Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7](=[O:15])[C:6]2[CH:16]=[C:17]([CH2:20][C:21]([O:23]C)=[O:22])[CH:18]=[CH:19][C:5]1=2)[CH2:2][CH3:3].[OH-].[Na+].CO>O>[CH2:1]([N:4]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7](=[O:15])[C:6]2[CH:16]=[C:17]([CH2:20][C:21]([OH:23])=[O:22])[CH:18]=[CH:19][C:5]1=2)[CH2:2][CH3:3]
Reactant: CCCN1Cc2ccccc2C(=O)c2cc(CC(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN1Cc2ccccc2C(=O)c2cc(CC(=O)O)ccc21
Yield: 79.4 %

Procedure:
A mixed liquid of methyl 5,6-dihydro-5-n-propyl-11-oxodibenz[b,e]azepine-2-acetate (0.5 g), sodium hydroxide (2 g), methanol (20 ml) and water (10 ml) was treated in the same manner as described in Example 21 to afford the desired compound (0.38 g) as yellow powdery crystals.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:8]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:33]([C:35]1[N:36]=[CH:37][N:38](C(OC(C)(C)C)=O)[CH:39]=1)=[CH2:34]>CN(C=O)C.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>[NH:38]1[CH:39]=[C:35](/[CH:33]=[CH:34]/[C:2]2[CH:25]=[CH:24][C:5]([O:6][C:7]3[C:8]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:9]=4[S:10][C:11]=3[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[CH:4][CH:3]=2)[N:36]=[CH:37]1
Reactant: Oc1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(Br)cc2)cc1
Reactant: C=Cc1cn(C(=O)OC(C)(C)C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(/C=C/c3c[nH]cn3)cc2)cc1
Temperature: 150 °C
Yield: 14.1 %

Procedure:
To a microwave vial containing 3-(4-bromophenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (20 mg, 0.05 mmol) in DMF (2 mL) was added triethyl amine (0.202 mL, 1.45 mmol), tert-butyl 4-vinyl-1H-imidazole-1-carboxylate (28.2 mg, 0.15 mmol) and Pd(PPh3)2Cl2 (3.40 mg, 4.84 μmol). The system was flushed with nitrogen and heated at 150° C. for 1 h under microwave irradiation. The mixture was cooled to room temperature and diluted with DCM and sat. aq. NH4CI. The organic layer was collected (phase separator), concentrated in vacuo and purified by reverse phase HPLC (basic condition, 0.1% NH4OH in 1-100% CH3CN/H2O) to afford (E)-3-(4-(2-(1H-imidazol-4-yl)vinyl)phenoxy)-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (3 mg, 7.03 μmol, 15% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.57 (s, 1 H), 7.43 (d, J=8.59 Hz, 2 H), 7.30 (d, J=8.59 Hz, 2 H), 6.96-7.14 (m, 3 H), 6.74-6.96 (m, 4 H), 6.53-6.74 (m, 3 H), LC/MS (m/z, MH+): 427.3.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][C:13]3[C:14]4[CH2:15][C:16]5[N:21]6[CH:22]=[C:23]([C:25]([O:27]CC)=[O:26])[N:24]=[C:20]6[C:19](=[O:30])[NH:18][C:17]=5[C:31]=4[CH:32]=[CH:33][CH:34]=3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)(=O)C>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][C:13]3[C:14]4[CH2:15][C:16]5[N:21]6[CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=[C:20]6[C:19](=[O:30])[NH:18][C:17]=5[C:31]=4[CH:32]=[CH:33][CH:34]=3)[NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(Cc2nc(-c4ccccc4)c[nH]2)c1C3
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(Cc2nc(-c4ccccc4)c[nH]2)c1C3
Yield: 61.3 %

