Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]3)=[O:14])[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([CH2:21][O:22][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:17][CH2:16]3)=[O:14])[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCC(CO)CC3)nc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)N3CCC(COS(C)(=O)=O)CC3)nc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 34 %

Procedure:
4-Hydroxymethyl-piperidine-1-carboxylic acid (4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-amide (300 mg, 0.43 mmol) and N-ethyldiisopropylamine (95 μl, 0.56 mmol) were dissolved in CH2Cl2 (10 ml), methanesulfonyl chloride (36 μl, 0.47 mmol) was added and the mixture stirred at ambient temperature for 3 days. Purification as described in the general procedure E afforded the product as a white solid (34%). MS: m/e=466 (M+H+).
Reaction SMILES: [I:1][C:2]1[NH:3][C:4]([I:8])=[C:5]([I:7])[N:6]=1.[H-].[Na+].[C:11]([NH:18][CH2:19][CH2:20]Br)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CN(C=O)C>[C:14]([O:13][C:11](=[O:12])[NH:18][CH2:19][CH2:20][N:3]1[C:4]([I:8])=[C:5]([I:7])[N:6]=[C:2]1[I:1])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: Ic1nc(I)c(I)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCn1c(I)nc(I)c1I
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a yellow solution of 2,4,5-triiodo-1H-imidazole (15.295 g; 34.313 mmol) in anhydrous DMF (200 ml) was added portionwise, at rt, 55-65% sodium hydride moistened with oil (2.058 g; 51.469 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 20 min. The mixture was then heated to 100° C., and a colorless homogeneous solution of 2-(Boc-amino)-ethylbromide (11.534 g; 51.469 mmol) in anhydrous DMF (100 ml) was added dropwise, over 1 h, with an addition funnel. After completion of the addition, the resulting mixture was further heated at 100° C. for 1 h. The reaction mixture was cooled to 0° C., and water (200 ml) was added slowly. This mixture was extracted with ether (5×200 ml). The combined organic layers were washed with brine (100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give a yellow oil. The crude was purified by FC (heptane/EA=3/2) to give the pure product [2-(2,4,5-triiodo-imidazol-1-yl)-ethyl]-carbamic acid tert-butyl ester as a colorless solid which was further dried under HV (8.540 g; 42%). LC-MS: tR=0.93 min.; [M+H]+=589.89 g/mol.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:7]([OH:9])=O)(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>C(Cl)Cl.CN(C=O)C>[C:1]([O:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:7]([N:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CC(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
(S)-3-Acetoxy-2-(benzyloxycarbonylamino)-propanoic acid (1.5 g, 5.33 mmol) was dissolved in CH2Cl2 (15 mL). N-Methylmorpholine (NMM) (0.64 mL, 5.87 mmol) and isobutyl chloroformate (IBCF) (0.72 mL, 6.12 mmol) were added at −15° C. and stirred for 30 minutes under inert atmosphere. A mixture of (S)-tert-butyl pyrrolidine-2-carboxylate (1) (998 mg, 5.87 mmol) and NMM (0.64 mL, 5.87 mmol) in DMF (5 mL) were added drop wise to the reaction mixture and stirring was continued for another 3 h at RT. The reaction mixture was diluted with DCM (200 mL), washed with water (50 mL), citric acid solution (10 mL) and brine (10 mL). The separated organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The obtained crude residue was purified by silica gel column chromatography eluting with 30% EtOAc/Hexane to afford compound 2 (1.6 g, 69.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][O:25][P:26]([OH:28])[OH:27].CCN(C(C)C)C(C)C.C/C(/[O:46][Si](C)(C)C)=N\[Si](C)(C)C.C1C=C(SSC2N=CC=CC=2)N=CC=1>O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][O:25][P:26](=[O:46])([OH:27])[OH:28]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)COP(O)O)C(=O)OC2
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)COP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of phosphorous acid mono-{4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enyl}ester (27 mg, 0.06 mmol) in dioxane (1 mL) was stirred with DIEA (21 μL, 0.12 mmol) and N,O-bis(trimethylsilyl)acetamide (29 μL, 0.12 mmol) at room temperature for 3 hours. To the reaction solution was added 2,2′-dipyridyldisulfide (16 mg, 0.072 mmol) and the mixture was allowed to stir for an additional 2 hours at room temperature. The reaction mixture was diluted by addition of H2O and the solution was stirred for 2 more hours when it was concentrated. The residue was dissolved in a solution of 10% TFA/CH2Cl2 and stirred at room temperature for 9 hours. The reaction mixture was dried under reduced pressure and the product was purified by reverse-phase HPLC to provide the desired product as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.87 (s, 3H), 2.16 (s, 3H), 3.47 (d, 2H, J=7 Hz), 3.79 (s, 3H), 4.28 (d, 2H, J=6 Hz), 5.26 (s, 2H), 5.50-5.61 (m, 1H); 31P (121.4 MHz, CD3OD) δ 0.50; MS (m/z) 357 [M−H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.Cl.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]1.C(N(CC)CC)C>C1COCC1>[OH:39][C@H:36]1[CH2:37][CH2:38][C@H:33]([NH:32][C:12]2[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:30])[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=2)[CH2:34][CH2:35]1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(N[C@H]2CC[C@H](O)CC2)nc2c1ccc(=O)n2-c1ccccc1F
Reaction time: 48 h

