Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH2:18][CH3:19])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:24]3[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=3)[CH:7]=2)=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[N:11]=1)[CH3:19]
Reactant: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of Example A8 (1.10 g, 3.93 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.06 g, 5.11 mmol), K2CO3 (1.631 g, 11.80 mmol) and Pd(PPh3)4 (227 mg, 0.197 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar and heated at 80° C. for 24 h. The mixture was cooled to RT, treated with EtOAc, washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford crude 2-ethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (100% yield assumed) without further purification. MS (ESI) m/z: 326.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH:13][CH3:14])=[CH:6][C:3]=1[C:4]#[N:5]>CCO.[Pd]>[NH2:10][C:8]1[C:7]([NH:13][CH3:14])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Br:1])[CH:9]=1
Reactant: CNc1cc(C#N)c(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1cc(C#N)c(Br)cc1N

Procedure:
A stirred solution of 2-bromo-5-(methylamino)-4-nitrobenzonitrile (0.3 g, 0.001 mol) in EtOH (10 ml) was hydrogenated using Pd/C for 2 h at room temperature. The reaction was filtered through CELITE® and the filter bed was thoroughly washed with EtOH. The resulting solution was concentrated to provide 4-amino-2-bromo-5-(methylamino)benzonitrile, as a brownish a solid. Crude LCMS (M+1): 226.12. Purity: 63%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7]Br)[CH3:2].[NH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22].C([O-])(O)=O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[C:4]([CH2:5][CH2:6][CH2:7][NH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[C:21](=[O:23])[CH3:22])([O:3][CH2:1][CH3:2])=[O:9]
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCCNc1cc(OC)c(OC)cc1C(C)=O
Temperature: 110 °C
Yield: 62 %

Procedure:
Ethyl-4-bromobutyrate (190.7 g, 978 mM) was added with stirring to 2'-amino-4',5'-dimethoxyacetophenone (31.8 g, 163 mM) in triethylamine (33.9 mM) and the reaction mixture was heated at 110° C. for one hour. After cooling to room temperature 100 mL of 2% NaHCO3 was added and the reaction mixture was stirred for sixteen hours. A yellow solid formed which was dissolved in CHCl3 (250 mL). The aqueous phase was extracted with CHCl3 (4×200 mL), the organic extracts were combined and dried over MgSO4, filtered, and the solvent removed in vacuo to give a semisolid residue. The residue was chromatographed on SilicAR CC-7 and the appropriate fractions were crystallized upon standing from ether to afford the title compound in 62% yield, ,mp 74°-76° C.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15]C(OCC)=O)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1.CC[O-].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([CH2:38]/[C:39](=[N:42]/[H])/[NH:40][OH:41])[CH:35]=[CH:36][CH:37]=1>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][C:15]3[O:41][N:40]=[C:39]([CH2:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=4)[N:42]=3)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: [H]/N=C(/Cc1cccc(Cl)c1)NO
Reactant: CCCCCn1c(=O)n(CCCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3cccc(Cl)c3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C
Yield: 49.3 %

Procedure:
Ethyl 5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)pentanoate (70 mg, 0.19 mmol) was dissolved in EtOH. The solution was treated with a 21% solution of NaOEt in EtOH (78 μl, 0.21 mmol) and (1Z)-2-(3-chlorophenyl)-N-hydroxyethanimidamide (38 mg, 0.21 mmol). The reaction was heated in the microwave at 140° C. for 10 min. The mixture was partitioned between EtOH and 2M HCl (aq). The organic layer was decanted off and concentrated. The crude product was purified on the MDAP. The product fractions were combined and concentrated to give the title compound as a white solid (46 mg, 49%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:16])=[CH:10][C:11]([O:13]CC)=O)[CH:5]=[CH:6][CH:7]=1>S(=O)(=O)(O)O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:11]([OH:13])=[CH:10][C:9]([CH3:16])=[CH:8]2
Reactant: CCOC(=O)C=C(C)Cc1cccc(Br)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(O)c2ccc(Br)cc2c1

