Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:17])([O:15][CH3:16])[O:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.OS(O)(=O)=O.[N+:23]([O-])([O-:25])=[O:24].[K+]>>[C:1](=[O:17])([O:15][CH3:16])[O:2][C:3]1[CH:8]=[C:7]([N+:23]([O-:25])=[O:24])[C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)Oc1ccc(F)cc1C1CCCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
2-Cyclopentyl-4-fluorophenyl methyl carbonate (2.246 g, 9.43 mmol) was added portion-wise to H2SO4 (6.9 mL, 130.0 mmol) to generate a colorless homogeneous solution. This solution was then cooled to 0° C. and KNO3 (1.143 g, 11.31 mmol) was added portion-wise maintaining the internal temperature below 5° C. The reaction was stirred for 2 h and then poured on ice water. The aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (10% ethyl acetate/hexanes) provided 2-cyclopentyl-4-fluoro-5-nitrophenyl methyl carbonate (2.063 g, 77% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 8.19 (d, J=6.9 Hz, 1H), 7.63 (d, J=12.5 Hz, 1H), 3.89 (t, J=5.9 Hz, 3H), 3.18-3.12 (m, 1H), 1.99-1.92 (m, 2H), 1.82-1.74 (m, 2H), 1.69-1.51 (m, 4H). MS (ESI) m/z (M+H+): 284.3.
Reaction SMILES: [CH3:1][C:2]([CH3:60])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:57])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:56])[CH2:21][CH2:22][C@@:23]3([C@@H:40]4[O:44][C:43](=[O:45])[N:42]([C:46]5([C:49]6[N:54]=[CH:53][C:52]([Cl:55])=[CH:51][N:50]=6)[CH2:48][CH2:47]5)[CH2:41]4)[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:59])[CH3:58])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:55][C:52]1[CH:51]=[N:50][C:49]([C:46]2([N:42]3[CH2:41][C@H:40]([C@:23]45[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]4[C@@H:25]4[C@@:20]([CH3:56])([CH2:21][CH2:22]5)[C@@:19]5([CH3:57])[C@@H:28]([C@:29]6([CH3:32])[C@@H:16]([CH2:17][CH2:18]5)[C:15]([CH3:58])([CH3:59])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:60])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]6)[CH2:27][CH2:26]4)[O:44][C:43]3=[O:45])[CH2:48][CH2:47]2)=[N:54][CH:53]=1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2([C@H]2CN(C3(c4ncc(Cl)cn4)CC3)C(=O)O2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2([C@H]2CN(C3(c4ncc(Cl)cn4)CC3)C(=O)O2)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of 1-tert-butyl 4-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-3-(1-(5-chloropyrimidin-2-yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (109) (80 mg, 0.094 mmol) in DCM (10 mL) was added TFA (1 mL, 0.094 mmol). The reaction mixture was stirred at rt overnight, then diluted with DCM (20 ml) and washed with water (2×15 ml), saturated sodium bicarbonate solution (20 ml) and brine (20 ml), dried over sodium sulfate, filtered and concentrated to get a residue. The residue was purified on silica gel using petroleum ether/EtOAc (4:1 to 1:1) as eluent to give the product 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-3-(1-(5-chloropyrimidin-2-yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (111) (50 mg, 67%) as a white solid. This material was lyophilized to give a white powder. Stereochemistry was tentatively assigned as drawn but not fully confirmed spectroscopically. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.58 (s, 2H), 5.04 (t, J=8.5 Hz, 1H), 4.51 (dd, J=4.6, 10.9 Hz, 1H), 3.41-3.04 (m, 4H), 2.75-2.44 (m, 3H), 2.36 (d, J=13.3 Hz, 1H), 2.12-0.72 (m, 49H); LC/MS: m/z calculated 791.4. found 792.3 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:41][OH:42]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14]([NH:41][OH:42])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc([C@@H](CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)NO)N2C(=O)c3ccccc3C2=O)ccc1OC
Yield: 91.5 %

Procedure:
(3R)-3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide was prepared by the procedure of Example 1 from (3R)-3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropanoic acid (14.6 g, 39.5 mmol), carbonyldiimidazole (7.1 g, 43.5 mmol) and hydroxylamine hydrochloride (3.3 g, 47.4 mmol) in tetrahydrofuran (50 mL) to afford (3R)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-phthalimidopropionamide as a white solid (13.9 g, 91% yield): mp, 257.0–259.5° C.; 1H NMR (DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H, CH3), 3.11 (d, J=7.9 Hz, 2H, CH2), 3.72 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.67 (t, J=7.8 Hz, 1H, NCH), 6.90 (br s, 2H, Ar), 7.02 (br s, 1H, Ar), 7.86 (br s, 4H, Ar), 8.79 (br s, 1H, OH), 10.59 (br s, 1H, NH); 13C NMR (DMSO-d6) δ 14.67, 34.22, 50.18, 55.44, 63.71, 111.73, 112.36, 119.65, 123.11, 131.18, 131.21, 134.56, 147.67, 148.53, 165.97, 167.61. Anal Calcd for C20H20N2O6: C, 62.49; H, 5.24; N, 7.29. Found: C, 62.79; H, 5.24; N, 7.23;
Reaction SMILES: C1(O[C:8](=O)[C:9]2[C:14]([OH:15])=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=[C:11]([Br:20])[C:10]=2[CH3:21])C=CC=CC=1.[NH2:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[S:31]([NH2:34])(=[O:33])=[O:32].BrCl>>[Br:20][C:11]1[CH:12]=[C:13]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:14]([OH:15])=[C:9]([C:8]2[NH:34][S:31](=[O:33])(=[O:32])[C:25]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=3[N:23]=2)[C:10]=1[CH3:21]
Reactant: Cc1c(Br)cc(C(C)(C)C)c(O)c1C(=O)Oc1ccccc1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Agent: ClBr
Product: Cc1c(Br)cc(C(C)(C)C)c(O)c1C1=Nc2cc(Cl)ccc2S(=O)(=O)N1

Procedure:
From 3-bromo-5-tert-butyl-6-hydroxy-2-methyl-benzoic acid phenyl ester and 2-amino-4-chlorobenzenesulfonamide; obtained as white crystals following column chromatography (silica gel/EtOAc-heptane-CH2Cl2 1:6:3); mp 270-271° C. (decomp., ebullition); 1H NMR (DMSO): δ 12.58 (s, 1H, NH), 9.64 (s, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.55 (dd, J˜8.3, 1.9 Hz, 1H), 7.48 (s, 1H), 7.34 (d, J=1.9 Hz, 1H), 2.20 (s, 3H), 1.37 (s, 9H); LC-MS: m/z 457/459/461 (M+H; BrCl isotope pattern), 935/937/939/941 (2M+Na; Br2Cl2 isotope pattern); Rt=2.24 min.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6](=O)[C:7]2[N:8]([CH:10]=[CH:11][CH:12]=2)[CH:9]=1)([CH3:3])[CH3:2].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:6]1[C:7]2[N:8]([CH:10]=[CH:11][CH:12]=2)[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1cn2cccc2c(=O)[nH]1
Product: CC(C)c1cn2cccc2c(Cl)n1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
3-isopropylpyrrolo[1,2-a]pyrazin-1(2H)-one from step b (1.6 g, 4.7 mmol) was combined with POCl3 (20 mL) and stirred at 70° C. for 20 minutes. POCl3 was removed under reduced pressure. The residue was taken up in DCM and washed twice with saturated sodium bicarbonate. Afterward the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 5-10% MTBE/hexanes) to provide chloro-3-isopropylpyrrolo[1,2-a]pyrazine (1.09 g, 62% yield).
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9]([CH:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=3)[OH:13])[CH:10]=[CH:11][C:2]1=2>C(Cl)Cl.O=[Mn]=O>[O:1]1[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]([O:22][CH3:23])[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=3)=[O:13])[CH:10]=[CH:11][C:2]1=2
Reactant: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCCO3)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)c2ccc3c(c2)OCCCO3)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A mixture of (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-(3,5-dimethoxy-phenyl)-methanol (1.8 g, 5.7 mmol) and MnO2 (2.6 g, 30 mmol) in methylene chloride (40 mL) was stirred at room temperature for 4 h. More MnO2 (1.3 g) was added and kept for overnight. The suspension was filtered thru a pad of Celite. Removal of solvent gave (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-(3,5-dimethoxy-phenyl) -methanone as an oil (1.3 g, 72% yield): 1H NMR (CDCl3) δ 2.22-2.28 (m, 2H, CH2), 3.82 (s, 6H, 2CH3), 4.28-4.31 (m, 4H, 2CH2), 6.64 (t, J=2 Hz, 1H, Ar), 6.88 (d, J=2 Hz, 2H, Ar), 6.99 (d, J=8 Hz, 1H, Ar), 7.42 (dd, J=1, 9 Hz, 1H, Ar), 7.48 (d, J=2 Hz, 1H, Ar).
