Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([O:27]C)[C:5]2[N:6]=[C:7]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.C(S)(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:26]=[C:25]([OH:27])[C:5]2[N:6]=[C:7]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: COc1cc(F)cc2c1N=C(N1CCN(C)CC1)c1c(sc3ccccc13)N2
Agent: CC(S)S
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN1CCN(C2=Nc3c(O)cc(F)cc3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 62 and using 8-fluoro-10-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine, dichloromethane, ethanedithiol and aluminium chloride, 8-fluoro-10-hydroxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: O=C1C2C=CC=C3C4C(N(C=23)C=C1C(O)=O)CCCC4.ClC(OCC(C)C)=O.[OH-].[Na+].[CH:31]1[CH:36]=[CH:35][C:34]([C@@H:37](N)[C:38]([OH:40])=[O:39])=[CH:33][CH:32]=1.Cl>C(Cl)Cl.CN(C)C=O.C(N(CC)CC)C>[C:34]1([CH2:37][C:38]([OH:40])=[O:39])[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1
Reactant: N[C@@H](C(=O)O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: O=C(O)c1cn2c3c(cccc3c1=O)C1CCCCC12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)Cc1ccccc1

Procedure:
1.34 g of 7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboxylic acid was suspended in 20 ml of methylene chloride and 0.85 ml of triethylamine was added to the suspension while ice-cooling followed by allowing the mixture to react for 10 minutes. Then, 0.85 ml of isobutyl chloroformate was added thereto dropwise and allowed to react for 30 minutes at the same temperature as above. To the reaction mixture were added 110 ml of a 10% aqueous sodium hydroxide solution having dissolved therein 0.9 g of D-(-)-phenylglycine at the same temperature as above and then 80 ml of dimethylformamide followed by allowing the mixture to react for 3 hours. After completion of the reaction, the reaction mixture was rendered neutral with a 6 N hydrochloric acid and the solvent was removed under reduced pressure. 20 ml of water and 100 ml of a 10% aqueous sodium hydroxide solution were added to the residue to dissolve it and the solution was treated with activated carbon and filtered. The filtrate was adjusted to a pH of 2 with concentrated hydrochloric acid to obtain light yellow crystals, which were washed with water, dried, mixed with 50 ml of chloroform with stirring and filtered. The filtrate was mixed with 30 ml of petroleum ether to obtain 1.1 g of D-(-)-2-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboxamido)phenylacetic acid as light yellow needles having a melting point of 165° to 167° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: Cc1ccc(Br)nc1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(N2CCNCC2)nc1

Procedure:
A solution of piperazine (215 mg, 2.5 mmoles), 2-bromo-5-methyl-pyridine (172 mg, 1 mmoles) in dioxane (1 mL) and potassium carbonate (276 mg, 2 mmoles) was irradiated by microwaves for 60 minutes at 180° C. The dioxane was removed under reduced pressure and the residue partitioned between aqueous potassium carbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts washed twice with water, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified (silica gel, 0-10% methanol in dichloromethane) to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][NH:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])O.[Na+]>CCOC(C)=O.O>[Cl:1][CH2:2][C:3]([N:13]1[CH2:14][CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:12]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: c1ccc([C@@H]2NCCc3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCc2ccccc2[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A mixture of chloroacetyl chloride (1.03 g) and EtOAc (5 mL) was added dropwise with stirring to a mixture of (1S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (1.58 g), sodium hydrogen carbonate (960 mg), water (25 mL) and EtOAc (25 mL), followed by stirring at room temperature for 2 hours. The reaction liquid was extracted with EtOAc, and the extract was washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-AcOEt, 4:1) to obtain (1S)-2-(chloroacetyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (2.14 g).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[S:6]1[C:10]([CH2:11][C:12]2[O:16][C:15]([CH3:17])=[C:14]([CH3:18])[CH:13]=2)=[CH:9][C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2.[C:23](Cl)(=O)[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>C(=S)=S>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]2[C:9]3[C:8]4[C:7](=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:6][C:10]=3[CH:11]=[C:12]3[O:16][C:15]([CH3:17])=[C:14]([CH3:18])[C:13]=23)=[CH:25][CH:26]=1
