the desired title compound (30 mg, 73%) as a colorless amorphous.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CC(=O)OCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([CH:7]=1)[CH:13]=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=CC(=O)OCC
Reactant: COc1ccc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cc(Cl)ccc1OC
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution of 10.6 g (48.2 mmol) of 2-bromo-4-chloroanisole in 30 ml of triethylamine was treated with 1 0.1 ml (81.2 mmol) of ethyl acrylate, 1.23 g of tri-o-tolylphosphine, and 0.45 g of palladium(II) acetate in an argon atmosphere. The reaction mixture was stirred at 100° C. for 2 days, then diluted with EA and filtered through Celite. The filtrate was washed with 1 N HCl and saturated NaCl solution, dried over Na2SO4, and concentrated. After chromatographic purification over SiO2 using EA/heptane (1:8) as an eluent, 0.85 g of the title compound resulted as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cnc2ccccc2c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cnc4ccccc4c3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (243 mg), 3-hydroxyquinoline (100 mg), and 4-dimethylaminopyridine (348 mg) were dissolved in o-dichlorobenzene (13 ml) to prepare a solution which was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (213 mg, yield 93%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]#[N:22].C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[C:21]=1[NH2:22]
Reactant: COc1ccc(N=[N+]=[N-])cc1
Reactant: N#CCc1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-n2nnc(-c3ccc(Cl)cc3Cl)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-4-methoxy-benzene (0.750 g, 1 eq) and commercial (2,4-dichloro-phenyl)-acetonitrile (1.12 g, 1.2 eq) in ethanol (10 ml) kept under nitrogen, a solution of sodium methoxide (0.408 g, 1.5 eq) in ethanol (10 ml) is added drop-wise (25 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (40 ml), washed with water (2×50 ml), dried over MgSO4 and evaporated to dryness. The yellow semisolid residue (0.842 g) is purified by flash chromatography using 60-120 mesh silica gel and eluting with 15% ethylacetate in hexane, to afford the title compound as a white solid (0.428 g, 24% yield). M.p. 154.6-163.9° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([O:14][Si](C(C)(C)C)(C)C)[CH2:11][CH:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH:12]([OH:14])[CH2:11][CH:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[C:9]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CC(O[Si](C)(C)C(C)(C)C)CN(Cc2ccccc2)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC(O)CN(Cc2ccccc2)C1=O
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To a stirred solution of compound 1E (2.33 g, 5.36 mmol) in 13 mL of THF at room temperature under argon was added (in one portion) 6.7 mL or 1M tetrabuylammonium fluoride (in THF, 6.7 mmol). After 1 h, the reaction mixture was diluted with EtOAc and washed once with saturated sodium bicarbonate solution. The organic extract was dried over MgSO4, filtered and evaporated under reduced pressure. The resulting white solid was dried in vacuo to give the title compound (1.74 g, 100% material balance) and used in the next reaction without additional purification. MS [M+H]+: found 321.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.O[CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:15])([O:17][CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH3:16])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: OCCN1CCOCC1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C(C)(C)OCCN3CCOCC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in Example 14, step (d), 50.0 mg, 0.132 mmol) in 1 mL of DCM at −15° C. was added oxalyl chloride (16 μL, 0.20 mmol) under Ar. After stirring at RT for 1 h, the mixture was cooled back to −15° C. To the reaction was added 2-hydroxylethylmorpholine (80 μL, 0.66 mmol) and the resulting mixture was warmed to RT and stirred for 16 h under Ar. Treated with EtOAc (30 mL), the mixture was washed with aqueous saturated NH4Cl (10 mL), H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1-3% MeOH/DCM) to afford the title compound (29 mg, 44%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.68 (s, 1H), 8.31 (d, 1H, J=8.6 Hz), 7.72 (s, 1H), 7.37 (dd, 1H, J=8.6, 2.3 Hz), 7.21 (d, 1H, J=2.3 Hz), 5.77 (m, 1H), 3.71 (t, 4H, J=4.7 Hz), 3.34 (t, 2H, J=6.2 Hz), 2.61 (t, 2H, J=6.2 Hz), 2.54 (m, 4H), 2.25-2.31 (m, 2H), 2.07-2.13 (m, 2H), 1.59 (t, 2H, J=6.3 Hz), 1.52 (s, 6H), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C28H37N5O3, 492.3 (M+H). found 492.0.
Reaction SMILES: I[C:2]12[CH2:6][C:4]([CH3:7])([CH2:5]1)[CH2:3]2.C([Li])(C)(C)C.[C:13](=[O:15])=[O:14]>C(OCC)C>[CH3:7][C:4]12[CH2:6][C:2]([C:13]([OH:15])=[O:14])([CH2:5]1)[CH2:3]2
Reactant: CC12CC(I)(C1)C2
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC12CC(C(=O)O)(C1)C2
Temperature: 25 °C
Yield: 50.9 %

Procedure:
To a solution of 1-iodo-3-methylbicyclo[1.1.1]pentane (1.62 g, 7.79 mmol; prepared according to Eur. J. Org. Chem. 1137-1155 (2000)) in diethyl ether (26 mL), a solution of tert-butyllithium (9.16 mL, 15.57 mmol, 1.7 M in pentane) was added over a period of 40 min at −78° C. After stirring the reaction mixture for 1 h at this temperature, carbon dioxide gas was bubbled through the reaction mixture for 5 min and then the mixture was allowed to warm to room temperature. The reaction mixture was extracted twice with a 5% aqueous sodium bicarbonate solution. The combined aqueous phases were acidified to pH 2-3 with concentrated hydrochloric acid at 0° C., saturated with sodium chloride, and extracted with diethyl ether. The combined organic phases were dried and, after evaporation of the solvent under reduced pressure, purified by column chromatography (0-20% ethyl acetate in hexanes) to afford 3-methylbicyclo[1.1.1]pentane-1-carboxylic acid (0.5 g, 3.96 mmol, 50.9% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 12.21 (s, 1H), 1.82 (s, 6H), 1.14 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.CCOC(C)=O>[Pd].CO>[F:1][C:2]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:3]=1[NH:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1ccc(NCCCN2CCOCC2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc(NCCCN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-fluoro-N-(3-morpholinopropyl)-4-nitroaniline (1.78 g, 6.28 mmol) in mixed solvents of EtOAc (15 mL) and MeOH (15 mL) was added catalyst Pd/C (0.30 g). The reaction was stirred at rt under H2 for 2 h, then filtered. The filtrate was concentrated in vacuo to give the crude product for the next step without further purification.