Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][O:7][C:8]1[C:13]2[CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH2:18][C:12]=2[CH:11]=[CH:10][CH:9]=1>C(#N)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>[CH3:6][O:7][C:8]1[C:13]2[CH2:14][CH2:15][CH2:16][C:17](=[O:19])[CH2:18][C:12]=2[CH:11]=[CH:10][C:9]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cccc2c1CCCC(=O)C2
Agent: [K+]
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1c([N+](=O)[O-])ccc2c1CCCC(=O)C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34.6 %

Procedure:
To potassium nitrate in acetonitrile (50 mL) and trifluoroacetic anhydride (100 mL) at 0° C. was added dropwise 1-methoxy-5,7,8,9-tetrahydro-benzocyclohepten-6-one (25 g, 0.131 mol) in 50 mL acetonitrile. The reaction was stirred for 2.5 hours while warming to RT. The reaction was concentrated without heat on a rotary evaporator. MeOH was added and stirred briefly. Reconcentrated and worked-up by partitioning between dichloromethane and sat. sq. sodium bicarbonate solution. The organic layer was separated and dried (Mg2SO4), concentrated and purified by chromatography ISCO (330 g silica cartridge: gradient elution—10 to 50% EA:HEX over 60 minutes) affording two isomers. The title compound was the later eluting (10.7 grams, 34.6% yield). 1H-NMR (400 MHz, CDCl3) 7.70 (d, J=8.3 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 2H), 3.13-3.09 (m, 2H), 2.60 (t, J=7.0 Hz, 2H), 2.10-2.03 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].CS(C)(=O)=O.O1[CH2:49][CH2:48]OCC1>>[CH2:10]([N:5]1[CH2:49][CH2:48][N:11]([C:14]2[N:13]=[C:12]([NH:11][C@H:7]3[CH2:8][CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6]3)[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=2)[CH2:7][CH2:6]1)[CH3:9]
Reactant: C1COCCO1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Product: CCN1CCN(c2ncc(-c3cnc4[nH]ccc4n3)c(N[C@H]3CCCN(S(C)(=O)=O)C3)n2)CC1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1,1-ethyl-piperazine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give [2-(4-ethyl-piperazin-1-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-((S)-1-methanesulfonyl-piperidin-3-yl)-amine. MS (ES+): 486.
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].Cl.CON.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[NH:23][C:24](=O)[CH3:25]>>[C:2]([O:6][N:7]1[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=[C:24]1[CH3:25])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)Nc1cnc2ccccc2c1Cl
Reactant: CC(C)(C)ON
Agent: CON
Agent: Cl
Product: Cc1nc2cnc3ccccc3c2n1OC(C)(C)C
Yield: 51.9 %

Procedure:
The method of Part B of Example 25 was followed using O-(tert-butyl)hydroxylamine hydrochloride (2.0 g, 16 mmol) in lieu of O-methylhydroxylamine hydrochloride to treat N-(4-chloroquinolin-3-yl)acetamide (3.2 g, 14.5 mmol) with the modification that the reaction was heated at reflux for three hours. Following the work-up procedure, the resulting blue oil was purified by column chromatography on silica gel (eluting with 5% methanol in dichloromethane containing 5 mL of aqueous ammonium hydroxide per liter of eluent) to provide 1.92 g of 1-tert-butoxy-2-methyl-1H-imidazo[4,5-c]quinoline as a blue oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[S:16]1[CH:20]=[C:19]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[NH2:26])[N:18]=[CH:17]1>>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([NH:26][C:25]1[CH:24]=[CH:23][S:22][C:21]=1[C:19]1[N:18]=[CH:17][S:16][CH:20]=1)=[O:15]
Reactant: O=C(O)CN1C(=O)CCc2ccccc21
Reactant: Nc1ccsc1-c1cscn1
Product: O=C(CN1C(=O)CCc2ccccc21)Nc1ccsc1-c1cscn1

Procedure:
The title compound was prepared from 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (88 mg, 0.43 mmol) and 2-(thiazol-4-yl)thiophen-3-amine (79 mg, 0.43 mmol) according to protocol A. Retention time (min)=5.703, method [7], MS (ESI) 370.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 11.2 (s, 1H), 8.49 9d, J=2.7 Hz, 1H), 8.13 (d, J=5.4 Hz, 1H), 7.19-7.25 (m, 4H), 7.02-7.08 (m, 2H), 4.81 (s, 2H), 3.05-3.09 (m, 2H), 3.2.85-2.89 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:40][C:41]1[N:42]=[C:43]([CH3:46])[S:44][CH:45]=1.C(N(CC)CC)C>CN(C)C=O.O>[CH2:12]([C:7]1[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[C:5]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:40][C:41]3[N:42]=[C:43]([CH3:46])[S:44][CH:45]=3)[CH:3]=2)[N:8]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(O)cc23)cc1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCc4csc(C)n4)cc23)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.4 %

