Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:23]2[C:31]3[C:26](=[C:27]([N:32]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=[CH:29][CH:30]=3)[CH:25]=[N:24]2)([CH2:21][CH3:22])/[CH:17]=[CH:18]/[C:19]#[N:20])=[CH:12][CH:11]=1>CS(C)=O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([N:23]2[C:31]3[C:26](=[C:27]([N:32]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:42])[CH3:43])[S:33]([CH3:36])(=[O:34])=[O:35])[CH:28]=[CH:29][CH:30]=3)[CH:25]=[N:24]2)([CH:17]2[CH2:4][CH:18]2[C:19]#[N:20])[CH2:21][CH3:22])=[CH:14][CH:15]=1
Reactant: C[S+](C)(C)=O
Reactant: CCC(/C=C/C#N)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(c1ccc(Cl)cc1)(C1CC1C#N)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of NaH (22 mg) in anhydrous DMSO (0.9 mL) was added trimethylsulfoxonium iodide (128 mg) at 0° C. and the mixture was stirred at rt for 3 h until the solution became clear. Then was added the solution of (E)-N-(1-(3-(4-chlorophenyl)-1-cyanopent-1-en-3-yl)-1H-indazol-4-yl)-N-((2-(trimethylsilyl)ethoxy)methyl) methanesulfonamide (42 mg) in anhydrous DMSO (0.1 mL) and the reaction mixture was stirred at 70° C. for 16 h. The solution was quenched with saturated NH4Cl solution, extracted with ethyl acetate (15 mL). The organic layer was washed with brine, dried over dry sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=4/1) to afford the title compound as a white solid. LC/MS m/z=559.2 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:10](=[O:35])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[N:13][C:12]=2[NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:36]([NH2:40])[CH2:37][CH2:38][NH2:39]>CN1C(=O)CCC1>[NH2:39][CH2:38][CH2:37][CH2:36][NH:40][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:10](=[O:35])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[N:13][C:12]=2[NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NCCCN
Reactant: N#Cc1ccccc1-c1ccc(C(=O)NCc2cccc(Br)n2)c(NCCc2cccc(F)c2)n1
Solvent: CN1CCCC1=O
Product: N#Cc1ccccc1-c1ccc(C(=O)NCc2cccc(NCCCN)n2)c(NCCc2cccc(F)c2)n1
Yield: 56.3 %

Procedure:
A solution of N-((6-bromopyridin-2-yl)methyl)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamide (50 mg, 0.095 mmol) and propane-1,3-diamine (396 ul, 4.75 mmol) in NMP was stirred in microwave at 15° C. for 15 min. The reaction mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O gave N-((6-(3-aminopropylamino)pyridin-2-yl)methyl)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamide (28 mg, 56%). LRMS (M+H+) m/z 524.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([OH:22])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].ClC1C=C(C(=O)CCC2C=CC=C(O)C=2)C=CC=1C(O)=O>>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([OH:22])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Agent: O=C(CCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Product: O=C(O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Yield: 90 %

