Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[S:15][C:14]([CH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[CH:13][CH:12]=2)[C:8]([O:22][CH3:23])=[CH:7][N:6]=1)(=O)=O.[CH3:24][C:25]1([CH3:34])[CH2:30][CH:29]([NH2:31])[CH2:28][C:27]([CH3:33])([CH3:32])[NH:26]1.CCN(C(C)C)C(C)C>CO>[CH3:23][O:22][C:8]1[C:9]([C:11]2[S:15][C:14]([CH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[CH:13][CH:12]=2)=[N:10][C:5]([NH:31][CH:29]2[CH2:30][C:25]([CH3:34])([CH3:24])[NH:26][C:27]([CH3:33])([CH3:32])[CH2:28]2)=[N:6][CH:7]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: COc1cnc(S(C)(=O)=O)nc1-c1ccc(CCC(C)(C)O)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cnc(NC2CC(C)(C)NC(C)(C)C2)nc1-c1ccc(CCC(C)(C)O)s1
Temperature: 120 °C

Procedure:
4-[5-(2-Methanesulfonyl-5-methoxy-pyrimidin-4-yl)-thiophen-2-yl]-2-methyl-butan-2-ol (240 mg, 0.673 mmol) was mixed with 2,2,6,6-Tetramethyl-piperidin-4-ylamine (0.5 ml, 2.86 mmol) and DIEA (0.5 ml, 2.92 mmol) and heated to 120° C. in a closed flask for 2 hours. The residue was then diluted with MeOH and purified by preparative HPLC to give the title compound. Yield: 8 mg (3%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[Br:20][C:21]1[CH:34]=[CH:33][C:24]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:23][C:22]=1[CH2:35]Br.[Cl-].[NH4+]>C1COCC1.CCCCCC>[Br:20][C:21]1[CH:34]=[CH:33][C:24]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:23][C:22]=1[CH2:35][C:13]1([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N#CC1CCCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CBr)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CC2(C#N)CCCC2)c1
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere, to a solution of diisopropylamine (0.36 mL) in THF (7.0 mL) was added a 1.6 M solution of n-butyllithium in hexane (1.6 mL) at 0° C., and the mixture was stirred for 10 min. Cyclopentanecarbonitrile (0.28 mL) was added at −78° C., and the mixture was stirred for 30 min. A solution of (4-bromo-3-(bromomethyl)phenoxy) (tert-butyl)dimethylsilane (503 mg) in THF (3.0 mL) was added, and the mixture was stirred at −78° C. for 4 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (471 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[C:19]([C:21]1[CH:26]=[C:25]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:24]=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cccc(C#N)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, white solid (63 mg, 77%), MS (ISP) m/z=325.6 [(M+H)+], mp 266° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3-cyanophenylboronic acid (47.8 mg, 0.325 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:23]3[O:22]/[C:21](=[CH:24]\[C:25]4[C:33]5[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=5)[NH:27][CH:26]=4)/[C:20](=[O:38])[C:19]=3[CH:18]=[CH:17][C:16]=2[OH:39])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[OH:39][C:16]1[CH:17]=[CH:18][C:19]2[C:20](=[O:38])/[C:21](=[CH:24]/[C:25]3[C:33]4[C:28](=[CH:29][C:30]([C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=4)[NH:27][CH:26]=3)/[O:22][C:23]=2[C:15]=1[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COC(=O)c1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCNCC4)C3=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
A solution of methyl (Z)-3-[(7-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}-6-hydroxy-3-oxobenzofuran-2(3H)-ylidene)methyl]-1H-indole-6-carboxylate (0.020 g, 0.037 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, then the residue was added with an excessive amount of triethylamine, and the mixture was azeotroped with toluene. The resulting residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain methyl (Z)-3-{[6-hydroxy-3-oxo-7-(piperazin-1-ylmethyl)benzofuran-2(3H)-ylidene]methyl}-1H-indole-6-carboxylate (0.007 g, 43%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].[C:20](Cl)(=[O:22])[CH3:21]>ClCCl.O>[C:20]([C:10]1[CH:11]=[C:2]([Br:1])[CH:3]=[C:4]2[C:9]=1[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Reaction time: 0.17 h
Yield: 67.4 %