Procedure:
To a solution of tert-butyl {[6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.40 g, 0.95 mmol) in N,N-dimethylformamide (10 ml) were added potassium carbonate (0.28 g, 2.0 mmol), 4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (0.37 g, 2.0 mmol) and triethylamine (0.31 ml, 2.2 mmol) and the mixture was stirred at room temperature for 6 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl ({2-isobutyl-4-(4-methylphenyl)-6-[(2-methyl-1,3-thiazol-4-yl)methoxy]quinolin-3-yl}methyl)carbamate (0.32 g, yield 63%) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:10])=[CH:4][CH:3]=1.[C:16](=[S:18])=[S:17].[OH-].[Na+].Br[CH2:22]Br>CC(C)=O>[S:17]1[CH2:22][S:18][C:16]1=[C:11]([C:9](=[O:10])[NH:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: BrCBr
Reactant: S=C=S
Reactant: COC(=O)CC(=O)Nc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)C(C(=O)Nc1ccc(F)cc1)=C1SCS1
Reaction time: 2 h

Procedure:
A mixture of methyl 2-[N-(4-fluorophenyl)carbamoyl]acetate (10 g), carbon disulfide (3.2 ml) and acetone (200 ml) was cooled to 5°-10° C., to which 50% aqueous sodium hydroxide (4.2 ml) was added dropwise. The mixture was stirred at same temperature for 2 hrs, then dibromomethane (4 ml) was added dropwise and the reaction mixture was stirred at room temperature for 1 hr and refluxed for 2 hrs. The solid was removed by filtration and the filtrate was poured onto ice-water. The solid formed was filtered, and dissolved in methylene chloride. The solution was washed with 10% aqueous sodium hydroxide solution and water, then dried. The solvent was evaporated and the residue was purified with ethyl acetate and ethyl ether to give the titled compound as a white solid. (8.5 g, 60%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C@:10]2([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:11](=[O:12])[C@@H:6]([C@:7]([CH3:28])([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:8]([O:18][CH2:19][O:20][CH3:21])[CH2:9]2)[C:5](=[O:29])[CH:4]=1.Cl[Si:31]([CH3:34])([CH3:33])[CH3:32].[Li]N1C(C)(C)CCCC1(C)C>C1COCC1>[CH3:1][O:2][C:3]1[C@:10]2([CH2:13][CH:14]=[C:15]([CH3:16])[CH3:17])[C:11](=[O:12])[C@@H:6]([C@:7]([CH3:28])([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:8]([O:18][CH2:19][O:20][CH3:21])[CH2:9]2)[C:5](=[O:29])[C:4]=1[Si:31]([CH3:34])([CH3:33])[CH3:32]
Reactant: C[Si](C)(C)Cl
Reactant: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@H](C(=O)C=C2OC)[C@]1(C)CCC=C(C)C
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Product: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@H](C(=O)C([Si](C)(C)C)=C2OC)[C@]1(C)CCC=C(C)C
Yield: 95 %