Procedure:
This compound was prepared in 90% yield from 2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propyl]benzoic acid, methyl ester (Example 19) by the procedure described for 2-chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]benzoic acid (Example 41). The product was a racemic mixture and was not resolved.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:20])=[CH:5][C:6]([OH:19])=[C:7]([C:9](=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:8]=1)[CH3:2].Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.O1C2C(=CC=CC=2)C=CC1C([O-])=O>N1C=CC=CC=1.CCCCCC.CCOC(C)=O>[CH2:26]([O:25][C:23](=[O:24])[C:22](=[O:28])[CH:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:9]([C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]([OH:20])=[CH:5][C:6]=1[OH:19])=[O:18])[CH3:27]
Reactant: CCc1cc(C(=O)Cc2ccc(F)cc2)c(O)cc1O
Reactant: CCOC(=O)C(=O)Cl
Agent: Cl
Agent: O=C([O-])C1C=Cc2ccccc2O1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)C(C(=O)c1cc(CC)c(O)cc1O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(5-Ethyl-2,4-dihydroxy-phenyl)-2-(4-fluoro-phenyl)-ethanone (10.3 g, 37.6 mmol) in dried pyridine (100 ml) at 0° C., ethyl chlorooxoacetate (15.4 g, 112.8 mmol) was added. The solution was stirred at 0° C. for 4 hours and at room temperature for 16 hours. The aq. layer was neutralised with 1M HCl and extracted with DCM (2×100 ml). The combined DCM layers were then washed with 2M HCl (2×80 ml), sat. NaHCO3 (1×100 ml), brine (1×100 ml) and dried with Na2SO4. After filtration and evaporation of the solvent, dark brown oil was obtained (11.4 g). Rf=0.22 (EtOAc:n-hexane/1:2). LCMS shows it is a mixture of desired product [(M−1)−=373.1, RT=7.27) and the cyclised chromene carboxylate [(M−1)−=355.4, RT=7.83) in a ratio of ca. 6:1. A small amount of sample was purified by prep. TLC for spectroscopic analysis. 1H NMR (do-acetone) δ=7.75 (1H, s); 7.30 (2H, m); 7.00 (1H, m); 6.45 (1H, s); 4.65 (1H, s); 4.25 (211, q); 2.55 (2H, q) and 1.10 (6H, t)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][S:66](=[O:69])[CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][S:66](=[O:69])[CH2:65][CH2:64]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: O=S1CCNCC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCS(=O)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and thiomorpholine-1-oxide in DMSO at ambient temperature.
Reaction SMILES: CON(C)[C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOC(C)=O>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[O:22])(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: CON(C)C(=O)c1ccccc1CS(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Cc2ccccc2C=O)cc1
Temperature: 25 °C

Procedure:
To a solution of N-methoxy-N-methyl-2-{[(4-methylphenyl)sulfonyl]methyl}benzamide (0.645 mmol) in 5 mL THF at −78° C. is added 1.0 M solution of LiAlH4 in THF (0.709 mmol) slowly with stirring. The reaction is stirred at −78° C. for 1 hr and gradually warmed up to RT. The reaction mixture is diluted with EtOAc and washed with H2O. The solution is dried over Na2SO4 and the solvent is evaporated to give a quantitative yield of 2-{[(4-methylphenyl)sulfonyl]methyl}benzaldehyde.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([OH:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:9]([O:17][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Brc1cnc(Br)nc1
Reactant: CCCCCCCCO
Product: CCCCCCCCOc1ncc(Br)cn1

Procedure:
Analogously to the above procedure, 5.95 g of 2,5-dibromopyrimidine are reacted with 7.9 g of 1-octanol to give 2-octyloxy-5-bromopyrimidine. The product is purified by chromatography on silica gel.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]2[CH:44]=[C:45]3[N:50]([CH:51]=2)[CH:49]=[CH:48][C:47]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:46]3)O1>O1CCOCC1.C([O-])(O)=O.[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:43]3[CH:44]=[C:45]4[N:50]([CH:51]=3)[CH:49]=[CH:48][C:47]([C:52]([O:54][CH2:55][CH3:56])=[O:53])=[CH:46]4)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccn2cc(B3OC(C)(C)C(C)(C)O3)cc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccn2cc(-c3nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc2c1
Temperature: 100 °C