Procedure:
A mixture of 0.4 g of ethyl 9-(4-phenyl-1H-imidazol-2-ylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate and 12.5 ml of acetic acid and 2.5 ml of 6 N hydrochloric acid is heated for 24 hours at a temperature close to 100° C. The reaction medium is filtered while hot on sintered glass and the solid residue obtained is washed with three times water and then dried under reduced pressure at 60° C. 0.23 g of 9-(4-phenyl-1H-imidazol-2-ylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylic acid is thus obtained in the form of a white solid melting at a temperature greater than 260° C. (Analysis: C24H17N5O3, 3.96 H2O, 0.91 C2H4O2 : % calculated C: 68.07, H: 4.05, N: 16.54, % found C: 68.1, H: 4.1, N:16.5).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CC1(C)C(C)(C)OB([C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH:24]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.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.C(OCC)(=O)C>[CH3:9][O:8][C:6]1[C:5]([O:10][CH3:11])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH:24]=2)[CH:7]=1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)C1
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1cc(C2=CC(C)(C)CC(C)(C)C2)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
To a solution of 1-bromo-4,5-dimethoxy-2-nitrobenzene (1.06 g, 4.04 mmol) produced in Example (87a) in 1,2-dimethoxyethane (30 mL) were added 4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane (1.28 g, 4.85 mmol) produced in Example (4b), tripotassium phosphate (1.29 g, 6.06 mmol) and water (1.5 mL). Tetrakis(triphenylphosphine)palladium (230 mg, 0.20 mmol) was then added to the mixture while stirring at room temperature under a nitrogen atmosphere. The mixture was then stirred for 13 hours at an external temperature of 70° C., and stirring was continued for 3 hours at an external temperature of 100° C. Tetrakis(triphenylphosphine)palladium(0) (230 mg, 0.20 mmol) and water (2 mL) were added to the reaction mixture, and it was further stirred for 9 hours at an external temperature of 100° C. and then for 11 hours at an external temperature of 70° C. After cooling the reaction mixture, ethyl acetate was added and the mixture was filtered through Celite. The filtrate was concentrated and extracted with ethyl acetate, and the obtained organic layer was washed with brine. The organic layer was then dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 1.1 g of the title compound as a brown oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:22]=[CH:21][C:17]4[O:18][CH2:19][O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:23][N:24]([CH3:34])[C:25]1[CH:30]=[CH:29][C:28]([C:2]2[N:7]=[C:6]([NH:8][C:9]([C:11]3([C:14]4[CH:22]=[CH:21][C:17]5[O:18][CH2:19][O:20][C:16]=5[CH:15]=4)[CH2:13][CH2:12]3)=[O:10])[CH:5]=[CH:4][CH:3]=2)=[CH:27][CH:26]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: O=C(Nc1cccc(Br)n1)C1(c2ccc3c(c2)OCO3)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2cccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)n2)cc1
Temperature: 80 °C

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (6-bromo-pyridin-2-yl)-amide (36 mg, 0.10 mmol) was dissolved in 1 mL of N,N-dimethylformamide in a reaction tube. 4-(Dimethylamino)phenylboronic acid (21 mg, 0.13 mmol), 0.1 mL of an aqueous 2 M potassium carbonate solution, and (Pd(dppf)Cl2 (6.6 mg, 0.0090 mmol) were added and the reaction mixture was heated at 80° C. for three hours. The resulting material was cooled to room temperature, filtered, and purified by reverse-phase preparative liquid chromatography to yield the pure product as a trifluoroacetic acid salt. ESI-MS m/z calc. 401.2, found 402.5 (M+1)+. Retention time 2.96 minutes. 1H NMR (400 MHz, CD3CN) δ 1.23-1.27 (m, 2H), 1.62-1.66 (m, 2H), 3.04 (s, 6H), 6.06 (s, 2H), 6.88-6.90 (m, 2H), 6.93-6.96 (m, 1H), 7.05-7.07 (m, 2H), 7.53-7.56 (m, 1H), 7.77-7.81 (m, 3H), 7.84-7.89 (m, 1H), 8.34 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=O.C([CH2:15][S:16]([CH2:19][S:20]([CH2:23][C:24](O)=O)(=[O:22])=[O:21])(=[O:18])=[O:17])(O)=O>C(O)(=O)C>[OH:11][C:10]1[CH:9]=[CH:8][C:5](/[CH:24]=[CH:23]/[S:20]([CH2:19][S:16](/[CH:15]=[CH:6]/[C:5]2[CH:8]=[CH:9][C:10]([OH:11])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:17])=[O:18])(=[O:21])=[O:22])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: COc1cc(C=O)ccc1O
Solvent: CC(=O)O
Product: COc1cc(/C=C/S(=O)(=O)CS(=O)(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Yield: 60 %