Procedure:
A flame-dried round-bottom flask with magnetic stir bar was charged with 380 mg (0.939 mmol, 1 equiv.) starting material 50 followed by 9.4 mL THF and 596 μL (4.70 mmol, 5 equiv.) of chlorotrimethylsilane with stirring. The solution was cooled in an acetone/dry ice bath for 10 minutes prior to the addition of 9.4 mL of a 0.5M solution of lithium tetramethylpiperidide in THF (4.7 mmol, 5 equiv.). The mixture was stirred at −78° C. for 10 minutes before placing the reaction in a water/ice bath for an additional 10 minutes. The reaction was quenched by the addition of 2 mL of saturated aqueous sodium bicarbonate and transferred to a separatory funnel by the addition of 50 mL hexane. The organic layer was then washed with saturated aqueous sodium bicarbonate, 10% aqueous hydrochloric acid, water, and saturated brine solution. The organic layer was then dried with MgSO4 and concentrated in vacuo to give a yellow oil. Purification by silica gel chromatography (Rf=0.25 in 9:1 hexane:ethyl acetate) gave 425 mg (95% yield) of 51 as a clear oil. 1H NMR (500 MHz, CDCl3) δ ppm 5.06 (tt, J=7.0, 1.3 Hz, 1H), 4.99 (tt, J=6.9, 1.4 Hz, 1H), 4.59 (dd, J=35.6, 6.8 Hz, 2H), 3.92 (s, 3H), 3.60 (dd, J=11.5, 5.2 Hz, 2H), 3.33 (s, 3H), 3.17 (s, 1H), 2.55 (dd, J=14.5, 6.3 Hz, 1H), 2.38-2.38 (m, 0H), 2.40 (dd, J=14.6, 7.4 Hz, 1H), 2.27-2.34 (m, 1H), 2.24 (dd, J=13.5, 5.2 Hz, 4H), 1.84-1.94 (m, 1H), 1.81 (dd, J=13.4, 11.6 Hz, 2H), 1.63-1.68 (m, 12H), 1.55 (ddd, J=13.0, 4.5 Hz, 1H), 1.17-1.26 (m, 1H), 0.91 (s, 3H), 0.23-0.24 ppm (m, 9H). 13C NMR (126 MHz, CDCl3) δ ppm 205.9, 197.8, 185.8, 134.2, 131.8, 127.4, 124.4, 119.4, 97.3, 79.2, 70.8, 64.4, 58.4, 55.8, 46.5, 37.7, 37.4, 29.8, 26.0, 25.9, 21.6, 18.1, 17.8, 16.4, 0.7. HRMS-ESI (m/z): [M+H]+ calculated C27H44O5Si, 477.3031. found 477.3031.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:25]>>[CH2:1]([CH:8]([CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:9]([Cl:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccccc1)Cc1cccc2ccccc12
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C(Cc1ccccc1)Cc1cccc2ccccc12

Procedure:
A solution of 5.0 g (17.2 mmole) of 2-benzyl-3-(1-naphthyl)propionic acid (EP-186,977) in 30 ml SOCl2 was stirred overnight at room temperature. The mixture was stripped to 5.48 g of an oil which was used without further purification in the following reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(C)Br
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)Oc1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To 20.0 g of p-(benzyloxy)phenol in 80 ml of dry hexamethylphosphoramide is added 5.4 g of sodium methoxide. The mixture is stirred 10 minutes and 18.1 g of ethyl 2-bromopropionate is added (exotherm). After 15 minutes the mixture is heated on a steam bath for 16 hours. The mixture is poured onto ice, extracted with ether, the ether extracts washed with water, dried over magnesium sulfate and concentrated in vacuo to give off-white crystals, mp 36°-44° C. Two recrystallizations from ethanol give off-white crystals, mp 46°-49° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[CH2:11][N:12]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:13][CH2:14][C:15]=2[CH:16]=1)=[O:7])[CH3:4].[H][H].[C:27]([O:31][C:32](=O)[O:33]C(C)(C)C)([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O.O.C(OCC)C>[C:27]([O:31][C:32]([N:9]1[C:10]2[CH2:11][N:12]([C:17]([O:19][CH2:20][C:21]([Cl:23])([Cl:24])[Cl:22])=[O:18])[CH2:13][CH2:14][C:15]=2[CH:16]=[C:8]1[C:6]([O:5][CH2:3][CH3:4])=[O:7])=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc2c([nH]1)CN(C(=O)OCC(Cl)(Cl)Cl)CC2
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1C(=O)OC(C)(C)C)CN(C(=O)OCC(Cl)(Cl)Cl)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
A suspension of diethyl ether washed sodium hydride (1.22 g, 0.041 mole) in dry dimethylformamide (50 ml) under nitrogen at 0° C. was treated with a solution of 2-ethoxycarbonyl-6-(2,2,2-trichloroethoxycarbonyl)-4,5,6,7-tetrahydro-6-azaindole from Example 3 (13.4 g, 0.036 mole) in dry dimethylformamide (35 ml) dropwise over 10 minutes. Evolution of hydrogen was noted and the mixture stirred at room temperature for 10 minutes. The solution was cooled to 0° C. and treated dropwise with a solution of di-tert-butylcarbonate (8.94 g, 0.041 mole) in dry dimethylformamide (25 ml) over 10 minutes. The mixture was allowed to stand at room temperature overnight, water (100 ml) added and the resulting solution evaporated under vacuum to low bulk. The residue was diluted with water (200 ml) extracted with ethyl acetate (4×100 ml) the combined extracts washed with water (50 ml) and brine (3×100 ml), dried over sodium sulphate and evaporated to give a brown viscous oil, which was chromatographed on silica gel (250 g) eluting with hexane:dichloromethane (2:1), followed by dichloromethane to give the title product as a pure viscous oil (15.3 g, 80%). Found: C, 46.42; H, 5.08; N, 5.72. C18H23Cl3N2O6 requires C, 46.02; H, 4.93; N, 5.96%.
Reaction SMILES: FC(F)(F)C([N:5]=[C:6]1[N:10]([CH2:11][CH2:12][OH:13])[C:9]2[CH:14]=[CH:15][C:16]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:17][C:8]=2[S:7]1)=O.NC1SC2C=C(OC(F)(F)F)C=CC=2N=1.[Br:40]CCO>C(O)C>[BrH:40].[NH:5]=[C:6]1[N:10]([CH2:11][CH2:12][OH:13])[C:9]2[CH:14]=[CH:15][C:16]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:17][C:8]=2[S:7]1
Reactant: O=C(N=c1sc2cc(OC(F)(F)F)ccc2n1CCO)C(F)(F)F
Reactant: OCCBr
Agent: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: CCO
Product: Br
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CCO
Temperature: 20 °C