Procedure:
The product of Example 59 (200 mg, 0.47 mmol), trans-4-aminocyclohexanol hydrochloride (151 mg, 1 mmol), and triethylamine (0.28 mL, 2 mmol)were combined in THF (10 mL) and stirred under Ar at 50° for 2 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography with 0-20% EtOAc/CH2Cl2 followed by recrystallization from CH2Cl2/hexane gave the product as a pale yellow crystalline solid. mp 148-151°, LC MS m/z=463 (MH+) Retention time=2.0 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]([CH3:17])([CH3:16])[CH2:14]O.N1C=CC=CC=1>O=S(Cl)Cl>[CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:12][C:13]([CH3:17])([CH3:16])[CH3:14])=[O:5]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CC(C)(C)CO
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1C(=O)OCC(C)(C)C
Yield: 67.9 %

Procedure:
Using General Esterification Method C; 2-methyl-4-bromo-benzoic acid (1.82 g, 8.47 mmols) was refluxed for 3 h with 10 mL SOCl2. The resulting solution was concentrated under reduced pressure and the crude acyl chloride combined with 2,2-dimethylpropanol (0.75 g, 8.47 mmols) and pyridine (1.4 mL, 16.9 mmols) to give the title compound (1.64 g, 68%) after work-up and column chromatography (2-5% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=1>CO.[OH-].[OH-].[Pd+2]>[F:11][C:6]1[C:5]([NH:12][S:13]([CH2:16][CH2:17][CH3:18])(=[O:15])=[O:14])=[CH:4][CH:3]=[CH:2][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1F
Reaction time: 2 h

Procedure:
To 6-chloro-2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (14, 0.69 g, 2.3 mmol) in 10 mL of methanol, 20% palladium hydroxide on carbon (200 mg) was added. The reaction was stirred under hydrogen at 50 psi for 2 hours. The reaction was filtered and the filtrate concentrated under vacuum to provide the desired compound 15 as a white solid that was used in the next step. MS(ESI) [M−H+]−=260.1. Additional material was prepared similarly for use in the next step.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[C:9]1([S:15]([N:18]2[C:26]3[CH:25]=[C:24]([Sn:27]([CH3:30])([CH3:29])[CH3:28])[CH:23]=[C:22]([NH2:31])[C:21]=3[CH:20]=[N:19]2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>N1C=CC=CC=1>[C:9]1([S:15]([N:18]2[C:26]3[C:21](=[C:22]([NH:31][C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)=[O:7])[CH:23]=[C:24]([Sn:27]([CH3:29])([CH3:28])[CH3:30])[CH:25]=3)[CH:20]=[N:19]2)(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: c1ccncc1
Product: C[Sn](C)(C)c1cc(NC(=O)c2ccco2)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Reaction time: 1 h

Procedure:
2-Furancarbonyl chloride (0.199 ml) was added to a stirred solution of 1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (580 mg) in pyridine (10 ml) at RT. The mixture was stirred for 1 h. After this time, the mixture was acidified with 5 N HCl and extracted into ether (2×40 ml). The combined extracts were washed with aq sodium bicarbonate (20 ml), water (50 ml), dried (frit) and evaporated to dryness. The residual oil was purified on a 20 g Si isolute cartridge using ether as the eluent. The appropriate fractions were evaporated to give the title compound, 510 mg as a colourless solid.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:2]1=[S:3].[C:12]1([CH:18]([O:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:27]=O)[C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[C:12]1([CH:18]([O:23][C:24]2[CH:25]=[C:26]([CH:27]=[C:7]3[S:1][C:2](=[S:3])[N:4]([CH2:8][C:9]([OH:11])=[O:10])[C:5]3=[O:6])[CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: O=Cc1ccc(OCCc2ccccc2)c(OC(c2ccccc2)C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)CN1C(=O)C(=Cc2ccc(OCCc3ccccc3)c(OC(c3ccccc3)C(F)(F)F)c2)SC1=S
Temperature: 25 °C
Reaction time: 84 h
Yield: 40.6 %