Reaction SMILES: [F:1][C:2]1[C:23]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:22][CH:21]=[C:20]([F:38])[C:3]=1[C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][CH2:16][C:17]([OH:19])=O)[CH:13]=2)[NH:8][CH:7]=1)=[O:5].[CH2:39]([NH2:41])[CH3:40].Cl.CN(C)CCCN=C=NCC>O1CCCC1>[F:1][C:2]1[C:23]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=2)(=[O:26])=[O:27])=[CH:22][CH:21]=[C:20]([F:38])[C:3]=1[C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][CH2:16][C:17]([NH:41][CH2:39][CH3:40])=[O:19])[CH:13]=2)[NH:8][CH:7]=1)=[O:5]
Reactant: CCN
Reactant: O=C(O)CCc1cnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCNC(=O)CCc1cnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid (P-0034, 42 mg, 0.076 mmol) dissolved in tetrahydrofuran (3 mL) was added a 2.0 M solution of ethylamine in tetrahydrofuran (110 μL, 0.23 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 16 hrs, then extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography (methanol/dichloromethane), with the eluting solvents removed via lyophilizing to provide a white fluffy solid (P-0035, 13 mg, 30%). MS(ESI) [M+H+]+=581.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[F:22]>CN(C=O)C.O>[F:22][C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc([N+](=O)[O-])cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a stirred suspension of methyl glycol (2.2 mL, 28.28 mmol, 1.5 eq.) and K2CO3 (7.8 g, 56.60 mmol, 3.0 eq.) in DMF (20 mL) was added 1,2-difluoro-4-nitrobenzene (3.0 g, 18.85 mmol, 1.0 eq.) and the mixture was stirred for 16 h at 70° C. The reaction mixture was cooled and diluted with water (30 mL) and extracted with ethyl acetate (40 mL). The organic layer was separated and washed with water (50 mL), brine (50 mL), and dried over sodium sulfate and the solvent evaporated under vacuum. The crude product was washed with n-pentane (30 mL) to obtain 2-fluoro-1-(2-methoxyethoxy)-4-nitrobenzene (3 g, 74%, as solid; TLC system: EtOAc/PE (1:9), Rf: 0.2).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:31]=[CH:30][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[CH:18][CH:17]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)=[CH:30][CH:31]=2)=[O:10])=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)cc1
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)phenyl)acetate (20 mg, 0.043 mmol) was diluted with DCM (1 mL) followed by the addition of TFA (1 mL). After stirring for 2 hours, the reaction was concentrated, diluted with ether and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)phenyl)acetic acid (17 mg, 97% yield) as a white solid. 1H NMR (400 MHz, CD3Cl3, CD3OD) 7.70 (d, 2H), 7.30 (m, 4H), 7.19 (m, 2H), 7.00 (m, 4H), 3.62 (m, 4H), 2.90 (t, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15]CCCC1)([O-])=O>P(OCC)(OCC)OCC>[N:10]1[C:9]23[CH2:8][CH2:7][NH:6][CH2:5][CH:4]2[NH:1][CH:8]=[CH:9][C:4]3=[N:1][CH:15]=1
Reactant: O=[N+]([O-])c1cnccc1N1CCCCC1
Agent: CCOP(OCC)OCC
Product: C1=CC2=NC=NC23CCNCC3N1
Temperature: 110 °C
Yield: 104.1 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a reflux condenser and magnetic stirrer was purged with nitrogen and charged with 159a (6.00 g, 29.0 mmol) and triethyl phosphite (200 mL). After heating at 110° C. for 24 h, the triethyl phosphite was removed under reduced pressure, and the residue was partitioned between methylene chloride (200 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with methylene chloride (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 53% yield (2.66 g) of 159b as a yellow solid: mp 94-95° C.; 1H NMR (500 MHz, CDCl3) d 8.98 (s, 1H), 8.37 (d, 1H, J=6.0 Hz), 7.22 (d, 1H, J=6.0 Hz), 4.09 (t, 2H, J=6.0 Hz), 3.11 (t, 2H, J=6.0 Hz), 2.15 (m, 2H), 2.05 (m, 2H); MS (APCI+) m/z 174.1 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[O:10][N:9]=2)[S:5][C:4]=1[CH2:26][N:27]1[CH2:30][CH:29]([C:31]([O:33]C)=[O:32])[CH2:28]1)[CH3:2].[OH-].[Na+].C(O)(=O)C>>[CH2:1]([C:3]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)[O:10][N:9]=2)[S:5][C:4]=1[CH2:26][N:27]1[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]1)[CH3:2]