Procedure:
The 2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol may be prepared according to the following process: 9.4 g of 2-amino-6-trifluoromethoxybenzothiazole and 10 g of 2-bromoethanol in 30 cm3 of absolute ethanol are heated at boiling temperature for 95 hours. The mixture is then cooled to a temperature in the region of 20° C. The precipitate formed is filtered and washed with 100 cm3 of ethyl ether. 6.4 g of 2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol hydrobromide with a melting point of 219° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].OS(O)(=O)=O>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Yield: 36 %

Procedure:
In a similar fashion using route 11 general procedure 57, 4-chloroquinoline 462 (5.0 g, 30.7 mmol), fuming HNO3 (8.3 ml) and concentrated H2SO4 (16.6 ml) to give the title compound (2.3 g, 36%) which was used in the next step without further purification.
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S([O-])(=O)=O)=[CH:4][CH:3]=1.[NH+]1C=CC=CC=1.C(N(CC)CC)C.[NH4+].[Cl-].C1[CH2:32][O:31][CH2:30]C1>>[OH:1][CH:30]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:32][O:31]1
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: O
Agent: [Cl-]
Agent: [NH4+]
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Product: OC1OCCc2ccccc21
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 95 %

Procedure:
To a solution of methyl-3-(2'-formyl-3'-6'-dimethoxy)phenyl-2-methoxyisopropyloxy-propionate (4.2 g, 12.4 mmol) in THF (75 ml) containing water (4 ml) was added pyridinium p-toluenesulfonate (230 mg). After stirring at room temperature for 1.75 hours, triethylamine (3 ml) and saturated NH4Cl solution (60 ml) were added. THF was removed at 25° C. and the mixture was extracted with ether (3×150 ml). Ether extract was washed with brine, dried and evaporated yielding 3.9 g of 1-hydroxyisochroman (95%) (quite pure from NMR spectrum). (MP. 127°-129° C.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:16][CH2:17][CH2:18][CH3:19])=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH2:17]([S:16][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:25]([C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)(=[O:27])=[O:26])=[C:10]2[C:6]=1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:9]2)[CH2:18][CH3:19]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCCSc1ccc(N)c2[nH]c(C(=O)OCC)cc12
Solvent: c1ccncc1
Product: CCCSc1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)OCC)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a mixed solution of ethyl 7-amino-4-(propylthio)-1H-indole-2-carboxylate (0.90 g) and pyridine (10 mL) was added 2-thiophenesulfonyl chloride (0.72 g) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-1:3), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (0.64 g, yield 47%) as colorless needle crystals. melting point 150-151° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:27])([CH3:26])[CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:27])([CH3:26])[CH2:23][CH2:24][O:25][S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)(CCO)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(C)(O)COc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