Procedure:
A stirred, cooled (−78° C.) solution of 6-bromo-2,2,4,4-tetramethyl chroman (1 g, 3.72 mmol) in anhydrous dichloromethane (10 mL) was treated with aluminum chloride (0.8 g, 6.8 mmol) followed by acetyl chloride (0.4 mL, 6.08 mmol). After 10 minutes, the reaction mixture was diluted with water and extracted with diethyl ether. The organic phase was washed with water, and dried over anhydrous sodium sulfate, filtered and evaporated to a residue that was subjected to flash column chromatography on silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound as a solid (0.78 g, 67%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:14][C:13]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:12]=[CH:11][N:10]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:29])[CH3:28]
Reactant: OC(c1ccccc1)(c1ccccc1)c1nccn1Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(c1ccccc1)(c1ccccc1)c1nccn1Cc1ccccc1

Procedure:
A slurry of (1-benzyl-1H-imidazol-2-yl)(diphenyl)methanol (1-2, 16.0 g, 47.0 mmol, 1 equiv) in acetic anhydride (120 mL) and pyridine (130 mL) was heated at 60° C. for 18 h. The resulting orange slurry was concentrated to dryness. The residue was suspended in saturated aqueous sodium carbonate solution (300 mL) and the resulting precipitate was filtered and washed with water (2×100 mL) followed by ethyl ether (50 mL). The resulting solid was suspended in ethanol, collected by filtration and air dried to afford (1-benzyl-1H-imidazol-2-yl)(diphenyl)methyl acetate (1-3) as white crystals. 1H NMR (300 MHz, CDCl3) δ 7.43 (m, 3H), 7.30 (m, 10H), 7.12 (d, 1H, J=1.2 Hz), 6.86 (m, 2H), 6.77 (d, 1H, J=1.2 Hz), 4.83 (s, 2H), 1.84 (s, 3H). LRMS m/z (M-OAc) 323.1 found, 323.2 required.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([I:31])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2Cl)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:36]C(F)(F)C1C=C(C(C)(C)C(N(C2C=NC(Cl)=CC=2C2C=CC(F)=CC=2)C)=O)C=C(C(F)(F)F)C=1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:33])([CH3:32])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([I:31])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:36])=[CH:26][CH:25]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(I)cc1-c1ccccc1Cl
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccc(F)cc1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(I)cc1-c1ccc(F)cc1

Procedure:
The title compound is prepared according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-iodo-pyridin-3-yl]-N-methyl-isobutyramide (Example 25) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide (Example 30) instead of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:9]([F:10])[C:7]([F:8])=[C:5]([F:6])[C:3]=1F.C([Mg:15][Br:16])C>C(OCC)C>[C:3]1([Mg:15][Br:16])[C:5]([F:6])=[C:7]([F:8])[C:9]([F:10])=[C:11]([F:12])[C:2]=1[F:1]
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F

Procedure:
reacting C6F6 with ethyl magnesium bromide in a medium comprising ethyl ether to produce C6F5MgBr in solution in said medium;
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[S:11](Cl)(=[O:13])=[O:12])[CH3:2].[CH3:15][C:16]1[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][C:20]([C:27]([F:30])([F:29])[F:28])=[CH:19][C:17]=1[NH2:18]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[S:11]([NH:18][C:17]1[CH:19]=[C:20]([C:27]([F:28])([F:29])[F:30])[CH:21]=[C:22]([C:23]([F:24])([F:25])[F:26])[C:16]=1[CH3:15])(=[O:13])=[O:12])[CH3:2]
Reactant: CCc1cccc(CC)c1S(=O)(=O)Cl
Reactant: Cc1c(N)cc(C(F)(F)F)cc1C(F)(F)F
Solvent: c1ccncc1
Product: CCc1cccc(CC)c1S(=O)(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.3 %