Reactant: CCc1cc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)sc1CN1CC(C(=O)OC)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1cc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)sc1CN1CC(C(=O)O)C1
Yield: 96.3 %

Procedure:
The title compound (0.16 g) was synthesized in a yield of 95% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 3 (3e) using methyl 1-({3-ethyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methyl)azetidine-3-carboxylate (0.17 g, 0.36 mmol) that was obtained in Example 22 (22g), a 1 N aqueous solution of sodium hydroxide (1.1 mL, 1.1 mmol), and acetic acid (62 μL, 1.1 mmol).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24](=[O:26])[CH3:25])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.FC(F)(F)S(O[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[C:40]([Si:37]([CH3:39])([CH3:38])[O:26][C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[CH:15]=[CH:14][C:12]2[NH:13][C:9]([CH2:8][O:7][C:6]3[CH:27]=[CH:28][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:4][CH:5]=3)=[N:10][C:11]=2[CH:17]=1)=[CH2:25])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 1-{2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-phenyl}-ethanone (0.215 g, 0.524 mmol) in CH2Cl2 (8 mL) at 0° C. was added tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (0.304 g, 1.15 mmol) and triethylamine (0.29 mL, 2.10 mmol). After stirring 2 h, the reaction mixture was concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 2:1) to afford the title compound as a yellow oil (0.242 g, 88%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:28][O:29][CH2:30][CH3:31])[N:14]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.CCOCC.C>Cl.CCO.CO>[NH2:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:28][O:29][CH2:30][CH3:31]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl 2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (14.45 g, 33.6 mmol) was dissolved in 50 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 3 h, the reaction was cooled to room temperature and treated with ether (100 mL). The HCl salt of the product was collected by vacuum filtration The free base was made by dissolving the hydrochloride salt in 75 mL of water and treating with concentrated NH4OH until pH 12 was reached. The aqueous suspension was extracted with CH2Cl2 (4×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to give a thick orange oil. The oil was dissolved in MeOH (100 mL), treated with 2 g of activated charcoal and heated to reflux. After 2 h, the mixture was filtered through a pad of Celite and rinsed with portions of MeOH. The filtrate was concentrated to yield 1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a sticky orange solid.
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][C:4]=1[Cl:13].[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:17]([O-:19])=[O:18])[C:6]([C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:5][C:4]=1[Cl:13]
Reactant: COC(=O)Oc1ccc(C(C)(C)C)cc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 2740.6 %

Procedure:
4-tert-Butyl-2-chlorophenyl methyl carbonate (36.0 g, 0.15 mol) was dissolved in conc. H2SO4 (100 mL) at 0° C. KNO3 (0.53 g, 5.2 mmol) was added in portions over 25 min. The reaction was stirred for 1.5 h and poured into ice (200 g). The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with aq. NaHCO3, dried over Na2SO4 and concentrated under vacuum to give 4-tert-butyl-2-chloro-5-nitrophenyl methyl carbonate (41.0 g), which was used without further purification.