Procedure:
A solution of rhodanine-3-acetic acid (87 mg, 0.46 mmol, 1 eq), 3-(1-phenyl-2,2,2-trifluoroethoxy)-4-(2-phenylethoxy)benzaldehyde (183 mg, 0.46 mmol, 1 eq) and sodium acetate (112 mg, 1.37 mmol, 3 eq) in acetic acid (2 mL) was heated to 150□C and stirred for 3.5 days. The reaction mixture was then cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (50 mL) and the two layers separated. The organic layer was washed with 1M HCl (2×50 mL), and loaded onto silica. Elution with ethyl acetate:methanol (4:1) gave a yellow gum. This was dissolved in hot ethyl acetate and filtered (to remove some insoluble material). The filtrate was allowed to cool to room temperature and diethyl ether added. This gave a suspension which was again filtered. The filtrate was evaporated and the residue redissolved in diethyl ether. Addition of petroleum ether to the solution gave a precipitate which was filtered off. The mother liquor was evaporated and the resulting gum was crystallized from diethyl ether and petroleum ether to give the product as a yellow powder (107 mg, 41%) mp 170° C.: 1H NMR (d6 DMSO) δ 7.67 (s, 1H, C═C—H), 6.17 (q, 1H, J 6.5 Hz, CHCF3), 4.70 (s, 2H, CH2CO2H), 4.33 (t, 2H, J 5.9 Hz, OCH2CH2Ph), 3.09 (t, 2H, J 6.2 Hz, OCH2CH2Ph).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][N:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][Si](C(C)C)(C(C)C)C(C)C)[CH:23]=1)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.O.CCOC(C)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][N:14]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)CCN(Cc1cccc(O[Si](C(C)C)(C(C)C)C(C)C)c1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2c(cc1OCc1ccccc1)CCN(Cc1cccc(O)c1)C2