Procedure:
2,6-Diethylbenzenesulfonyl chloride (0.100 g, 0.430 mmol) was added to a solution of 2-methyl-3,5-bis(trifluoromethyl)aniline (0.106 g, 0.434 mmol) in dry pyridine (1 mL). The reaction was capped and stirred at room temperature for 1 day then stirred at 30° C. for 1 day. The reaction was then concentrated under vacuum. To this was added diethyl ether (60 mL) and the mixture was washed with 0.1 N HCl (3×20 mL) followed by 0.1 N NaOH (2×20 mL) then saturated NaCl (2×20 mL). After drying the organic layer over MgSO4, the solution was filtered and concentrated under vacuum. The crude compound was purified by silica gel chromatography using hexanes/ethyl acetate (4:1) to afford the title compound (0.080 g, 42% yield). LCMS (M+Na) 461.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]#[N:7])(=[O:3])[CH3:2].[CH:8]([NH:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([F:18])=[CH:13][C:12]=1[Cl:19])=[O:9].[Na]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]([O:4][CH2:5][C:6]#[N:7])(=[O:3])[CH3:2].[C:6]([CH2:5][N:10]([CH:8]=[O:9])[C:11]1[C:12]([Cl:19])=[CH:13][C:14]([F:18])=[CH:15][C:16]=1[Cl:17])#[N:7]
Reactant: O=CNc1c(Cl)cc(F)cc1Cl
Agent: CC(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: ClCCl
Product: N#CCN(C=O)c1c(Cl)cc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyanomethyl acetate was prepared according to the method described in Synth. Commun. 2, 215 (1972). A mixture of 2.78 g (10 millimole) of tetrabutylammonium chloride and 1 g (10 millimole) of cyanomethyl acetate was dissolved in 10 ml of dichloromethane. To the reaction mixture were added 2 g (9.6 millimoles) of N-formyl-2,6 dichloro-4-fluoroaniline and 3 ml (12 millimoles) of a 4 mole/l sodium hydroxyde aqueous solution. After stirring for 1 hour at room temperature, N-cyanomethyl-N-formyl-2,6-dichloro-4-fluoroaniline was obtained.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].Br[CH2:13][CH2:14][OH:15].C[O-].[Na+]>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:13][CH2:14][OH:15]
Reactant: Oc1ccc2ccccc2c1
Reactant: OCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCOc1ccc2ccccc2c1
Reaction time: 48 h

Procedure:
A solution of 14.4 g of 2-naphthol, 12.1 g of 2-bromoethanol and 5.9 g of sodium methoxide in 100 ml of ethanol is allowed to stand two days at room temperature. The solvent is removed under vacuum and the residue extracted with ether. The ether extract is washed with water dried (magnesium sulfate) and the solvent removed under vacuum to give crystals, mp 65°-70° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:38])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH2:22][CH3:23])=[N:19][CH:20]=3)[N:14]=1)[N:11](CC1C=CC=CC=1)[C:10](=[O:31])[C:9]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:8]2)=[O:4].[NH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:9]([N:14]1[C:13]([C:15]2[CH:20]=[N:19][C:18]([O:21][CH2:22][CH3:23])=[N:17][CH:16]=2)=[C:12]2[C:7](=[CH:8][CH:9]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:10](=[O:31])[NH:11]2)[C:3]([OH:4])=[C:5]1[C:6]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOc1ncc(-c2nc(C(=O)OC)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)cn1
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1ncc(C2=C3NC(=O)C(c4ccccc4)C=C3C(O)=C(C(=O)NCCC(=O)O)N2Cc2ccccc2)cn1
Temperature: 25 °C
Yield: 121.7 %

Procedure:
A mixture of 1-benzyl-8-(2-ethoxy-pyrimidin-5-yl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (58 mg, 0.11 mmol), β-alanine (818 mg, 9.13 mmol) and NaOMe solution (13.7 mL, 6.85 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-70% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 38 mg of the title compound as a light yellow solid. MS: (+) m/z 566.38 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([O:20]CC)=[O:19])[NH:6]2>CO.O>[CH3:1][C:2]1[C:10]2[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:9]=2[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:18]([OH:20])=[O:19])[NH:6]2
Reactant: CCOC(=O)c1cc2c(C)c3sc4ccccc4c3cc2[nH]1
Solvent: O
Solvent: CO
Product: Cc1c2cc(C(=O)O)[nH]c2cc2c1sc1ccccc12
Temperature: 25 °C

Procedure:
Ethyl 4-methyl-1H-[1]benzothieno[2,3-f]indole-2-carboxylate (1.0 g, 3.2 mmol) was suspended in a mixture of methanol (110 ml) and water (30 ml). Casium carbonate (10 g) was added and the mixture was heated at reflux under nitrogen for 2 h. The solution was allowed to cool to room temperature, and the methanol was removed in vacuo. The solution was acidified with 0.1 Molar Hydrochloric acid and the resulting yellow precipitate was collected by fitration and washed with water. The wet precipitate was dissolved in acetone and the solvent removed in vacuo to give the product as a yellow solid with m.p. 271°-272° C.; δH [2H6 ]-DMSO 11.88 (1H, s, 1-NH), 8.29 (1H, dd, J 6, 3, 9H), 8.18 (1H, s, 10-H), 7.89-7.99 (1H, m, 6-H), 7.44-7.54 (2H, m, 7-H, 8-H), 7.35 (1H, d, J 2, 3-H), 2.72 (3H, s, 4-CH3); m/z (%) 281 (90, M+), 263 (100), 235 (69).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2>CS(C)=O>[NH2:23][C:20]1[N:19]=[CH:18][C:17]([C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([NH:10][CH2:9][CH2:4][N:3]([CH3:24])[CH3:2])[N:3]3[CH2:24][CH:25]3[CH2:27][CH2:26]3)=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]=2)=[CH:22][N:21]=1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Solvent: CS(C)=O
Product: CN(C)CCNc1nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc2n1CC1CC1
Temperature: 150 °C
Reaction time: 4 h
Yield: 149.1 %