Procedure:
A solution of ethyl 4-(3-bromophenyl)-3-methylbut-2-enoate (8.07 g, 28.5 mmol) in concentrated sulfuric acid (20 mL) was stirred at 60° C. for 90 minutes. The reaction mixture was poured onto ice and diluted with water and extracted with ethyl acetate. The organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give the desired compound. 1H-NMR: 400 MHz, (CDCl3) δ: 7.98 (d, J=10.4 Hz, 1H), 7.83 (s, 1H), 7.43 (d, J=7.2 Hz, 1H), 7.08 (s, 1H), 6.67 (s, 1H), 2.42 (s, 3H). LCMS-ESI− (m/z): [M−H]− calcd for C11H9BrO: 236.09. Found: 236.9.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]#[N:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].O>C1COCC1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:13]([C:14]#[N:15])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: N#CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 44.94 %

Procedure:
3,5-Bis(trifluoromethyl)-phenylacetonitrile (1.4 mL, 1.0 eq.) was dissolved in THF (20 mL). The reaction mixture was cooled to −78° C. where a solution of NaHMDS (35% in THF) (4.34 mL, 1.05 eq.) was added dropwise. The reaction mixture was allowed to warm to 10° C. and stirred for 15 min. Then it was cooled to −78° C. where ethyl bromoacetate (0.87 mL, 1.0 eq.) was added. The reaction mixture was then allowed to warm to room temperature where it was stirred for 16 h. Reaction mixture was poured into water (50 mL) and was extracted with EtOAc (3×20 mL) The combined organic layers were washed with brine solution (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 3.5 g of crude product, which was purified by chromatography (4% ethyl acetate in hexane) to give 1.2 g of ethyl 3-(3,5-bis(trifluoromethyl)phenyl)-3-cyanopropanoate (Yield 44.94%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH2:11])=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[C:16]([O:20][C:21]([O:23]C(OC(C)(C)C)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][O:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:8][C:7]=1[C:12]([F:14])([F:15])[F:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(N)nc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(NOC(=O)OC(C)(C)C)nc1C(F)(F)F
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
A suspension of ethyl-2-amino-4-trifluoromethyl-thiazole-5-carboxylate (5.05 g, 21.02 mmol), di-t-butyldicarbonate (4.82 g, 22.07 mmol) and 4-dimethylaminopyridine (260 mg, 2.1 mmol) in dichloromethane (209 mL) was stirred under nitrogen for 1.5 h. The solvent was evaporated in vacuo. The residue was chromatographed on a silica gel column. Elution with 5% EtOAc in hexanes, followed by 15% EtOAc in hexanes afforded the title compound (6.57 g, 92%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=O)[CH2:13][CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH2:16]([NH2:19])[C:17]#[CH:18]>C(#N)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][C:4]=2[C:5]2[CH2:14][CH2:13][C:12](=[N:19][CH2:16][C:17]#[CH:18])[C:6]1=2
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2=O
Reactant: C#CCN
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC#N
Product: C#CCN=C1CCc2c1n(C)c1ccc(O)cc21
Reaction time: 16 h

