Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4].[NH2:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([Cl:23])[N:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>CN1C(=O)CCC1.O>[CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C:20]3[CH:19]=[C:18]([Cl:23])[N:17]=[C:16]([NH2:15])[N:21]=3)=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4]
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: COC(=O)c1coc2cc(O)ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1coc2cc(Oc3cc(Cl)nc(N)n3)ccc12
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
A mixture of 6.20 g (32.3 mMol) 6-hydroxy-benzofuran-3-carboxylic acid methyl ester, 8.5 g (51.8 mMol) 2-amino-4,6-dichloropyrimidine and 14.2 g (67 mMol) K3PO4 in 250 ml NMP is stirred for 3.5 h at 60° C. Then the mixture is poured into 1 l EtOAc and 1 l water, the aq. layer separated off and extracted 3 times with EtOAc. The organic phases are washed with water and brine and dried (Na2SO4). Then char coal is added, the mixture filtered and the filtrate concentrated. Trituration from ether gives the title compound: m.p.: 213-214° C. More product can be obtained from the filtrate by column chromatography (SiO2; hexane/EtOAc 2:1) as described in step 9.4.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:10][C:11]=2[CH2:12][CH2:13][C:14]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:24].[Na+].[OH2:26].Cl>C(O)C>[C:1]1([C:7]2[N:8]=[C:9](/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:10][C:11]=2[CH2:12][CH2:13][C:14]([OH:26])=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: N#CCCc1oc(/C=C/c2ccccc2)nc1-c1ccccc1
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCc1oc(/C=C/c2ccccc2)nc1-c1ccccc1
Yield: 65 %

Procedure:
To a solution of 3-[4-phenyl-2-((E)-2-phenylethenyl)-5-oxazolyl]propionitrile (1.3 g) in ethanol (18 mL) was added 2N aqueous sodium hydroxide solution (9 mL) and the mixture was stirred with heating under reflux for 5 hrs. The reaction mixture was cooled and water was added. The mixture was acidified with 2N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 3-[4-phenyl-2-((E)-2-phenylethenyl)-5-oxazolyl]propionic acid (0.9 g, yield 65%) as colorless prism crystals. melting point: 138–139° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[N:8][O:9][C:10]=1[CH:11]([CH3:13])[CH3:12])=[O:5])C.O[Li].O>C1COCC1.O>[CH:11]([C:10]1[O:9][N:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:6]=1[C:4]([OH:5])=[O:3])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1c(-c2cccc(F)c2)noc1C(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2cccc(F)c2)c1C(=O)O

Procedure:
A mixture of 15 g crude 5-isopropyl-3-(3-fluoro-phenyl)-isoxazole-4-carboxylic acid ethyl ester and 10.08 g (240 mmol) LiOH.H2O in 75 mL THF, 50 mL water was heated under reflux for 15 h. The mixture was concentrated, acidified and extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4 and evaporated to yield 4.1 g (33% in two steps) of the title compound as a light yellow solid. (m/e): 250.1 (MH+; 100%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:26]=[CH:25][C:9]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][C:21](=[O:24])[CH2:20]3)=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:27]([CH2:29][NH2:30])O.C(=O)([O-])[O-].[K+].[K+].[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[C:37]([N:30]1[C:21]2([CH2:22][CH2:23][N:19]([C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C:9]4[CH:25]=[CH:26][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=4)=[CH:14][CH:15]=3)[CH2:20]2)[O:24][CH2:27][CH2:29]1)(=[O:39])[CH3:38]
Reactant: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC(=O)C3)cc2)cc1
Reactant: NCCO
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC4(C3)OCCN4C(C)=O)cc2)cc1
Reaction time: 48 h

Procedure:
A mixture of 4-butoxy-N-[4-(3-oxopyrrolidin-1-yl)phenyl]benzamide (70 mg), ethanolamine (12 mg), potassium carbonate (27 mg) and dichloromethane (3 ml) was stirred for 48 hours, and then acetyl chloride (16 mg) was added. After 20 hours, the mixture was diluted with dichloromethane, washed with water, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 437.54 (C25H31N3O4); MS (ESI): 438 (M+H+) was obtained in this way.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].[SH-:11].[K+].C(O)C.C[O-].[Na+].CO.Cl[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]2[N:28]=[CH:29][CH2:30][N:23]12>CO>[S:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:11][C:27]1[CH:26]=[CH:25][C:24]2[N:23]([CH:30]=[CH:29][N:28]=2)[N:22]=1)(=[O:9])(=[O:8])[NH2:10]
Reactant: [SH-]
Reactant: ClN1C=CC=C2N=CCN21
Reactant: NS(=O)(=O)CCCCCCl
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: NS(=O)(=O)CCCCCSc1ccc2nccn2n1
Temperature: 70 °C