Procedure:
N,N-Dimethylethylehediamine (113 mg, 1.3 mmol) and dimethyl sulfoxide (1 ml) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (100 mg, 0.26 mmol) and the resulting mixture was stirred at 150° C. for 4 hours. The reaction mixture was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (85 mg, 68%) as a pale yellow solid.
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C@:7]2([CH2:22][C:16]3=[N:17][CH:18]=[C:19](Cl)[CH:20]=[C:15]3[CH2:14]2)[C:6]1=[O:23])([CH3:4])([CH3:3])[CH3:2].[C:24]([O-])([O-:26])=[O:25].[K+].[K+].Cl>CN1C(=O)CCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)CCCP(C2CCCCC2)C2CCCCC2)CCCCC1>[C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C@:7]2([CH2:22][C:16]3=[N:17][CH:18]=[C:19]([C:24]([OH:26])=[O:25])[CH:20]=[C:15]3[CH2:14]2)[C:6]1=[O:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)N1C(=O)[C@]2(Cc3cc(Cl)cnc3C2)c2cccnc21
Agent: [Pd+2]
Agent: C1CCC(P(CCCP(C2CCCCC2)C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)N1C(=O)[C@]2(Cc3cc(C(=O)O)cnc3C2)c2cccnc21
Temperature: 120 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
A mixture of 58 (5.0 g, 14.5 mmol), K2CO3 (5.01 g, 36.2 mmol), Pd(OAc)2 (33 mg, 0.145 mmol), 1,3-bis(dicyclohexylphosphino)propane (DCPP, 127 mg, 0.290 mmol) and water (0.522 mL, 29.0 mmol) in NMP (32 mL) was heated at 120° C. under 30 psi of CO for 24 h. After cooling to room temperature, the resulting slurry was diluted with water (100 mL). The pH was slowly adjusted to 3-4 with 2 N HCl. The slurry was aged at room temperature for 1 h, filtered, rinsed with water (40 to 50 mL), dried under oven at 60° C. to give 59 (4.64 g, 95%) as a solid. 1H NMR (DMSO-d6, 500 MHz): δ 8.90 (s, 1H), 8.19 (d, J=5.2 Hz, 1H), 7.54 (d, J=7.3 Hz, 1H,), 6.99 (dd, J=7.3, 5.2 Hz, 1H), 3.33 (m, 4H), 1.72 (s, 9H); 13C NMR (DMSO-d6, 125 MHz): δ 180.16, 167.44, 166.97, 158.07, 149.76, 146.61, 135.39, 133.09, 130.36, 128.81, 125.48, 118.44, 58.19, 51.12, 44.56, 41.24, 28.91.
Reaction SMILES: [C:1]([O:10][CH:11]([CH2:13][C:14]#[C:15][CH2:16][CH3:17])[CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]>[Pd].C(O)C>[C:1]([O:10][CH:11]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH3:17])[CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: CCC#CCC(C)OC(=O)c1ccccc1O
Agent: [Pd]
Solvent: CCO
Product: CC/C=C\CC(C)OC(=O)c1ccccc1O
Yield: 92.2 %