Reactant: Cc1cc(Cc2cc3ccccc3s2)oc1C
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Product: COc1ccc(-c2c3c(C)c(C)oc3cc3sc4ccccc4c23)cc1
Temperature: 0 °C
Yield: 18.8 %

Procedure:
Tin tetrachloride (7.6 mL, 65.2 mmnol) was added dropwise to a −78° C., stirred solution of benzo[b]thiophen-2-yl-(2,3-dimethyl-furan-5-yl)-methane (3.96 g, 16.3 mmol) and anisoyl chloride (3.07 g, 17.93 mL) in carbon disulfide (100 mL) under a try N2 atmosphere over a period of 30 min. After the addition completed, the solution was allowed to warm to 0° C. After 9 h. the reaction mixture was carefully quenched with and further diluted with water (350 mL). Aqueous mixture was extracted with ethyl ether. The ethyl ether extracts were washed with water, 10% aqueous sodium bicarbonate and water and dried with brine. Silica gel (90 mL) was added. Solvents were removed and the silica adsorbate was flash chromatographed (eluent 99:1 petroleum ether:ethyl acetate) to provide the title compound as a light yellow solid (1.1 g, 25%): NMR (CDC13); δ 7.81 (s, 1H), 7.76 (d, J=8, Hz, 1H), 7.36-7.24 (m, 3H), 7.11-7.00 (m, 3H), 6.85 (d, J=8 Hz, 1H), 3.96 (s, 3H), 2.37 (s, 3H), 1.55 (s, 3H); MS (EI): [M+], 358.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br.C([N:15]([CH2:27][C@H:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33](Br)[CH:34]=2)[O:29]1)[CH2:16][C@H:17]([OH:26])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C1C=CC=CC=1.[C:39]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)([O:41][CH3:42])=[O:40].C([O-])=O.[Na+].[CH3:56][S:57]([OH:60])(=[O:59])=[O:58]>O.[Pd].C(OCC)(=O)C.C(O)(C)C>[CH3:56][S:57]([OH:60])(=[O:59])=[O:58].[OH:26][C@H:17]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:16][NH:15][CH2:27][C@H:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:46]3[CH:47]=[CH:48][C:43]([C:39]([O:41][CH3:42])=[O:40])=[CH:44][CH:45]=3)[CH:34]=2)[O:29]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O[C@H](COc1ccccc1)CN(Cc1ccccc1)C[C@H]1CCc2cc(Br)ccc2O1
Agent: [Pd]
Agent: Br
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC[C@H](CNC[C@H](O)COc2ccccc2)O3)cc1
Temperature: 40 °C
Yield: 25 %

Procedure:
In a 500-mL three-neck round bottom flask was dissolved K2CO3 (37.3 g, 270 mmol, 3.8 eq.) in 120 mL water. (2S)-1-(benzyl{[(2R)-6-bromo-3,4-dihydro-2H-chromen-2-yl]methyl}amino)-3-phenoxy-2-propanol hydrobromide (Example 86, 40 g, 180 mmol, 1.0 eq.) was then added. To the resulting suspension was then added 130 mL isopropanol, p-carbomethoxyphenyl boronic acid (20.5 g, 114 mmol, 1.6 eq.) and 10% Pd/C (3.77 g, 1.78 mmol, 0.025 eq.). The resulting suspension was heated at reflux for 4 hours, cooled to 40° C., and 159 mL ethylacetate was added. This suspension was heated to 50° C. and filtered and washed with 100 mL warm (55° C.) ethylacetate. The filtrate separated to two phases. The aqueous phase was separated, and the organic phase was transferred to a 1-L three-neck round bottom flask, to which was added 300 mL ethyl acetate, 10% Pd-C (7.2 g, 0.89 mmol, 0.05 eq.) and a solution of sodium formate (14.4 g, 211 mmol, 3.0 eq.) in 80 mL water. The resulting suspension was refluxed for 6 hours. Methanesulfonic acid (28 g, 146 mmol, 4.1 eq.) was added to the reaction at a temperature ≧50° C. The resulting suspension was filtered; the organic filtrate was separated and washed with 60 mL water. The organics were distilled to half of the original volume, cooled and methyl 4-[(2R)-2-({[(2S)-2-hydroxy-3-phenoxypropyl]amino}methyl)-3,4-dihydro-2H-Chromen-6-yl]benzoate methanesulfonate filtered and washed with ethylacetate. The dry white crystalline product (15.5 g, 80% yield) was used without further purification. NMR (DMSO-d6) δ1.77 (m, 1H), 2.10 (m 1H), 2.42 (s, 3H, HSO3CH3), 2.90 (m, 2H), 3.12 (dd, J=8, 1.8 Hz, 1H), 3.36 (m, 2H), 3.85) (s, 3H), 4.02 (m, 2H), 4.25 (m, 1H), 4.50 (tt, J=7, 1.5 Hz, 1H), 5.87 (bs, 1H, OH), 6.95 (m, 4H, ArH), 7.33 (t, J=7 Hz, 2H, ArH), 7.52 (m, 2H, ArH), 7.77 (d, J=8 Hz, 2H, ArH), 7.95 (d, J=8 Hz, 2H, ArH); MS (EI): m/z 448 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[C:4]#[N:5].O=[C:15]([CH3:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH:11]([CH3:13])[CH3:12])[N:1]=[C:15]([CH3:22])[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)Oc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(OC(C)C)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-isopropoxybenzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as an off-white solid (32%). 