Procedure:
To a solution of 1.57 g of 5-chloropentanesulfonamide in 40 ml of methanol was added 40 ml of 2N-potassium hydrosulfide-ethanol solution, followed by heating at 70° C. for 45 minutes. To the reaction mixture was added 1.54 g of 28% sodium methoxide-methanol solution and 1.16 g of 5-chloroimidazo[1,2-b]pyridazine, which was refluxed for an hour. The reaction mixture was concentrated to dryness under reduced pressure. The residue was extracted with 40 ml of chloroform and 40 ml of 0.1N-hydrochloric acid. The aqueous layer was extracted three times with chloroform. Then the combined organic layers were dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was subjected to a silica gel column chromatography, eluting with methanol-chloroform (1:35). The corresponding fractions were concentrated. The residue was recrystallized from methanol to obtain 0.62 g of the title compound.
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:32]=[CH:31][C:9]([CH2:10][NH:11][C:12]2[C:13]([NH2:30])=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:17]=2)=[CH:8][CH:7]=1.[CH3:33][C:34]1([CH3:47])[C@@H:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C@@H:35]1[C:42](OCC)=O>C(Cl)Cl>[Br:5][C:6]1[CH:32]=[CH:31][C:9]([CH2:10][N:11]2[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:14][C:13]=3[N:30]=[C:42]2[C@H:35]2[C@H:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:34]2([CH3:33])[CH3:47])=[CH:8][CH:7]=1
Reactant: Nc1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(Br)cc1
Reactant: CCOC(=O)[C@H]1[C@H](C(=O)OCC)C1(C)C
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)C1(C)C
Temperature: 90 °C
Reaction time: 12 h

Procedure:
A solution of trimethyl aluminum (0.2 mL, 2 M in toluene) was added to 25 mL round-bottomed flask containing N1-(4-bromobenzyl)-4-(quinolin-2-ylmethoxy)benzene-1,2-diamine (100 mg, 0.23 mmol), trans-diethyl 3,3-dimethylcyclopropane-1,2-dicarboxylate (49 mg, 0.23 mmol), and DCM (4 mL). After 12 h, the solution was partitioned between sat. NaHCO3 (30 mL) and EtOAc (30 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combine organic layers were dried with sodium sulfate, filtered, and concentrated to dryness. To the residue was added ethanol (2 mL) and concentrated HCl (0.1 mL, 12 N). The solution heated to 90° C. After 5 h, the mixture was cooled, concentrated to dryness, and purified by reverse phase HPLC to afford the title compound. MS (ESI): mass calcd. for C32H30BrN3O3, 583.15; m/z found, 584.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:12]([N:28]=1)=[CH:13][C:14]1[CH2:15][N:16]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17](=[O:20])[C:18]=1[CH:19]=2.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH2:37][C@@H:38]([NH2:40])[CH3:39].CCN(C(C)C)C(C)C>CCO>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[CH2:37][C@@H:38]([NH:40][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:12]([N:28]=1)=[CH:13][C:14]1[CH2:15][N:16]([CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:17](=[O:20])[C:18]=1[CH:19]=2)[CH3:39]
Reactant: C[C@H](N)Cc1cc(F)ccc1Cl
Reactant: O=C1c2cc3[nH]c(-c4c(Cl)cc[nH]c4=O)nc3cc2CN1CCN1CCCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cc1cc(F)ccc1Cl)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN1CCCC1)C3
Yield: 36.1 %