Reaction SMILES: [ClH:1].Cl.[CH:3]1(NC(C2C3C=C(C4C([Cl:24])=CN=C(NCCCC5CCN(C6CC6)CC5)N=4)SC=3C=CC=2)=O)[CH2:5][CH2:4]1.[CH3:38][NH:39][C:40]([C:42]1[C:50]2[CH:49]=[C:48]([C:51]3[C:56]([Br:57])=[CH:55][N:54]=[C:53]([NH:58][CH2:59][CH2:60][CH:61]4[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]4)[N:52]=3)[S:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)=[O:41]>>[ClH:24].[ClH:1].[CH3:38][NH:39][C:40]([C:42]1[C:50]2[CH:49]=[C:48]([C:51]3[C:56]([Br:57])=[CH:55][N:54]=[C:53]([NH:58][CH2:59][CH2:60][CH:61]4[CH2:62][CH2:63][N:64]([CH:3]5[CH2:5][CH2:4]5)[CH2:65][CH2:66]4)[N:52]=3)[S:47][C:46]=2[CH:45]=[CH:44][CH:43]=1)=[O:41]
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCN(C5CC5)CC4)ncc3Cl)cc12
Reactant: CNC(=O)c1cccc2sc(-c3nc(NCCC4CCNCC4)ncc3Br)cc12
Agent: Cl
Product: CNC(=O)c1cccc2sc(-c3nc(NCCC4CCN(C5CC5)CC4)ncc3Br)cc12

Procedure:
Using the method of 2-{5-chloro-2-[3-(1-cyclopropylpiperidin-4-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound is synthesized from 2-[5-bromo-2-(2-piperidin-4-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid methylamide and isolated as a yellow solid. ES+(m/z) 514 (79Br) and 516 (81Br) [M(free base)+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:16][CH3:17])[C:9](Br)=[CH:10][C:11]=2[O:13][CH3:14])[C:6]([O:18][CH3:19])=[CH:5][C:4]=1Br.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:16][CH3:17])[C:9]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[CH:10][C:11]=2[O:13][CH3:14])[C:6]([O:18][CH3:19])=[CH:5][C:4]=1[C:28]1[S:27][CH:26]=[CH:30][CH:29]=1
Reactant: COc1cc(Br)c(OC)c2c(OC)cc(Br)c(OC)c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(-c2cccs2)c(OC)c2c(OC)cc(-c3cccs3)c(OC)c12
Yield: 96 %

Procedure:
1,4,5,8-Tetramethoxy-2,6-dibromonaphthalene (7.80 g., 0.019 mol.) and 2-(tributylstannyl)thiophene (18.00 g., 0.048 mol.) were dissolved in 200 mL dry toluene under argon atmosphere. Pd(PPh3)4 (100 mg.) was introduced into the reaction flask using a Schlenk tube under argon. The resultant mixture was subsequently refluxed for 18 hrs. The brownish black solution was cooled and poured into 500 mL of petroleum ether to afford crude yellow solid. Upon recrystallization from CH2Cl2/petroleum ether (1:3) the desired product was obtained as a light yellow solid. Yield: 96%. M.p. 233.5-237° C. Anal. Calcd. for C22H20O4S2: C, 64.06%; H, 4.89%; S, 15.54%. Found: C, 64.12%; H, 4.90%; S, 15.12%. Mass spectrum: 411.84 (M+). 1H-NMR (CDCl3; in ppm.): 3.73 (s, 3H), 4.05 (s, 3H), 7.13 (dd, 2H), 7.19 (s, 2H), 7.41 (dd, 2H), 759 (dd, 2H,). 13C-NMR (CDCl3; in ppm.): 56.7, 61.7, 107.5, 122.5, 124.4, 125.7, 126.6, 126.9, 139.1, 146.5, 152.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH:12]=[O:13])=[CH:6]2.[CH2:14]([Mg]Br)[CH3:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12](=[O:13])[CH2:14][CH3:15])=[CH:6]2
Reactant: COc1ccc2[nH]c(C=O)cc2c1
Reactant: CC[Mg]Br
Product: CCC(=O)c1cc2cc(OC)ccc2[nH]1
Yield: 82 %

Procedure:
Reaction of 5-methoxy-1H-indole-2-carbaldehyde with ethylmagnesium bromide using the procedure described in example 404 gave (822) (82%), mp 170–171.5° C. 1H NMR δ [(CD3)2SO] 11.56 (s, 1H), 7.34 (d, J=9.1 Hz, 1H), 7.22 (d, J=1.7 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 6.93 (d, J=9.1, 2.4 Hz, 1H), 3.77 (s, 3H), 2.96 (q, J=7.3 Hz, 2H), 1.13 (t, J=7.3 Hz, 3H). Found: C, 71.15; H, 6.45; N, 7.07. C12H13NO2 requires: C, 70.92; H, 6.45; N, 6.89.