Procedure:
A solution of 3-methoxy-4-hydroxybenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 60% yield. m.p. 125-127° C.
Reaction SMILES: [Mg].I[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].[Cl-].[NH4+].[CH3:11][O:12][CH:13]([O:22][CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>C1COCC1.[Cu]I.C(OCC)(=O)C>[CH3:11][O:12][CH:13]([O:22][CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6])[CH:15]=1
Reactant: COc1ccc(C(OC)OC)cc1
Reactant: FC(F)(F)CCI
Agent: [Cu]I
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(OC)OC)cc1CCC(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 229A (15.8 g, 60 mmol) in dry THF (120 ml) was added to magnesium turnings (4.1 g, 170 mmol) at RT. The mixture was heated to 60° C. for 5 min, which initiated an exothermic reaction. The heating bath was removed and the mixture was allowed to reflux gently. Upon subsidence of the reaction (approximately 5 min), the mixture was heated to reflux for an additional 20 min and then was allowed to cool to RT. The clear green supernatant was transferred via canula away from excess magnesium and into a separate flask containing copper (I) iodide (575 mg, 3.0 mmol) under a nitrogen atmosphere. To this mixture was added 1-iodo-3,3,3-trifluoropropane (15 g, 67 mmol) and the resulting mixture was allowed to stir for 16 h, during which time a thick white precipitate developed. Aqueous ammonium chloride solution, ethyl acetate, and hexanes were added, and the organic layer was dried over sodium sulfate. Evaporation followed by silica gel chromatography of the residue using 3:1 hexanes/ethyl acetate as eluant provided 7.7 g of a mobile, slightly yellow oil, which was a 6:1 (mol ratio) mixture of 229B and 4-methoxybenzaldehyde dimethyl acetal, as determined by proton NMR. This mixture was used without further purification.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][C:9]2[O:13][N:12]=[C:11]([C:14]([O:16]CC)=O)[N:10]=2)=[CH:6][CH:5]=1.Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][CH2:35][NH:36][C:14]([C:11]1[N:10]=[C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:20][CH:19]=2)[O:13][N:12]=1)=[O:16]
Reactant: CCOC(=O)c1noc(Cc2ccc(OC(F)(F)F)cc2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccc(OC(F)(F)F)cc2)n1
Yield: 36.5 %

Procedure:
This compound was prepared according to method F with ethyl 5-(4-(trifluoromethoxy)benzyl)-1,2,4-oxadiazole-3-carboxylate (0.109 g; 0.346 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.080 g; 0.346 mmol), HATU (0.131 g; 0.346 mmol), N,N diisopropylethylamine (0.149 mL; 0.865 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.0587 g (36%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(4-(trifluoromethoxy)benzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]2[CH2:42][CH:41]([OH:43])[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([O:44][C:45]4[CH:50]=[CH:49][C:48]([N+:51]([O-])=O)=[CH:47][N:46]=4)[CH:39]=3)[O:34]2)[CH:30]=[CH:31][CH:32]=1>[Zn]>[NH2:51][C:48]1[CH:49]=[CH:50][C:45]([O:44][C:38]2[CH:39]=[C:40]3[C:35](=[CH:36][CH:37]=2)[O:34][CH:33]([C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=2)[CH2:42][CH:41]3[OH:43])=[N:46][CH:47]=1
Reactant: COc1cccc(C2CC(O)c3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)c1
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: [Zn]
Product: COc1cccc(C2CC(O)c3cc(Oc4ccc(N)cn4)ccc3O2)c1