Procedure:
A solution of 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (50 mg, 0.126 mmol), (1S)-2-(2-chloro-5-fluorophenyl)-1-methylethylamine (30 mg, 0.164 mmol) and DIEA (66 uL, 0.38 mmol) in 2 mL of EtOH was heated at 80° C. for 24 h. Then the solvent was evaporated and the residue was purified by column (silicagel, DCM:MeOH 9:1) to give 2-(4-((1S)-2-(2-chloro-5-fluorophenyl)-1-methylethylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(2-pyrrolidin-1-ylethyl)-6,7-dihydroimidazo[4,5-f]isoindol-5(3H)-one (25 mg, 36%) as pale yellow oil. ESI-MS: m/z (MH+) 549.5. 1H NMR (300 MHz, CD3OD): δ 8.0 (d, J=60.6 Hz, 1H), 7.67 (d, J=52.5 Hz, 1H), 7.33 (m, 1H), 7.15 (m, 2H), 6.89 (m, 1H), 6.09 (m, 1H), 4.66 (m, 2H), 3.98 (m, 2H), 3.68 (m, 1H), 3.30 (m, 2H), 3.15 (m, 6H), 2.02 (m, 4H), 1.43 (d, J=6.60 Hz, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O.[Ag-]=O>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([N:17]3[CH2:20][CH:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18]3)=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: BrCc1ccccc1
Reactant: O=C(CCOCCc1ccc2sccc2c1)N1CC(O)C1
Agent: O=[Ag-]
Solvent: CN(C)C=O
Product: O=C(CCOCCc1ccc2sccc2c1)N1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 31 h

Procedure:
In 8 mL of N,N-dimethylformamide was dissolved 1.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-(3-hydroxy-1-azetidinyl)-1-propanone, and 1.90 g of silver(I) oxide and 0.97 mL of benzyl bromide were added to the solution, after which the resulting mixture was stirred at room temperature for 31 hours. The insoluble materials were filtered off and water and ethyl acetate were added to the residue, after which the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; toluene:ethyl acetate=3:1 to 1:4) to obtain 1.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-[3-(benzyloxy)-1-azetidinyl]-1-propanone as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[NH:26][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: COc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and m-anisidine (22 μl, 0.193 mmol) similar to Example 13 and isolated as a yellow solid (31 mg, 46%). 1H NMR (CDCl3): 8.77-8.75 (m, 2H), 8.28-8.25 (m, 2H), 7.36 (t, J=8.3 Hz, 1H), 7.13 (s, 1H), 7.03 (s, 1H), 6.98-6.96 (m, 2H), 6.83-6.81 (m, 1H), 3.84 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl[CH2:20][CH2:21][C@H:22]([O:29][C:30]1(OC2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH2:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:43](=[O:46])([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.O>[CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:20][CH2:21][C@H:22]([O:29][C:30]3[CH:31]=[CH:32][C:33]([O:46][C:43]4[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=4)=[CH:34][CH:35]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: ClCC[C@H](OC1(Oc2ccccc2)C=CC=CC1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(Oc4ccccc4)cc3)c3ccccc3)CC2)c1
Yield: 149.4 %

Procedure:
A mixture of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (65.5 mg, 0.266 mmol), 4-{[(1S)-3-chloro-1-phenylpropyl]oxy}-(4-phenoxy)benzene (0.100 mg, 0.296 mmol), potassium carbonate (40.9 mg, 0.296 mmol) and sodium iodide (67.0 mg, 0.444 mmol) in DMF (1.0 mL) at 100° C. for 3 hours. The reaction mixture was poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3×30 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by Prep-TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] to give the desired product (0.109 g, 74.6%) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.40–7.30 (m, 4H), 7.20–7.10 (m, 6H), 7.09 (s; 1H), 6.99 (apparent d, 1H, J=7.8 Hz), 6.98 (apparent t, 1H, J=7.8 Hz), 6.93 (apparent d, 2H, J=8.4 Hz), 6.84 (m, 2H), 5.20 (apparent dd, 1H, J=4.4, 8.5 Hz), 3.03 (m, 2H), 2.51 (m, 4H), 2.24 (apparent sept, 1H, J=7.8 Hz), 2.20–2.10 (m, 3H), 1.90 (m, 4H), 1.25 (d, 6H, J=7.9 Hz); ESMS m/e: 549.41 (M+H)+; Anal. Calc. for C36H40N2O3: C, 78.80; H, 7.35; N, 5.11. Found: C, 78.58; H, 7.48; N, 5.09.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](O)=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:21]>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:21])=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Reaction time: 0.25 h