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=7.6 Hz, 3H), 1.38 (d, J=6.0 Hz, 6H), 2.54 (s, 3H), 4.3 (q, J=7.2 Hz, 2H), 4.83-4.89 (m, 1H), 6.93 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.4 Hz, 1H), 8.14 (s, 2H). MS 289 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH2:15]([C:18]1[C:26]2[O:25][N:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[C:22]=2[CH:21]=[CH:20][C:19]=1[OH:31])[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(OCC)(=O)C.O.CN(C=O)C>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][CH2:3][CH2:2][O:31][C:19]3[CH:20]=[CH:21][C:22]4[C:23]([C:27]([F:30])([F:29])[F:28])=[N:24][O:25][C:26]=4[C:18]=3[CH2:15][CH2:16][CH3:17])[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(OCCCOc2cccc3[nH]ccc23)ccc2c(C(F)(F)F)noc12
Temperature: 110 °C
Yield: 77.7 %

Procedure:
4-(3-Chloropropoxy)-1H-indole (0.100 g, 0.48 mmol), 7-propyl-3-trifluoromethyl-benzo[d]isoxazol-6-ol (0.117 g, 0.48 mmol), potassium carbonate (0.099 g, 0.72 mmol), potassium iodide (0.016 g, 0.10 mmol), and DMF (5 mL) were mixed and heated at 110° C. for 1.5 hours. The mixture was cooled to room temperature. Water (10 mL) and ethyl acetate (10 mL) were added and the resultant mixture was stirred for five minutes. The organic layer was separated and aqueous layer was extracted again with ethyl acetate (10 mL). The organic layer was combined, washed with water (6×20 mL) and brine (2×20 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo to give an oily residue, which was purified by filtering through a short silica column using hexane/dichloromethane (50/50) as an eluant to afford 6-[3-(1H-indol-4-yloxy)-propoxy]-7-propyl-3-trifluoromethyl-benzo[d]isoxazole (0.156 g, yield: 78%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30][CH2:31][CH3:32])=[CH2:29])CCC.Cl>CN(C)C=O.C(OCC)(=O)C.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>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:28]([O:30][CH2:31][CH3:32])=[CH2:29])[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(Br)c2)cnn1-c1ccc(F)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(OCC)c1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of 5-amino-4-(3-bromobenzoyl)-1-(4-fluorophenyl)pyrazole (3.5 g, 9.7 mmol) [prepared as described in Example 1 above], tributyl-(1-ethoxyvinyl)tin (4.3 ml, 12.36 mmol) and tetrakis(triphenylphosphine)palladium (1.0 g, 0.87 mmol) in dimethylformamide (25 ml) was heated at 95° C. under argon. After 16 h, the reaction mixture was cooled to room temperature and 10% aqueous hydrochloric acid (25 ml) was slowly added. After 30 min., the reaction mixture was diluted with ethyl acetate and filtered through Celite®. The organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution gradient: 10-60% ethyl acetate/hexane) to give 5-amino-4-[3-(1-ethoxyvinyl)benzoyl]-1-(4-fluorophenyl)pyrazole which was dissolved in tetrahydrofuran (50 ml). 1 N hydrochloric acid (20 ml) was added and the reaction mixture was stirred at room temperature for 16 h. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (elution gradient: 20-50% ethyl acetate/hexane) and then was recrystallized from a mixture of ethyl acetate/hexane to give 5-amino-4-[3-acetylbenzoyl]-1-(4-fluorophenyl)pyrazole (2.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:16](=[O:19])(=[O:18])[NH2:17])[C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:16](=[O:19])(=[O:18])[NH2:17])[C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:7])=[O:6])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCNc1c(N)cc(C(=O)O)cc1S(N)(=O)=O
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNc1c(NCc2ccccc2)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
A suspension of 3-amino-4 -butylamino-5-sulphamyl-benzoic acid (6.5 g) in water (30 ml) was adjusted to pH 7.5 by addition of 1N sodium hydroxide. Benzyl bromide (3.87 g) was added and, under stirring, the pH was kept at pH 7.5 by automatic titration with 1N sodium hydroxide. After the base consumption had become negligible, the pH was adjusted to 3 by addition of diluted hydrochloric acid. The precipitated 3-benzylamino-4-butylamino-5-sulphamyl-benzoic acid was collected and recrystallized several times from aqueous methanol, after which the compound was obtained with a melting point of 198.5°-199° C.