Procedure:
6-(5-Aminopyridin-2-yloxy)2-(3-methoxyphenyl)chroman-4-ol was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 using 138 mg 2-(3-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol (Example 102) and 457 mg of Zn. 1H NMR (400 MHz, d6-DMSO) δ: 7.52 (d, 1H, J 3.0 Hz), 7.32 (t, 1H, J 15.7, 7.8 Hz), 7.06 (dd, 1H, 8.7, 3.0 Hz), 7.01-7.04 (m, 3H), 6.91 (dd, 1H, J 8.6, 2.4 Hz), 6.78-6.80 (m, 1H), 6.76 (d, 1H, J 8.7 Hz), 6.71 (d, 1H, J 8.6 Hz), 5.54 (d, 1H, J 6.5 Hz), 5.19 (d, 1H, J 10.6 Hz), 5.01 (s, 2H), 4.88-4.94 (m, 1H), 3.78 (s, 3H), 2.27-2.32 (m, 1H), 1.87-1.96 (m, 1H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]([F:30])([F:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][S:15]([C:18]1[N:28]=[C:21]2[N:22]=[C:23]([CH3:27])[CH:24]=[C:25](O)[N:20]2[N:19]=1)(=[O:17])=[O:16]>C(#N)C>[F:6][C:7]([F:30])([F:29])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][S:15]([C:18]1[N:28]=[C:21]2[N:22]=[C:23]([CH3:27])[CH:24]=[C:25]([Cl:3])[N:20]2[N:19]=1)(=[O:17])=[O:16]
Reactant: Cc1cc(O)n2nc(S(=O)(=O)Nc3ccccc3C(F)(F)F)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3ccccc3C(F)(F)F)nc2n1
Reaction time: 72 h

Procedure:
Phosphorus oxychloride (135 ml, 1.47 mol) was diluted with 335 ml of dry acetonitrile and added to 15 g (40 mmol) of N-(2-trifluoromethylphenyl)-7-hydroxy-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide in a one liter flask and heated to reflux with stirring. After about 3 days, the reaction was found to be complete by thin layer chromatography. Volatiles were removed by evaporation under reduced pressure until the mixture became very viscous and the residue was poured onto about one liter of ice and water with stirring. After about 30 minutes, the solid that formed was collected by filtration, washed with ice water, and dried under reduced pressure at room temperature. It was then dissolved in methylene chloride and the resulting solution dried over magnesium sulfate for about five minutes and filtered. The volatiles were removed from the filtrate by evaporation under reduced pressure to obtain the title compound as a white solid residue. The product, the structure of which was confirmed by NMR analysis, amounted to 13.4 g (85.4 percent of theory).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:5]=2[N:6]=1.[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30]I)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:29][CH2:30][S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([OH:19])=[O:18])[C:5]=3[N:6]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1CCc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 34 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and 3,3-diphenylpropyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 34%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].Cl>C(Cl)Cl.CO>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:29](=[O:31])[CH3:30])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1NCCCN
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1nc2c(N)nc3ccccc3c2n1NCCCNC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
A solution of N1-(3-Aminopropyl)-2-ethyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.89 g, 3.1 mmol) in 30 mL of CH2Cl2 was placed under an atmosphere of nitrogen. The solution was treated first with triethylamine (0.92 mL, 6.6 mmol) and then slowly with acetyl chloride (0.234 mL, 3.29 mmol). After 16 h, another equivalent of acetyl chloride was added. After 3 h, the reaction was concentrated under reduced pressure to yield an orange oil. The oil was then treated with 20 mL of 1 M HCl in MeOH and stirred at ambient temperature to hydrolyze any bis-amide. After 16 h, the reaction was quenched with 25 mL of 10% Na2CO3 solution. The mixture was concentrated under reduced pressure to remove MeOH. The aqueous oily suspension was treated with 75 mL of 95:5 CHCl3:MeOH, transferred to a separatory funnel and separated. The organic portion was washed with brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a yellow foam. The foam was purified by chromatography (40 g SiO2, 25% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield a light yellow solid. The solid was recrystallized from MeCN to give N-{3-[(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)amino]propyl}acetamide (0.67 g) as yellow crystals. mp 167–169° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.42 (d, J=8.1 Hz, 1H), 7.85 (t, J=5.2 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.44–7.38 (m, 1H), 7.25–7.20 (m, 1H), 6.96 (t, J=5.3 Hz, 1H), 6.51 (s, 2H), 3.19–3.08 (m, 4H), 2.97 (q, J=7.4 Hz, 2H), 1.78 (s, 3H), 1.69 (p, J=7.0 Hz, 2H), 1.38 (t, J=7.5 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 169.5, 154.9, 152.0, 144.9, 132.1, 126.9, 126.1, 124.2, 121.1, 121.0, 114.9, 49.7, 36.8, 28.0, 23.0, 19.5, 12.4; MS (ESI) m/z 327 (M+H)+; Anal. Calcd for C17H22N6O: C, 62.56; H, 6.79; N, 25.75; Found: C, 62.40; H, 7.06; N, 25.82.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([CH2:14][Br:15])=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cc(C)ccc2s1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2cc(CBr)ccc2s1
Yield: 97.4 %