Procedure:
7-Methoxy-4-hydroxy-3-ethoxycarbonylquinoline (Step A, 21 g, 0.08 mol) and POCl3 (100 mL) were mixed together and the mixture was heated at reflux for 6 h. The excess POCl3 was removed under vacuum. The solid residue was suspended in ice-cold 1N NaOH and the mixture was stirred for 15 min. The solid was filtered off, washed several times with water and then by a minimum amount of MeOH to give 7-methoxy-4-chloro-3-ethoxycarbonylquinoline as an off-white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][CH:24]4[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]4)[C:21]([CH2:31][O:32][CH2:33][CH3:34])=[N:20][C:14]=3[C:15]([NH2:19])=[N:16][C:17]=2[CH:18]=1)C1C=CC=CC=1.CO>C(#N)C.[OH-].[Pd+2].[OH-]>[NH2:19][C:15]1[C:14]2[N:20]=[C:21]([CH2:31][O:32][CH2:33][CH3:34])[N:22]([CH2:23][CH:24]3[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]3)[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:18][C:17]=2[N:16]=1
Reactant: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC1COC(C)(C)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC1COC(C)(C)O1
Reaction time: 24 h

Procedure:
Palladium hydroxide (Pearlman's catalyst) (20% palladium w/w on carbon, 900 mg) was added to a solution of 7-benzyloxy-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-ylamine (9.00 g, 19.46 mmol, 1 eq), prepared as described in Example 152, in acetonitrile (300 mL) and methanol (300 mL) in a sealed vessel and the reaction mixture was placed under hydrogen pressure (30 psi, 2.1×105 Pa) for 24 hours. The crude reaction mixture was filtered through a layer of CELITE filter aid and the filtrate was concentrated under reduced pressure and triturated with acetonitrile. The resulting crystalline material was collected by filtration and washed with acetonitrile to afford 3.66 of 4-amino-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-7-ol as an off-white solid. Additional product (0.36 g) was isolated from the filtrate of the initial trituration by concentration under reduced pressure, trituration with acetonitrile, and filtration for a total yield of 4.02 g of 4-amino-1-[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-7-ol, isolated as an off-white solid, mp 240-242° C. 1H-NMR (300 MHz, DMSO) δ 9.51 (br s, 1H), 7.96 (d, J=8.9 Hz, 1H), 6.95 (d, J=2.5 Hz, 1H), 6.76 (dd, J=8.9, 2.6 Hz, 1H), 6.46 (br s, 2H), 4.92-4.60 (m, 4H), 4.57-4.45 (m, 1H), 4.18 (dd, J=8.6, 6.4 Hz, 1H), 3.83 (dd, J=8.6, 6.5 Hz, 1H), 3.54 (q, J=7.0 Hz, 2H), 1.34 (s, 3H), 1.19 (s, 3H), 1.15 (t, J=7.0 Hz, 3H); 13C-NMR (75 MHz, DMSO) δ 156.41, 152.0, 148.1, 147.2, 133.9, 124.4, 121.7, 111.7, 109.7, 109.0, 107.9, 74.4, 66.0, 65.2, 64.3, 47.6, 26.2, 24.9, 14.8; MS (APCI) m/z 373.0 (M+H)+; Anal, calcd for C19H24N4O4: C, 61.28; H, 6.50; N, 15.04. Found: C, 61.12; H, 6.53; N, 14.98.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][O:16][C:17](=[O:25])[C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[N:20][CH:19]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[C:41]3[C:40]([CH2:42][CH2:43][CH2:44][CH2:45]O)=[N:39][CH:38]=[N:37][C:36]=3[S:35][CH:34]=2)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[C:41]3[C:40]([CH2:42][CH2:43][CH2:44][CH2:45][O:24][C:22]4[CH:21]=[N:20][CH:19]=[C:18]([CH:23]=4)[C:17]([O:16][CH3:15])=[O:25])=[N:39][CH:38]=[N:37][C:36]=3[S:35][CH:34]=2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1cncc(O)c1
Reactant: OCCCCc1ncnc2scc(-c3ccc(F)cc3)c12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cncc(OCCCCc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Reaction time: 16 h
Yield: 8 %