Procedure:
A solution of 6-(benzyloxy)-7-methoxy-2-(3-(triisopropylsilyloxy)benzyl)-1,2,3,4-tetrahydroisoquinoline (2.7 g, 5 mmol) in THF (50 mL) was cooled to 0° C. and 1M TBAF/THF (5.5 mL, 5.5 mmol) added drop wise. The solution was stirred at 0 C. for 1 h 30 min and water (20 mL) added as well as EtOAc (80 mL). The organic layer was washed with water, brine, dried with MgSO4, filtered and concentrated under reduced pressure. The resulting solid was washed with hexane, filtered and dried. 1.7 g (90%), white powder, mp=78-79° C.; Rf: 0.12 (Hexane/EtOAc 3:1), 1H NMR (270 MHz, CDCl3) δ 2.63-2.78 (4H, m, 2×CH2), 3.52 (2H, s, CH2), 3.58 (2H, s, CH2), 3.79 (3H, s, CH3O), 5.08 (2H, s, OCH2), 6.48 (1H, s, ArH), 6.60 (1H, s, ArH), 6.68 (1H, dd, J 8.2 and 2.5 Hz, ArH), 6.82 (1H, d, J 2.5 Hz, ArH), 6.88 (1H, d, J 7.7 Hz, ArH), 7.15 (1H, dd, J 8.2 and 7.7 Hz, 1H, ArH), 7.26-7.47 (5H, m, ArH). 13C NMR (67.5 MHz, CDCl3) δ 12.7((CH3)2CHSi), 18.0 ((CH3)2CHSi), 28.8 (CH2), 50.7 (CH2), 55.9 (CH2), 56.1 (CH3O), 62.7 (CH2), 71.2 (OCH2), 110.1 (CH(Ar)), 114.3 (CH(Ar)), 118.6 (CH(Ar)), 120.8 (CH(Ar)), 126.4 (C(Ar)), 127.4 (CH(Ar)), 127.6 (C(Ar)), 127.8 CH(Ar)), 128.6 (CH(Ar)), 129.2 (CH(Ar)), 137.4 (C(Ar)), 140.0 (C(Ar)), 146.6 (C(Ar)), 147.9 (C(Ar)) and 156.1 (C(Ar)). LC/MS (APCI+) tr=5.12 min m/z 376.59 (M++H); MeOH/H2O 50/50 to 95/5 (5 min); HPLC tr=3.26 min (100%). (CH3CN/H2O 90/10)
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(P(N(C)C)(N(C)C)=O)C.C([Li])CCC.[CH3:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([O:38][CH2:39][CH2:40]Cl)=[CH:30][CH:29]=1>C1COCC1.O>[C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:40][CH2:39][O:38][C:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]([CH3:27])=[CH:29][CH:30]=1)([OH:10])=[O:9]
Reactant: O=C(O)Cc1ccccc1
Reactant: Cc1ccc(OCCCl)c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Cc1ccc(OCCC(C(=O)O)c2ccccc2)c2ccccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a 1 1. three-neck round bottom flask fitted with a thermometer, nitrogen inlet tube, addition funnel and magnetic stirrer was added 5.9 g (43.6 mmol) of phenylacetic acid and 250 ml of tetrahydrofuran. To the mixture was added 7.6 ml (43.6 mmol) of HMPA. The mixture was cooled to approximately 0° C. and 6.4 ml (89.4 mmol) of 1.48M n-butyllithium was added dropwise to the reaction mixture. The mixture was warmed to room temperature over a period of approximately 50 minutes and cooled to approximately -78° C. To the reaction mixture was added a solution of 2-(4-methyl-1-naphthalenyloxy)ethyl chloride dissolved in 100 ml of THF. The reaction mixture was stirred at room temperature overnight and diluted with water. The mixture was washed twice with diethyl ether and the resulting aqueous phase was acidified. The aqueous phase was extracted twice with diethyl ether and the organic extracts were combined, washed twice with water, once with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The volatile constituents were evaporated under vacuum to provide 9.53 g of a light tan solid. The solid was recrystallized from diethyl ether and hexane to provide 5.62 g of the desired product. mp=130°-131.5° C.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:6][C:7]([C:9]1[N:29]=[CH:28][C:12]2[NH:13][C:14]3[C:19]([C:11]=2[C:10]=1[CH2:30][O:31][CH3:32])=[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17]=[CH:16][CH:15]=3)=[O:8])[CH3:5].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]Br)=[CH:37][CH:36]=1>O1CCCC1>[CH3:5][CH:4]([O:6][C:7]([C:9]1[N:29]=[CH:28][C:12]2[N:13]([CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][C:38]3[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:40][CH:39]=3)[C:14]3[C:19]([C:11]=2[C:10]=1[CH2:30][O:31][CH3:32])=[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17]=[CH:16][CH:15]=3)=[O:8])[CH3:3]
Reactant: COc1ccc(CCCCCCBr)cc1
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1c(OCc3ccccc3)cccc1n2CCCCCCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
10 mg of an 80% suspension of sodium hydride in oil is mixed with 10 ml of tetrahydrofuran and to 0° C. 404.5 mg of 5-benzyloxy-4-methoxymethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is added to the suspension, it is stirred for 10 minutes at 0° C., mixed with 406 mg of 6-(4-methoxyphenyl)-hexyl bromide, and the reaction mixture is stirred for 16 hours at room temperature. After the reaction mixture is worked up as described, 330 mg of 5-benzyloxy-4-methoxymethyl-9-[6-(4-methoxyphenyl)-hexyl]-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH2:13]([N:15]([CH2:11][C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: CCNCC
Reactant: O=Cc1ccc2c(n1)COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN(CC)Cc1ccc2c(n1)COC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.1 %

Procedure:
A solution of 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carbaldehyde (110 mg, 0.68 mmol) in dichloroethane (4 mL) is treated with diethylamine (75 μL, 0.68 mmol) followed by the addition of sodium triacetoxyborohydride (200 mg, 0.94 mmol). The reaction mixture is stirred at room temperature for 1.5 h. and then treated with saturated aqueous NaHCO3 solution. The aqueous layer is extracted twice with EtOAc (2×). The combined organic extracts are dried, and concentrated. The residue is chromatographed (silica gel, EtOAc/hexane). The product containing fractions are concentrated to give the title compound as white solid (90 mg, 61%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10](Br)[C:9]([O:13]C(C)C)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].CCO.[CH:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=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>[C:17]1([C:2]2[CH:11]=[C:10]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:9]([OH:13])=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)Oc1c(Br)cc(Br)c2cccnc12
Reactant: c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1c(-c2ccccc2)cc(-c2ccccc2)c2cccnc12
Yield: 91 %