Procedure:
A mixture of bis(triphenylphosphine)palladium chloride (13.09 mg, 0.019 mmol), tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (187 mg, 0.373 mmol), and ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolizine-7-carboxylate (118 mg, 0.373 mmol) in dioxane (4 mL) and saturated aqueous NaHCO3 (1 mL) were heated to 100° C. in a Biotage Initiator microwave for 1 hour. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(7-(ethoxycarbonyl)indolizin-2-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate, which was subsequently dissolved in DCM (5 mL) and TFA (5 mL). The resulting solution was stirred at room temperature for 20 minutes, concentrated, and purified by preparatory HPLC, eluting with a gradient of 10-40% ACN (0.035% TFA) and water (0.05% TFA). The collected fractions were combined and dried to give a TFA salt of the title compound as a tan solid (31 mg, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (t, J=6.80 Hz, 3H), 1.78-1.81 (m, 1H), 2.11-2.12 (m, 1H), 3.62-3.65 (m, 1H), 3.89-3.91 (m, 1H), 3.94-4.28 (m, 3H), 4.31 (q, J=6.83 Hz, 2H), 4.43 (d, J=8.3 Hz, 2H), 4.53-4.54 (m, 1H), 6.96 (dd, J=1.46, 7.32 Hz, 1H), 7.15 (d, J=4.88 Hz, 1H), 7.71 (s, 1H), 7.92-7.93 (m, 2H), 8.21 (s, 1H), 8.36 (d, J=7.32 Hz, 1H), 8.48 (s, 1H), 9.03 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C23H24FN5O4, 454. found, 454.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][C:21]=1[F:29]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(Cl)c(F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (74 mg, 84%), MS (ISP) m/z=354.3 [(M+H)+], mp 221.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)C(=O)O1.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[N:10]1[C:11]2[C:12](=[CH:13][N:14]=[CH:15][CH:16]=2)[C:6]([OH:8])=[CH:5][CH:9]=1
Reactant: CC1(C)OC(=O)C(=CNc2ccncc2)C(=O)O1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1ccnc2ccncc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,2-dimethyl-5-((pyridin-4-ylamino)methylene)-1,3-dioxane-4,6-dione (1.149 g, 4.63 mmol) in diphenyl ether was heated at 200° C. for 20 min, then cooled to RT. Hexane was added and the mixture was stirred at RT for 30 mins. The solid was filtered off and washed with hexane to furnish 1,6-naphthyridin-4-ol as an off-brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH:9]([C:25]#[N:26])[CH2:10][CH2:11][C:12]([O:23][CH3:24])([CH3:22])[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH2:28][OH:29]>CO>[Si:15]([O:14][CH2:13][C:12]([O:23][CH3:24])([CH3:22])[CH2:11][CH2:10][CH:9]([N:7]([CH3:8])[C:6](=[O:27])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:25]([NH:28][OH:29])=[NH:26])([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17]
Reactant: NO
Reactant: COC(C)(CCC(C#N)N(C)C(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Solvent: CO
Product: COC(C)(CCC(C(=N)NO)N(C)C(=O)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Temperature: 40 °C

Procedure:
To a solution of tert-butyl(5-{[tert-butyl(dimethyl)silyl]oxy}-1-cyano-4-methoxy-4-methylpentyl)methylcarbamate (4.37 kg, 10.91 mol) in MeOH (28 L) at 30° C. was added aqueous hydroxylamine (50% in water, 1.2 L, 19.63 mol). The resulting mixture was heated to 40° C. overnight, then cooled and concentrated in vacuo. The crude residue was dissolved in 1.5 L of toluene, concentrated under reduced pressure, and dried in vacuo. The crude material was used in the next step without further purification. LC-MS: 434.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[N:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:21][C:16]3=[N:15][CH:14]=1)[CH:9]=[C:8]2[CH:27]=[O:28].[N+:29]([CH2:31]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:30].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[N:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH2:24][O:25][CH3:26])=[CH:21][C:16]3=[N:15][CH:14]=1)[CH:9]=[C:8]2[C:27]1[O:28][CH:31]=[N:29][CH:30]=1
Reactant: COCCOc1ccn2c(-c3cc(C=O)c4cccc(OC)c4n3)cnc2c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCCOc1ccn2c(-c3cc(-c4cnco4)c4cccc(OC)c4n3)cnc2c1
Temperature: 25 °C
Yield: 73 %