Procedure:
To a stirred suspension of 7-hydroxy-4-methyl-1,4-dihydrocyclopent[b]indol-3(2H)-one (5.5 g) in acetonitrile (100 ml) was added propargyl amine (3.0 g), the solution was stirred at room temperature under a nitrogen atmosphere while titanium (IV) isopropoxide (15.6 g) was added in a dropwise manner. The mixture was stirred for 16 hours before quenching with ice water. The mixture was filtered, the solids were washed with CH2Cl2, the layers were separated and the organic portion was dried (Na2SO4). After concentration, the crude product was purified via flash chromatography eluting with hexane/acetone (2:1) to give 4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol.
Reaction SMILES: C([Li])(CC)C.CN(C)CCN(C)C.[CH2:14]([N:16]([CH2:27][CH3:28])[C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])[CH3:15].CN(C)[CH:31]=[O:32].Cl>C1COCC1>[CH2:27]([N:16]([CH2:14][CH3:15])[C:17](=[O:26])[C:18]1[C:19]([O:24][CH3:25])=[CH:20][CH:21]=[CH:22][C:23]=1[CH:31]=[O:32])[CH3:28]
Reactant: CN(C)C=O
Reactant: CCN(CC)C(=O)c1ccccc1OC
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1c(C=O)cccc1OC
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
Sec-butyl lithium (99.6 ml, 1.3 M in cyclohexane, 129.45 mmol, 1.3 equiv) was added dropwise at −78° C. to a solution of N,N,N′,N′-tetramethyl-ethane-1,2-diamine (15.04 g, 129.45 mmol, 1.3 equiv) in anhydrous THF (400 ml) under an atmosphere of argon. After 30 minutes at −78° C., a solution of N,N-diethyl-2-methoxy-benzamide (20.64 g, 99.58 mmol) in THF (100 ml) was added dropwise over 50 minutes. After 2 hours at −78° C., N,N-dimethylformamide (8.74 g, 119.49 mmol, 1.2 equiv) was added dropwise. 30 minutes after complete addition, TLC analysis indicated complete conversion. 6N aqueous HCl (90 ml) was carefully added at 0° C. After phase separation, the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine (2×100 ml), dried over Na2SO4, filtered and concentrated in vacuo to yield the title compound (24.71 g, quant.) in adequate purity for direct use in the next transformation. 1H NMR (400 MHz, CDCl3): δ=9.99 (s, 1H), 7.52 (dd, J=6.6/1.0 Hz, 1H), 7.46 (t, 7.6 Hz, 1H), 7.15 (dd, J=8.3/1.2 Hz, 1H), 3.86 (s, 3H), 3.78-3.68 (m, 1H), 3.58-3.49 (m, 1H), 3.10 (q, J=7.1 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H), 1.01 (t, J=7.3 Hz, 3H). MS (ES+): 236 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=[C:11]2[C:19]2[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.[N:35]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[C:36]=[O:37].O>C(Cl)Cl>[NH2:25][C:20]1[C:19]([C:11]2[N:10]([C:7]3[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:36]([NH:35][C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)=[O:37])=[CH:9][CH:8]=3)[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[N:12]=2)=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: NCc1ccc(-n2c(-c3cccnc3N)nc3cccnc32)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)NCc2ccc(-n3c(-c4cccnc4N)nc4cccnc43)cc2)cc1
Reaction time: 0.33 h
Yield: 15 %

Procedure:
3-(3-(4-(aminomethyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine HCl salt (63 mg, 0.2 mmol) was suspended in DCM (2 mL). Diisopropylethylamine (0.07 mL, 0.4 mmol) was added. After everything went into solution 1-isocyanato-4-methoxybenzene (29 mg, 0.2 mmol) were added. After 20 minutes, water (5 mL) was added and diluted with dichloromethane. The organic phase was separated and dried over Na2SO4. After filtration the solvent was removed under reduced pressure and it was purified by silica gel chromatography (0-20% methanol in dichloromethane) to yield the desired product (14 mg, 15% yield). Mp. 224-226° C.; 400 M Hz 1H NMR (CD3OD) δ: 8.36-8.28 (m, 1H), 8.22-8.15 (m, 1H), 8.0-7.92 (m, 1H), 7.56-7.47 (m, 2H), 7.46-7.36 (m, 3H), 7.36-7.29 (m, 1H), 7.29-7.22 (m, 2H), 6.89-6.81 (m, 2H), 6.5-6.42 (m, 1H), 4.47 (s, 2H), 3.75 (s, 3H); LCMS [M+H]: 466.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]([CH3:13])[CH:7]=[C:6]2[C:14]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH:15]=1.[H-].[Na+].[Cl:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40]Cl.C1CCCCC1.C(OCC)(=O)C>CN(C)C=O.O>[Cl:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:12][C:11]1[CH:10]=[C:9]2[C:5]([C:6]([C:14]3[N:22]([S:23]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)(=[O:25])=[O:24])[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[CH:15]=3)=[CH:7][N:8]2[CH3:13])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1O
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCOCCCl
Reaction time: 0.08 h
Yield: 39.1 %