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:28])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:15]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1.O>[CH:23]1([O:22][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=2[O:20][CH3:21])[CH2:13][C:12]2[O:28][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=3[N:11]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1ccc(CC(=O)Nc2cccc([N+](=O)[O-])c2O)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COc1ccc(Cc2nc3cccc([N+](=O)[O-])c3o2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
A solution of N-(2-hydroxy-3-nitrophenyl)-3-cyclopentyloxy-4-methoxy-phenylacetamide (2.0 g) and pyridinium p-toluene-sulphonate (500 mg) in xylene (140 ml) was heated at reflux, under nitrogen, overnight. The reaction mixture was cooled to room temperature, diluted with water (100 ml) and extracted with dichloro-methane (3×75 ml). The combined organic extracts were washed with water (3×100 ml), brine (100 ml), dried (CaSO4) and evaporated in-vacuo to yield an orange oil. The oil was purified by flash chromatography (SiO2; dichloromethane; ethanol; ammonia (50:1:0.1)) to yield the title compound (1.107 g, 58%) as an orange solid (mp 95-98.5° C.).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[N:5]([C:16]([O:18]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][CH:7]=2>C1COCC1.CCOCC>[CH3:1][NH:2][C:16]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[CH:8][CH:7]=2)[CH:12]=[C:4]1[CH3:3])=[O:18]
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2n1C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNC(=O)n1c(C)cc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
A 2.0 M solution of methylamine in THF (25 ml, 50 mmole) was added to a solution of 2-methyl-5-nitro-1-(4-nitrophenoxycarbonyl)indole 1a (2.11 g, 6.2 mmole) in THF (240 ml). The resultant reaction mixture was stirred at ambient temperature for 4 hours prior to removal of the solvent by concentration, in vacuo. The residue obtained was partitioned between EtOAc (200 ml) and H2O (200 ml). The layers were separated and the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic extracts were washed with sat'd NaHCO3 (150 ml), dried over Na2SO4 and concentrated, in vacuo, to give a yellow solid which was suspended in Et2O (35 ml), filtered and washed with Et2O (2×20 ml) to give 1.17 g (81%) of a pale yellow solid. 1H NMR (DMSO-d6): δ 8.52 (1H, q, J=4.5 Hz), 8.46 (1H, d, J=2.3 Hz), 8.03 (1H, dd, J=2.3, 9.1 Hz), 7.71 (1H, d, J=9.1 Hz), 6.62 (1H, s), 2.89 (3H, d, J=4.5 Hz), 2.51 (3H, s). Anal. Calcd. for C11H13N3O3: C, 56.65; H, 4.75; N, 18.02. Found: C, 56.56; H, 4.78; N, 17.82.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:5]2=O.O.[NH2:23][NH2:24]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])=[CH:7][NH:24][N:23]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: COc1ccccc1-c1coc2cc(O)c(Cl)cc2c1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccccc1-c1c[nH]nc1-c1cc(Cl)c(O)cc1O

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-7-hydroxy-3-(2-methoxy-phenyl)-chromen-4-one (2.0 g, 6.6 mmol), hydrazine hydrate (5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give 4-chloro-6-[4-(2-methoxy-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid. Rf 0.8 ethyl acetate/hexane (70/30).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[O:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[CH:39][C:40]3[N:44]=[C:43]([C:45]4[C:53]5[C:48](=[CH:49][CH:50]=[C:51]([NH2:54])[CH:52]=5)[N:47]([CH:55]5[CH2:60][CH2:59][CH2:58][CH2:57][O:56]5)[N:46]=4)[NH:42][C:41]=3[CH:61]=2)[CH2:33][CH2:32]1>CN(C=O)C>[F:11][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]([NH:54][C:51]2[CH:52]=[C:53]3[C:48](=[CH:49][CH:50]=2)[N:47]([CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][O:56]2)[N:46]=[C:45]3[C:43]2[NH:44][C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:35][CH2:36][O:31][CH2:32][CH2:33]4)=[CH:61][C:41]=3[N:42]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccc(N4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Reactant: O=C(O)C1CCC(F)(F)CC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.3 %