Procedure:
To 8-Methoxy-2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinoline-4-carbaldehyde (210 mg, 0.556 mmol) and 1-(isocyanomethylsulfonyl)-4-methylbenzene (130 mg, 0.668 mmol) in MeOH (5 mL) was added K2CO3 (154 mg, 1.11 mmol), followed by heating to reflux for 3 hours. The reaction was then cooled to ambient temperature, concentrated and purified by flash column chromatography (EtOAc/MeOH 10:1) providing the desired product (73%). MS APCI (+) m/z 417.2 (M+1) detected.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[C:4]([O:18][CH3:19])[CH:3]=1.C([Li])CCC.CCCCCC.[C:31]([N:38]1[CH2:41][C:40](=[O:42])[CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].O>O1CCCC1>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([C:40]3([OH:42])[CH2:39][N:38]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:41]3)=[CH:3][C:4]=2[O:18][CH3:19])=[CH:11][CH:12]=1)[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CCc1ccc(COc2ccc(Br)cc2OC)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(COc2ccc(C3(O)CN(C(=O)OC(C)(C)C)C3)cc2OC)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of 4-bromo-1-(4-ethylbenzyloxy)-2-methoxybenzene (1.2 g) prepared in (1) in THF (6.0 mL) was added dropwise 1.6 N n-butyllithium/hexane (2.8 mL) at −78° C. under argon atmosphere. The mixture was stirred at −78° C. for 30 min. A solution of 1-Boc-azetidin-3-one (0.64 g) in THF (6.0 mL) was added dropwise over 10 min to the mixture at −78° C. The reaction mixture was allowed to warm to RT and then stirred for 14 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=3/1 to 1/1) to give the title compound (0.88 g, 57%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>[N+:10]([C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1/[CH:20]=[CH:19]/[C:18]1[CH:21]=[CH:22][C:15]([OH:14])=[CH:16][CH:17]=1)([O-:12])=[O:11]
Reactant: C=Cc1ccc(OC)cc1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc(O)ccc1/C=C/c1ccc(O)cc1
Temperature: 80 °C
Yield: 79.2 %

Procedure:
To a stirred solution of 2-bromo-5-methoxynitrobenzene (5 g, 21.6 mmol) in dry acetonitrile (60 mL) were added 4-methoxystyrene (3.04 g, 22.6 mmol), N,N-diisopropylethylamine (8.36 g, 64.6 mmol), biphenyl-2-yl-di-t-butyl phosphine (385 mg, 1.3 mmol) and palladium acetate (290 mg, 1.3 mmol). The resulting mixture was heated at 80° C. overnight under N2. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, and dried over magnesium sulfate. Concentration under reduced pressure gave the crude product which was purified by column chromatography using ethyl acetate in hexane (5%-10%) to give the protected nitro-stilbene (4.4 g, 72%).
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]1)[CH2:20][CH2:19][CH2:18]2.[F-].C([N+:42](CCCC)(CCCC)CCCC)CCC>C1COCC1.CO.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:42][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]1)[CH2:20][CH2:19][CH2:18]2
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCCc3cc(Br)ccc32)C1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3cc(N)ccc32)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.1 %

Procedure:
A suspension of Pd2(dba)3 (46 mg, 0.05 mmol) in 2 mL anhydrous THF was treated with PtBu3 (600 μL of a 10% wt in hexanes solution, 0.2 mmol) and stirred at room temperature for 5 minutes. A solution of tert-butyl 3-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)pyrrolidine-1-carboxylate (381 mg, 1.00 mmol) followed by lithium hexamethyldisilizane (2.0 mL of a 1 M solution in THF, 2.0 mmol). The resulting dark brown suspension was heated at 95° C. for 1.5 hours. The mixture was cooled to room temperature and treated with 8 ml of a 1M tetrabutylammonium fluoride solution in THF then stirred at room temperature for 20 minutes. The mixture was partitioned between Et2O (100 mL) and H2O (20 mL). After extraction, the organic layer was separated and the aqueous layer was extracted once more with Et2O (50 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated to give a dark brown residue. This residue was subjected to flash chromatography on silica gel using 2.5% 2M NH3 in MeOH/CH2Cl2 to give a viscous dark brown residue (295 mg, 93.1%). 1H-NMR (CDCl3) δ 6.59-6.44 (m, 3H), 4.35-4.23 (m, 1H), 3.59-3.11 (m, 8H), 2.69 (t, J=6.3 Hz, 2H), 2.09-2.04 (m, 2H), 1.93-1.87 (m, 2H), 1.47 (s, 9H). MS (ESI): 318.2 (M+1, 100%).
Reaction SMILES: [F:1][C:2]([F:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][O:4][CH2:5][CH2:6][CH:7]=[O:8].[C:16]1(CCCCOCCC(O)CCC=C)[CH:21]=CC=[CH:18][CH:17]=1>>[F:1][C:2]([F:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][O:4][CH2:5][CH2:6][CH:7]([OH:8])[CH2:18][CH2:17][CH:16]=[CH2:21]
Reactant: C=CCCC(O)CCOCCCCc1ccccc1
Reactant: O=CCCOCC(F)(F)c1ccccc1
Product: C=CCCC(O)CCOCC(F)(F)c1ccccc1
Yield: 53 %