Procedure:
A mixture of 5-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (3.09 g.), N-bromosuccinimide (2.67 g.) and azobisisobutyronitrile (0.20 g.) in carbon tetrachloride (150 ml.) was heated under reflux for 5 hours. The mixture was then filtered and the filtrate was evaporated to give a solid which was crystallized from methanol to give 5-bromomethylbenzo[b]thiophene-2-carboxylic acid methyl ester (4.16 g.), m.p. 108°-110°.
Reaction SMILES: O[CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[C:19](=[O:25])[CH2:18][CH2:17]3)[CH:11]=[N:12][CH:13]=1.S(Cl)([Cl:28])=O>>[Cl:28][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[CH:9]=[C:10]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[C:19](=[O:25])[CH2:18][CH2:17]3)[CH:11]=[N:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc(N4CCC[C@H]4CO)c3)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc(N4CCC[C@H]4CCl)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-5 [B], 6-[5-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one (example 5) has been reacted with thionyl chloride to give the title compound as an orange oil. MS: 356.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[N:10][OH:11])[CH2:4][C:3]1([CH3:13])[CH3:12].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:10]([CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([CH3:1])[C:3]([CH3:13])([CH3:12])[CH2:4]1)[OH:11])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: CN1C(C)(C)CC(=NO)CC1(C)C
Product: CN1C(C)(C)CC(N(O)Cc2ccccc2)CC1(C)C
Yield: 40 %

Procedure:
Following the procedure of Example 1, the title compound is prepared from 1,2,2,6,6-pentamethylpiperidin-4-one oxime (5.0 g, 27 mmol) and benzyl bromide (4.6 g, 27 mmol) in a 40% yield to give 3.0 g of a white solid which melts at 107°-108° C. after recrystallization from ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][C:5]=1[CH2:21][CH2:22][OH:23])[CH3:2].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[CH2:21][CH2:22][O:23][C:31](=[O:32])[NH:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:2]
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)C(Cc1ccc(OCC)c(CCO)c1)OC(C)C
Product: CCOc1ccc(CC(OC(C)C)C(=O)O)cc1CCOC(=O)Nc1ccccc1

Procedure:
Using ethyl 3-[4-ethoxy-3-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:32])[CH2:13][CH2:14][C@H:15]([N:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:16]([OH:18])=[O:17])=[O:7])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[N-:40]=[N+:41]=[N-].[Na+]>CC(C)=O.O>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:32])[CH2:13][CH2:14][C@H:15]([N:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]([OH:18])=[O:17])=[O:7])=[CH:33][CH:34]=1)=[N+:40]=[N-:41]
Reactant: Nc1ccc(C(=O)OCCOC(=O)CC[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=Nc1ccc(C(=O)OCCOC(=O)CC[C@@H](C(=O)O)n2c3ccccc3c3ccccc32)cc1
Reaction time: 0.08 h
Yield: 84.2 %

Procedure:
To a stirred solution of 25 (0.38 g, 0.83 mmol) in acetone (8 mL) was added 5% HCl (8 mL) at 0° C. and the solution was stiffed for 5 min NaNO2 (0.70 g, 1.0 mmol) in 1 mL water was added dropwise to the above solution causing an immediate color change from colorless to orange. After 20 min of stiffing at 0° C., NaN3 (0.107 g, 1.65 mmol) in 1 mL water was added dropwise to the reaction mixture causing an immediate color changed from orange to colorless to pale yellow. The reaction mixture was stiffed for additional 30 min and extracted with ethyl acetate (100 mL), washed with water (30 mL) and brine (30 mL). The final organic layer was dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to obtain (S)-5-(2-(4-azidobenzoyloxy)ethoxy)-2-(9H-carbazol-9-yl)-5-oxopentanoic acid 26 (0.34 g, 85%) as an off white gummy solid.