Procedure:
A solution of 5-methoxy-1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-6-ol (2.998 g; 670 μmol) in dimethylformamide (3 ml) is placed in a 10 ml round-bottomed flask, sodium hydride (0.603 g; 2.01 mmol) is then added and the mixture is agitated for 5 minutes. The reaction mixture becomes green in color, and bis(2-chloroethyl) ether (0.235 ml; 2.01 mmol) is then added. The reaction mixture is then agitated for 1 hour 30 minutes at 20° C. Analysis by thin layer chromatography (50/50 cyclohexane/ethyl acetate) shows that the starting compound has been used up. The reaction mixture is run into water (30 ml) and then extracted with dichloromethane (20 ml). The organic extracts are combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure, to give the crude compound, which is purified by chromatography on silica gel (AIT cartridge, Flash Silica column, 20-40 μm, 25 g, ref: FC-25SI-BP-SUP, 10 ml/min, 70/30 to 50/50 cyclohexane/ethyl acetate). The fractions containing the expected compound are combined and then evaporated under reduced pressure, giving 2-{6-[2-(2-chloroethoxy)ethoxy]-5-methoxy-1-methyl-1H-indol-3-yl}-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.145 g; 39%), which is used as it is for the following step.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([Si](C(C)C)(C(C)C)C(C)C)[CH:13]=[C:12]3[CH2:28][C@H:29]2[CH2:33][CH2:32][CH2:31][N:30]2[CH3:34])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([C:4]1[S:8][C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[C:12]3[CH2:28][C@H:29]2[CH2:33][CH2:32][CH2:31][N:30]2[CH3:34])=[CH:6][CH:5]=1)(=[O:3])[NH2:2]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C[C@H]2CCCN2C)c2cc(-c3ccc(C(N)=O)s3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(-c3ccc(C(N)=O)s3)cc12

Procedure:
5-(5-Carbamoyl-2-thienyl)-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1-triisopropylsilylindole (see Preparation 61) was reacted with tetra-n-butylammonium fluoride in tetrahydrofuran, using a procedure similar to that described in Example 62. This yielded the title compound as an off-white foam. Found: C,64.93; H,6.33; N,11.60. C19H21N3OS.3/16CH2Cl2 requires: C,64.84; H,6.06; N,11.82%.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3].N1C=CC=CC=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O>[C:7]1([CH2:6][O:5][CH2:4][CH:2]([O:3][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)COCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC(C)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 73.9 %

Procedure:
CH3CH(OH)CH2OCH2Ph (50.0 g) and pyridine (150 ml) were put into a flask, and under cooling with ice, p-toluenesulfonic acid chloride (63.2 g) was added over a period of 30 minutes. The mixture was stirred at room temperature for 4 days, and then water (150 ml) was added, followed by extraction twice with dichloromethane (100 ml). The extracted organic phase was washed twice with a KHCO3 saturated aqueous solution (100 ml) and twice with water (100 ml), dried over magnesium sulfate, filtered and further concentrated to obtain PhCH2OCH2CH(CH3)OTs (71.2 g).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:19]([CH2:18][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH:24]=1
Reactant: Clc1ccc(OCc2ccccc2)c(CBr)c1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(Cc2cc(Cl)ccc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
3-Nitro-1H-pyrazole (Fluorochem) (0.505 g, 4.47 mmol) was dissolved in DMF (10 ml). Potassium carbonate (0.973 g, 7.04 mmol) and sodium iodide (75 mg, 0.50 mmol) were added. 2-(Bromomethyl)-4-chloro-1-[(phenylmethyl)oxy]benzene (WO2006066968) (1.33 g, 4.25 mmol) was added and washed in with further DMF (10 ml). The reaction was stirred at room temperature for 30 min, then concentrated in vacuo. The crude material was treated with water (150 ml). The aqueous mixture was extracted with EtOAc (3×150 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified on silica (70 g) using 0-100% EtOAc-cyclohexane. Appropriate fractions were concentrated in vacuo to give the title compound as a yellow solid (952 mg);
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[NH2:24]>>[F:19][C:20]([F:32])([F:33])[C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:25]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:27]=1
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COCC1COc2cc3ncnc(Nc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c3cc2O1
Yield: 47.1 %