Procedure:
4-Heptyn-2-yl salicylate (24.6 g; 0.1 mol) dissolved in 30 ml abs. ethanol are stirred over palladium on bariumsulfate (0.4 g; 0.02 mol) and under hydrogen for 3 hours. Filtration over Celite and evaporation of the ethanol under reduced pressure gives 26.2 g crude product which is distilled over a Vigreux column giving 23.5 g (96%) of a slightly yellowish oil at 98° C./0.1 Torr (0.133 mbar). Redistillation under the same conditions gives 21.6 g (88%) of colorless (Z)-4-hepten-2-yl salicylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[OH:45][CH2:46][C:47]1[O:48][C:49]([CH2:52]O)=[CH:50][CH:51]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:30]([CH2:52][C:49]4[O:48][C:47]([CH2:46][OH:45])=[CH:51][CH:50]=4)[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reactant: OCc1ccc(CO)o1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(CO)o4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 84.1 using 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine (1 mmol) and 2,5-di(hydroxymethyl)furan (10 mmol) to give the title compound.
Reaction SMILES: [I-].[CH3:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][N+:23]([CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][NH:30][C:29]3=[O:33])=[CH:22][CH:21]=2)[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[CH:9][C:8]([CH3:19])=[CH:7][CH:6]=2.[BH4-].[Na+]>C(O)C>[CH3:2][C:3]1[N:4]([C:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][NH:30][C:29]3=[O:33])[CH2:22][CH:21]=2)[C:5]2[C:10]([C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)=[CH:9][C:8]([CH3:19])=[CH:7][CH:6]=2
Reactant: Cc1ccc2c(c1)c(-c1ccc(F)cc1)c(C)n2-c1cc[n+](CCN2CCNC2=O)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(c1)c(-c1ccc(F)cc1)c(C)n2C1=CCN(CCN2CCNC2=O)CC1

Procedure:
4-[2,5-Dimethyl-3-(4-fluorophenyl)-1H-indol-1-yl]-1-[2-(imidazolidin-2-on-1-yl)ethyl]-pyridinium iodide 5a (6.3 g) was suspended in ethanol (100 ml) and sodium borohydride (2.1 g) was added in three portions during 3.5 h. Then the solvent was evaporated in vacuo and water (100 ml) was added. The mixture obtained was extracted with dichloromethane (2×50 ml). The combined organic phases were washed with brine (100 ml) and dried (MgSO4). Evaporation of the solvent gave the title compound as an oil, which was purified by column chromatography on silica gel (eluted with ethyl acetate/ethanol 8:1 containing 4% triethylamine). Yield: 2.5 g, mp 151°-153° C.
Reaction SMILES: ClC1C2C(=CC=CC=2)[N:5]=[CH:4]C=1[NH-].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][N:22]=2)[N:17]=[CH:16][C:15]=1[NH-:24].Cl.C(ON)C1C=CC=CC=1>>[NH:5]1[C:14]2[C:23]3[N:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=[CH:4]1
Reactant: [NH-]c1cnc2cccnc2c1Cl
Reactant: [NH-]c1cnc2ccccc2c1Cl
Agent: Cl
Agent: NOCc1ccccc1
Product: c1cnc2c(c1)ncc1nc[nH]c12

Procedure:
In step (2) of Reaction Scheme I, an N-(4-chloroquinolin-3-yl)amide or N-(4-chloro[1,5]naphthyridin-3-yl)amide of Formula XXI is reacted with O-benzylhydroxylamine hydrochloride to provide a benzyloxy substituted 1H-imidazo[4,5-c]quinoline or 1H-imidazo[4,5-c][1,5]naphthyridine of Formula XXII. The reaction can be carried out by combining a compound of Formula XXI and O-benzylhydroxylamine hydrochloride in an alcoholic solvent, such as isopropanol, and heating the resulting mixture.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:11][CH:12]=[CH2:13])=[CH:4][C:5]2[S:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.CC(N=NC(C#N)(C)C)(C#N)C.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(=O)(O)[O-].[Na+]>[OH:1][C:2]1[C:3]([CH2:11][CH2:12][CH2:13][S:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:5]2[S:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Sc1ccccc1
Reactant: C=CCc1cc2c(cc1O)CCS2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cc2c(cc1CCCSc1ccccc1)SCC2
Temperature: 90 °C

Procedure:
To a solution of 5-hydroxy-6-allyl-2,3-dihydrobenzothiophene (125 mg, 0.65 mmole) in 0.5 mL thiophenol was added 28 mg AIBN. The reaction mixture was purged with nitrogen and heated to 90° C. for 3 hours. TLC analysis (90/10 hexane/EtOAc) showed the reaction to be complete. The reaction mixture was diluted with 25 mL saturated sodium bicarbonate and extracted 3×25 mL EtOAc. The combined organics were washed with sodium bicarbonate (2×25 mL), H2O (1×25 mL) and brine (1×25 mL). Drying over Na2SO4, filtration and concentration afforded 568 mg crude product as an oil. Purification by flash chromatography (90/10, hexane/EtOAc) 126 mg (64%) pure product NMR 287 MS181.