Procedure:
4,4-Difluorocyclohexanecarboxylic acid (3.92 mg, 0.024 mmol), HOBt (4.84 mg, 0.036 mmol), EDC (6.87 mg, 0.036 mmol) and sodium bicarbonate (2.007 mg, 0.024 mmol) was added to a solution of 3-(6-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (10 mg, 0.024 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h after and then the solvent was removed in vacuo. Purification by flash column chromatography (6% CH3OH/CH2Cl2) afforded the title compound (6 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.49 (s, 1H), 7.76-7.70 (m, 2H), 7.57 (d, 1H, J=8.8 Hz), 7.17 (m, 1H), 7.07 (dd, 1H, J=2.0 & 8.8 Hz), 5.90 (dd, 1H, J=2.0 and 9.6 Hz), 4.01 (m, 1H), 3.86 (m, 4H), 3.81 (m, 1H), 3.17 (m, 4H), 2.65 (m, 1H), 2.53 (m, 1H), 2.43 (m, 1H), 2.18-2.10 (m, 2H), 1.99 (m, 3H), 1.92-1.82 (m, 4H), 1.75 (m, 3H); ESI-MS [M+H]+: 565.17.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2([CH2:26][O:27][CH2:28][C:29]3[CH:30]=[C:31]([C:38]([F:41])([F:40])[F:39])[CH:32]=[C:33]4[C:37]=3[NH:36][CH:35]=[CH:34]4)[CH2:18][CH2:17][N:16]([C:19](OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCCC1>[CH3:19][N:16]1[CH2:15][CH2:14][C:13]([CH2:26][O:27][CH2:28][C:29]2[CH:30]=[C:31]([C:38]([F:41])([F:39])[F:40])[CH:32]=[C:33]3[C:37]=2[NH:36][CH:35]=[CH:34]3)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3cc[nH]c23)(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cc[nH]c23)(c2ccccc2)CC1
Yield: 67.9 %

Procedure:
Lithium aluminum hydride (1M in tetrahydrofuran, 1.71 ml, 1.71 mmol) was added to a solution of tert-butyl 4-phenyl-4-(((5-(trifluoromethyl)-1H-indol-7-yl)methoxy)methyl)piperidine-1-carboxylate (93 mg, 0.19 mmol) in tetrahydrofuran (5 ml). The reaction was heated at reflux for 3 h. The reaction was quenched by sequential dropwise addition of water (0.2 mL), 1N sodium hydroxide (0.6 mL), and more water (0.2 mL). The mixture was filtered and the filtrate evaporated. The residue was chromatographed on silica gel with 15% methanol in dichloromethane. The product 7-(((1-methyl-4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-1H-indole (52 mg, 0.129 mmol, 67.9% yield) was isolated as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 7.92 (bs, 1H), 7.78 (s, 1H), 7.32-7.48 (m, 5H), 7.08 (s, 1H), 6.85 (s, 1H), 6.45 (s, 1H), 4.72 (s, 2H), 3.52 (s, 2H), 2.73 (m, 2H), 2.31 (s, 3H), 2.22-2.40 (m, 4H), 2.12 (m, 2H); Mass spec. (MH)+: 403.11.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16]CC)=[O:15])=[CH:11][CH:12]=2)[C:7](=O)[CH2:6][C@@H:5]1[CH3:20])(=[O:3])[CH3:2].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=2)[NH2:30])[CH2:23][CH2:22]1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:27]([N:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)[CH:28]=2)[CH2:6][C@@H:5]1[CH3:20])(=[O:3])[CH3:2]
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: CCOC(=O)c1ccc2c(c1)C(=O)C[C@H](C)N2C(C)=O
Product: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2cccc(N3CCOCC3)c2)C[C@@H]1C
Yield: 32 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 2, using ethyl (2S)-1-acetyl-4-oxo-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate and 3-morpholinoaniline, and subsequently, hydrolysis of the ester was carried out by a known method. Thus, 70 mg (32%) of the title compound was obtained as a light orange-colored powder.