4-[4-(2,4-Dihydroxy-2-methylbutoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (3.75 g, 9.9 mmol), tosyl chloride (2.07 g, 10.8 mmol), dichloromethane (38 ml) and triethylamine (2.75 ml, 19.7 mmol) were mixed and ice-cooled. 1,1,3,3,-Tetramethylpropanediamine (0.16 ml, 1.0 mmol) was added thereto and stirred at room temperature overnight. The reaction mixture was washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→40:60) to afford the title compound as a colorless oil (4.69 g, 89%).
Reaction SMILES: [CH3:1][C:2]([OH:5])([CH3:4])[CH3:3].CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:27]C)C=C4)N(CC2)C1.[Cl:64][C:65]1[CH:66]=C2[C:72](=[C:73]([O:75][CH:76]([F:78])[F:77])[CH:74]=1)[S:71][CH2:70]CC2=C>O>[Cl:64][C:65]1[CH:66]=[C:1]2[C:72](=[C:73]([O:75][CH:76]([F:78])[F:77])[CH:74]=1)[S:71][CH2:70][CH2:3][C@:2]2([OH:5])[CH2:4][OH:27]
Reactant: CC(C)(C)O
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=C1CCSc2c(OC(F)F)cc(Cl)cc21
Solvent: O
Product: OC[C@@]1(O)CCSc2c(OC(F)F)cc(Cl)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-Methyl-2-propanol (120 mL), H2O (120 mL), and AD-mix-β (13.3 g) were combined together and cooled to 0° C. Concurrently, 6-chloro-8-difluoromethoxy-4-methylenethiochromane (2.65 g, 10.1 mmol; from step (iv) above) was cooled to −5° C. in an ice/MeOH bath. Once sufficiently cooled, the AD-mix-β solution was added and stirred at <0° C. for 2 h, then at room temperature for 4 h. The reaction was quenched with solid sodium sulfite (ca. 5.0 g) resulting in a clear solution which was then partitioned between EtOAc/H2O (1:1, 300 mL) and further extracted with EtOAc (100 mL). The organic extracts were combined and washed with 5 M H2SO4 (75 mL), saturated NaHCO3 (150 mL), and brine (150 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford 2.99 g (ca. 100%) of the sub-title compound as a yellow solid which was used without further purification. 1H NMR (300 MHz, CD3OD) δ 7.55 (s, 1H), 7.08 (s, 1H), 6.78 (t, J=75 Hz, 1H), 3.70 (d, J=12 Hz, 1H), 3.50 (d, J=12 Hz, 1H), 2.97-3.20 (m, 2H), 2.46-2.55 (m, 1H), 1.91-2.02 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:23][C:24]([O:26]C)=[O:25])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=3[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH3:2].O>CO>[CH2:1]([C:3]1([CH2:23][C:24]([OH:26])=[O:25])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=3[O:17][CH2:18][C:19]([F:21])([F:20])[F:22])[CH3:2]
Reactant: CCC1(CC(=O)OC)OCCc2c1[nH]c1c(OCC(F)(F)F)ccc(C)c21
Solvent: O
Solvent: CO
Product: CCC1(CC(=O)O)OCCc2c1[nH]c1c(OCC(F)(F)F)ccc(C)c21

Procedure:
A mixture consisting of 4-methyl-7-(2,2,2-trifluoroethoxy)tryptophol (9.8 g, 0.036 mol), methyl 3-methoxy-2-pentenoate (5.0 g, 0.035 mol), CH2Cl2 (400 mL) and BF3.Et2O (1 mL) was stirred at room temperature for 3 hours, washed with 5% NaHCO3, water, dried (MgSO4) and concentrated to afford 12 g of crude 1-ethyl-1,3,4,9-tetrahydro-5-methyl-8-(2,2,2-trifluoroethoxy)-pyrano[3,4-b]indole-1-acetic acid, methyl ester. Flash chromatography using 13% EtOAc-hexane gave 7.2 g of solid ester, mp 138°-140° C. The above ester was hydrolyzed in 400 mL MeOH containing 7.0 g KOH and 10 mL water by refluxing for 4 hours. The reaction solution was concentrated, diluted with water and extracted with ether (2×200 mL). The aqueous phase was acidified with 6N HCl and extracted with chloroform (2×200 mL). The combined chloroform extracts were washed with water, dried (MgSO4) and concentrated to afford 6.4 g of solid 1-ethyl-1,3,4,9-tetrahydro-5-methyl-8-(2,2,2-trifluoroethoxy)-pyrano[3,4-b]indole-1-acetic acid. Recrystallization from toluene-petroleum ether afforded 5.0 g (37%) of pure product, m.p. 149°-151° C.