Procedure:
Obtained from Intermediate 82 (1.86 g, 8.7 mmol) by the procedure described in Intermediate 14. Purification by column chromatography with silica gel eluting with ethyl acetate/n-hexane (1:6) gave the title compound (1.24 g, 53%) as oil.
Reaction SMILES: [CH3:1]OCOC1C=CC=CC=1C(C1C=CC=CC=1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O-:28])=[O:27])[C:21]=1[F:29].[Li+].[Br-].[Na+].S(Cl)(Cl)=O>>[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O:28][CH3:1])=[O:27])[C:21]=1[F:29]
Reactant: COCOc1ccccc1C(=O)c1ccccc1
Reactant: O=C([O-])c1nccc(Cl)c1F
Agent: [Br-]
Agent: [Li+]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nccc(Cl)c1F
Temperature: 95 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedure described in Org. Prep. and Proc. Int., 29 (1), 117-122 (1997). A suspension of lithium 4-chloro-3-fluoropicolinate (20.0 g, 136 mmol) and sodium bromide (28.0 g, 272 mmol, 2 eq) in thionyl chloride (99 mL, 1.36 mmol, 10 eq) was heated to reflux (95° C.) with an argon flush. The reaction was refluxed for 2 days then thionyl chloride (50 mL, 680 mmol, 5 eq) was added again and the reaction was refluxed for 3 more days. The mixture was then evaporated and the residue cooled down to 0° C. Methanol (300 mL) was cautiously added by portions and the mixture was stirred at 23° C. overnight. The reaction was then partitioned into ethyl acetate/sat. aq sodium carbonate and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in boiling hexanes and the residual tar was decanted. The filtrate was evaporated to give the title material (24.36 g, 94%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.92 (3H, s), 8.01 (1H, t, J=5.1 Hz), 8.50 (1H, d, J=5.1 Hz). LC/MS (M+H)+: 190.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([CH2:28][CH2:29][CH3:30])[N:14]([CH2:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:31]>CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:14]3[C:10]4[C:9]5[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=[C:2]([NH2:31])[C:11]=4[N:12]=[C:13]3[CH2:28][CH2:29][CH3:30])[O:20][N:19]=2)=[CH:22][CH:23]=1
Reactant: N
Reactant: CCCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Solvent: CO
Product: CCCc1nc2c(N)nc3ccccc3c2n1Cc1cc(-c2ccc(F)cc2)no1
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-propyl-1H-imidazo[4,5-c]quinoline (0.806 g, 1.92 mmol) and 7 N ammonia in methanol (40 mL) was sealed in a pressure vessel and heated at 150° C. for 18 hours and allowed to cool to room temperature. The volatiles were removed under reduced pressure, and the resulting solid was stirred with 0.5 N sodium hydroxide in methanol. The solid was isolated by filtration, washed with diethyl ether, purified by column chromatography on silica gel (eluting with 5% to 10% CMA in chloroform), triturated with diethyl ether, isolated by filtration, and dried to provide 0.123 g of 1-{[3-(4-fluorophenyl)isoxazol-5-yl]methyl}-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, mp 226.0-227.0° C.