Procedure:
The titled compound (8 mg, 50%) was prepared in a similar manner as in Example 8, except for employing 4-chloro-7-methoxymethyl-[1,4]dioxano[2,3-g]quinazoline (10 mg, 0.037 mmol) and 3,5-bis(trifluoromethyl)aniline (17 mg, 0.075 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:8]2=O.C[Si]([C:26]#[N:27])(C)C.FC(F)(F)C(O)=O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>[C:26]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1)#[N:27]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Agent: Cc1ccccc1S(=O)(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2C#N
Temperature: 60 °C
Yield: 83.4 %

Procedure:
To a suspension of 10 g (35 mmol) of 5,6-dimethoxy-3-phenyl 1,2,3,4-tetrahydro 1-naphthalenone, the product of Example 1, was added 7.5 g (75.6 mmol) of trimethylsilyl cyanide (commercially available from Aldrich Chemical Company) and approximately 50 mg of anhydrous aluminum chloride (AlCl3). The reaction mixture was heated at 60° C. for 3 h then cooled to ambient temperature and diluted with 150 mL of toluene. The volume of the reaction mixture was reduced in vacuo to approximately 50 mL. The resultant trimethylsilyl adduct was dehydrated by treatment with 15 mL of trifluoroacetic acid and 100 mg of p toluene sulfonic acid in 200 mL of toluene at reflux temperature for 1 h. The reaction mixture was cooled to ambient temperature, the layers separated and the organic layer washed with water, aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a colorless oil. The oil was purified by column chromatography on silica gel eluted with 20% ethyl acetate in hexane to give 8.5 g (83% yield) of the title compound, m.p. 109°-110° C.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.B([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.CCCCCC>COCCOC.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:11][C:8]1([F:12])[O:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[NH:23][C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])[C:10]=2[O:9]1
Reactant: FC1(F)Oc2cccc(Br)c2O1
Reactant: Cc1ccc(NC(=O)C(C)(C)C)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(NC(=O)C(C)(C)C)c(-c2cccc3c2OC(F)(F)O3)c1

Procedure:
To a mixture of the title compound of Step B (10.0 g, 42.2 mmol) and the title compound of Step A (4.96 g, 21.1 mmol) in ethylene glycol dimethyl ether (100 mL) were added a solution of sodium carbonate (4.47 g, 42.2 mmol) in water (25 mL) and bis(triphenylphosphine) palladium (II) chloride (740 mg, 1.05 mmol) at room temperature. The mixture was heated at reflux for 2 h and then allowed to come to room temperature. The solvent was removed under reduced pressure and the residue was suspended in water. The aqueous mixture was extracted with ethyl acetate three times. The organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to obtain a brown liquid. Flash chromatography of the crude product on silica gel eluting with 1:6 ethyl acetate/hexane afforded the title compound of Step C, a compound of the invention, as a yellow oily solid (8 g, 55%). 1H NMR (CDCl3): δ1.12 (s,9H), 2.37 (s,3H), 7.1 (m,2H), 7.12 (s, 1H), 7.2 (t, 1H), 7.25 (m,1H), 7.3 (br s,1H), 7.9 (d, 1H).