Procedure:
Diisopropyl azodicarboxylate (0.040 g, 0.20 mmol) was added to a mixture of 5-hydroxynicotinic acid methyl ester (0.038 g, 0.25 mmol), 4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butan-1-ol (0.060 g, 0.20 mmol), triphenylphosphine (0.052 g, 0.20 mol) and tetrahydrofuran (3.0 mL) at room temperature with stirring. After 16 h, the solvent was removed in vacuo. The residue was diluted with ethyl acetate (50 mL) and washed with sodium bicarbonate (1×40 mL). The organic solution was concentrated and purified by column chromatography (1.5-5% methanol/dichloromethane) to give 7 mg (8%) methyl 5-4-[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]butoxynicotinate as white solid. MS [M+H]=438.1, LC/MS (EI) tR 4.63 min (Method D), 1H NMR (CDCl3) δ (ppm) 9.02 (s, 1H), 8.82 (s, 1H), 8.38 (s, 1H), 7.68 (s, 1H), 7.42-7.35 (m, 2H), 7.34 (s, 1H), 7.20-7.10 (m, 2H), 3.97 (s, 3H), 3.88 (t, J=6.3 Hz, 2H), 2.72 (t, J=7.2 Hz, 2H), 1.81-1.66 (m, 2H), 1.66-1.53 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:17]([C:20]1[CH:25]=[CH:24][C:23]([N:26]=O)=[CH:22][CH:21]=1)([O-])=O.S.[Na]>C(O)C>[NH2:17][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[N:16][C:13]2[CH:14]=[CH:15][C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[CH:11][CH:12]=2)=[CH:22][CH:21]=1
Reactant: O=Nc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: S
Agent: [Na]
Solvent: CCO
Product: Nc1ccc(N=Nc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)cc1

Procedure:
The preparation of a compound of formula XII in which m is the integer 2 and X is alkoxy and Y is p-nitrophenyl can be carried out, for example, by reacting 4-nitro-4'-aminobiphenyl with 4-nitro-nitrosobenzene, partially reducing the resulting compound with sodium hydrogen sulfide in ethanol according to Houben-Weyl XI/1, 418, to give 4-amino-4'-(p-nitrophenyl)azobenzene, diazotizing this with sodium nitrite and hydrochloric acid, coupling the diazonium salt with phenol and etherifying the resulting compound with a 1-bromoalkane in ethanol in the presence of potassium carbonate and sodium iodide.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)=[O:8])[CH2:5][CH2:4]1.[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1.CN(C=O)C>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:11]3[CH:10]=[C:9]([C:7]([NH:6][CH:3]4[CH2:4][CH2:5]4)=[O:8])[CH:13]=[N:12]3)(=[O:35])=[O:36])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C(NC1CC1)c1cn[nH]c1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NC4CC4)cn3)ccc2n1CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
Sodium hydride (0.98 g, 60%, 25 mmol) was added to a solution of N-cyclopropyl-1H-pyrazole-4-carboxamide (0.49 g, 3.5 mmol) (see following steps B and C for preparation) in 40 mL of THF-DMF (3:1) at 0° C. Stirring for 1 h at 0° C. and 0.5 h at room temperature, 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.30 g, 3.5 mmol) was added. The reaction mixture was stirred for 2 h at 0° C., quenched with NaHCO3 (10 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with NaCl (20 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 0.54 g (33%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.52-0.59 (m, 2 H), 0.71-0.79 (m, 2 H), 1.39-1.57 (m, 4 H), 1.60 (s, 9 H), 2.22-2.37 (m, 1 H), 2.71-2.79 (m, 1 H), 3.26-3.34 (m, 2 H), 3.86-3.93 (m, 2 H), 4.43 (d, J=7.62 Hz, 2 H), 7.91-7.95 (m, 1 H), 7.97-8.01 (m, 1 H), 8.03 (d, J=0.78 Hz, 1 H), 8.34 (d, J=1.37 Hz, 1 H), 8.74 (d, J=0.59 Hz, 1 H); MS (ESI) (M+H)+=485.8.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14][C:15]([CH3:19])([CH3:18])[C:16]#[CH:17]>CCN(CC)CC.[Cu]I.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>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([C:17]#[C:16][C:15]([CH3:19])([CH3:18])[CH3:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CC(C)(C)C)cc1OC
Temperature: 100 °C
Yield: 91.1 %

Procedure:
A mixture of methyl 4-bromo-2-methoxybenzoate (1.2 g, 0.0049 mol), copper(I) iodide (0.093 g, 0.00049 mol), 3,3-dimethyl-1-butyne (0.70 mL, 0.0059 mol) and bis(triphenylphosphine)palladium(II) chloride (0.34 g, 0.00049 mol) in Et3N (10 mL) was heated at 100° C. in a 50 mL sealed reaction vessel for 16 hours. After cooling, the mixture was filtered through Celite® and the filter cake was washed repeatedly with ethyl acetate. The filtrate was concentrated under vacuum and the residue was purified by column chromatography on silica gel to give a viscous oil (1.10 g, 91%).