Procedure:
Reaction of 5,7-diiodo-quinolin-8-ol with 2-bromopropane following the method described in Example 8 gave 5,7-dibromo-8-isopropoxy-quinoline 7 (93%): 1H NMR (CDCl3): δ 8.86 (dd, J=1.5 and 4.4, 1 H), 8.46 (s, 1H), 8.33 (dd, J=1.5 and 8.5, 1 H), 7.49 (dd, J=4.4 and 8.5, 1 H), 5.40 (m, 1H), 1.43 (d, J=6.1, 6 H). To a stirred mixture of 7 (200 mg, 0.51 mmol), phenylboronic acid (143 mg, 1.17 mmol), 2 N Na2CO3 (7.2 mL), EtOH (1.2 mL) and benzene (6 mL) was added, under a blanket of argon, Pd(PPh3)4 (21 mg). The mixture was stirred under reflux for 16 h, cooled and concentrated. This provided, after column chromatography on silica (ethyl acetate/hexane, 1:9), 5,7-diphenyl-8-isopropoxy-quinoline as a yellow solid (157 mg, 91%). Cleavage of the isopropoxy group following the method outlined in Example 8 gave 5,7-diphenyl-8-hydroxy-quinoline M1 in 91% yield. (See table 4 for data).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:10][C:9]=1[CH3:20])(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[CH2:18]([N:15]([CH2:16][CH3:17])[C:11]1[CH:10]=[C:9]([CH3:20])[C:8]([NH2:7])=[CH:13][C:12]=1[CH3:14])[CH3:19].[C:24]([OH:26])([C:23]([F:28])([F:27])[F:22])=[O:25]
Reactant: CCN(CC)c1cc(C)c(NC(=O)OC(C)(C)C)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)c1cc(C)c(N)cc1C
Reaction time: 2 h

Procedure:
To a solution of 41 in 2 mL dichoromethane, trifloroacetic acid (1 mL) was added. The reaction mixture was stirred for 2 h. At this point, LC-MS showed the reaction to be complete. The reaction was concentrated to remove the solvent and most of the TFA. The residue was then dried further in a high vacuum oven over 24 h to give the title compound 42 as TFA salt (100% yield).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[N+:11]([C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][CH:18]2[OH:23])([O-:13])=[O:12]>C1(C)C=CC=CC=1>[C:1]([O:23][CH:18]1[C:19]2[C:15](=[C:14]([N+:11]([O-:13])=[O:12])[CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc2c1CCC2O
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC1CCc2c1cccc2[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 100.9 %

Procedure:
A stirred solution of 40.0 g (0.51 mole) of acetyl chloride and 43.9 g (0.56 mole) of pyridine in 100 mL of toluene was cooled to 5° C., and a solution of 83.0 g (0.46 mole) of 4-nitro-1-indanol in 30 mL of toluene was added dropwise. Upon complete addition, the reaction mixture was stirred at 5° C. for 10 minutes, then was allowed to warm to ambient temperature and was stirred for 16 hours. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give 102.7 g of 4-nitro-1-indanyl acetate as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].C(N)C1C=CC=CC=1.C(O)(=O)C>C(O)C>[N+:8]([CH:11]=[CH:6][C:3]1[CH:4]=[CH:5][NH:1][CH:2]=1)([O-:10])=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cc[nH]c1
Solvent: CC(=O)O
Solvent: CCO
Solvent: NCc1ccccc1
Product: O=[N+]([O-])C=Cc1cc[nH]c1

Procedure:
A solution of 2.26 g (0.0238 mole) of pyrrole-3-carboxaldehyde, 1.28 ml (0.0238 mole) of nitromethane, 0.405 ml of benzyl amine (0.0038 mole) and 0.21 ml (0.0038 mole) of acetic acid in 8 ml of absolute ethanol is stirred overnight, collected and washed with ethanol to give as a yellow solid 3-(2-nitrovinyl)pyrrole; m.p. 160°-164° C (dec.).