Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[CH:24]([OH:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.N.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35]>C(O)C.C(Cl)Cl.C(C(C)=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[CH2:33]([O:26][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24](=[O:25])[N:16]1[CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)[CH3:34]
Reactant: O=C1c2ccccc2C(O)N1CCCN1CC=C(c2ccccc2)CC1
Agent: N
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCC(C)=O
Solvent: CCO
Product: CCOC1c2ccccc2C(=O)N1CCCN1CC=C(c2ccccc2)CC1
Reaction time: 4 h
Yield: 157.6 %

Procedure:
The same procedure is followed as in Example 2, but starting from an agitated solution of 2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-3-hydroxy-1-isoindolinone (7 g) in ethanol (265 cc) to which 37 cc of concentrated sulphuric acid is added at a temperature close to 20° C. and in the course of 15 minutes. Agitation is continued for 4 hours at a temperature close to 65° C. After cooling the solution to a temperature close to 0° C., 90 cc of a 33% aqueous solution of ammonia is added in the course of 1 hour. The precipitate formed is filtered and washed with methanol (50 cc). The filtrate is diluted with distilled water (200 cc) and a 33% aqueous solution of ammonia (70 cc) and extracted with methylene chloride (3×250 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (30 cc) and poured onto silica (500 g) contained in a column of 8 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (95-5 by volume). The first 1000 cc are eliminated, the next 900 cc are evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in methyl ethyl ketone (50 cc). A solution of oxalic acid (1.2 g) in methyl ethyl ketone (20 cc) is added and agitation is continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration. 4.9 g of 3-ethoxy-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 150° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].Cl.[N:31]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:49]=[CH:48][C:44]([C:45](O)=O)=[CH:43][CH:42]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:38][CH2:39][CH2:40][C:41]2[CH:49]=[CH:48][C:44]([CH2:45][CH2:2][CH2:1][NH:3][C:4]3[C:5]([CH:13]4[CH2:22][CH2:21][C:20]5[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16][C:15]=5[CH2:14]4)=[CH:6][C:7]4[O:11][CH2:10][O:9][C:8]=4[CH:12]=3)=[CH:43][CH:42]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Reactant: O=C(O)c1ccc(CCCN2CCCCCC2)cc1
Agent: Cl
Product: Oc1ccc2c(c1)CCC(c1cc3c(cc1NCCCc1ccc(CCCN4CCCCCC4)cc1)OCO3)C2
Yield: 58.5 %

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-(3-azepan-1-ylpropyl)benzoic acid hydrochloride (80 mg) according to an analogous synthetic method to Example 337 described below, the title compound (32 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[Br:11]Br>ClCCl>[Br:11][C:6]1[CH:5]=[C:4]([F:9])[C:3]([OH:10])=[C:2]([F:1])[C:7]=1[F:8]
Reactant: BrBr
Reactant: Oc1c(F)ccc(F)c1F
Solvent: ClCCl
Product: Oc1c(F)cc(Br)c(F)c1F
Reaction time: 168 h

Procedure:
10 g (0.0678 mol) of 2,3,6-trifluorophenol (prepared according to Examples 1a and 1b) are dissolved in 50 ml of dichloromethane, and this solution is admixed at 20° C. with 13 g (0.0811 mol) of bromine. After mixing by shaking, the mixture is left standing for 7 days.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH:21]([CH3:25])[CH2:22][O:23][CH3:24])=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[H][H]>CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH:21]([CH3:25])[CH2:22][O:23][CH3:24])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: [H][H]
Reactant: COCC(C)Nc1c([N+](=O)[O-])cnc2cc(-c3c(C)noc3C)c(OC)cc12
Solvent: CCOC(C)=O
Product: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Yield: 98.9 %

Procedure:
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N-(1-methoxypropan-2-yl)-3-nitroquinolin-4-amine (0.80 g, 2.070 mmol) was dissolved in EtOAc (120 ml) and hydrogenated using a flow hydrogenation apparatus (H Cube™, settings: full hydrogen, atmospheric pressure, 1 ml/min flow rate). The eluant was evaporated in vacuo to give the title compound as an orange gum (0.73 g, 99%). LCMS (formate) Rt 0.73 min, MH+ 357.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][CH2:19][CH2:18][C:17]3=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.OI(C1C=CC=CC=1)OS(C1C=CC(C)=CC=1)(=O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[O:20][CH:19]=[CH:18][C:17]3=[O:24])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc3c(c2)C(=O)CCO3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCc2ccc3occc(=O)c3c2)cc1
Yield: 33.2 %

Procedure:
The compound was produced with reference to the method described in the literature (Synth. Commun., 1994, 24 (18), 2637). A solution of 2-(4-oxo-3,4-dihydro-2H-chromen-6-yl)ethyl 4-methylbenzenesulfonate (RE6) (15.0 g, 43 mmol), [hydroxy(tosyloxy)iodo]benzene (20.4 g, 52 mmol) and p-toluenesulfonic acid monohydrate (375 mg) in acetonitrile (750 mL) was stirred at 50° C. for 16 hours. The solvent was distilled off under reduced pressure. Ethyl acetate (500 mL) was added to the obtained concentrated residue, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine in this order and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained concentrated residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→1:2) to obtain the title compound (RE7) (4.92 g, 33%) as a pale yellow solid.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.ClCCCN1CCCC(C2C=CC(OC)=CC=2)C1>>[ClH:14].[C:2]1([CH:8]2[CH2:9][CH2:10][N:11]([CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:22][CH2:23]3)[CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: ClCCCN1CCC(c2ccccc2)CC1
Agent: COc1ccc(C2CCCN(CCCCl)C2)cc1
Agent: Cl
Product: c1ccc(C2CCN(CCCN3CCC(c4ccccc4)CC3)CC2)cc1
Yield: 66.4 %

Procedure:
Using 4-phenylpiperidine hydrochloride (99 mg, 0.50 mmol) ′and 1-(3-chloropropyl)-4-phenylpiperidine 2 hydrochloride (110 mg, 0.40 mmol) instead of 4-(3-indolyl)piperidine and 1-(3-chloropropyl)-3-(4-methoxyphenyl)piperidine 3 hydrochloride, respectively, the reaction and purification were carried out in the same procedure as Example 2. The resulting crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; hexane:ether=2:1) to afford a free form (106 mg) of the title compound as white crystals. After adding hydrochloric acid/methanol to a solution of the free form in methanol, the mixture was concentrated and was then recrystallized from methanol/ether to afford the title compound (113 mg, yield: 65%) as white crystals.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]1=2.S(Cl)([Cl:21])=O>CCOCC>[Cl:21][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]1=2
Reactant: COc1ccc2c(c1)C(O)c1ccccc1CO2
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: COc1ccc2c(c1)C(Cl)c1ccccc1CO2
Temperature: 5 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
11-Hydroxy-2-methoxy-6,11-dihydrodibenz[b,e]oxepin (13.85 g, 0.057 mole) is dissolved in anhydrous ether (180 ml) and cooled to 5° C. under a dry nitrogen atmosphere. Thionyl chloride (7.37 g; 0.062 mole) in ether (20 ml) is added dropwise while maintaining the temperature below 5° C. (Near the end of the addition a solid precipitates from the solution). The reaction is stirred at ambient temperature for 3 hours and filtered. The filtrate is removed in vacuo to give a solid which is combined with the filtered solid and recrystallized from cyclohexane to provide 10.5 g (70%) of crystals of 11-chloro-2-methoxy-6,11-dihydrodibenz[b,e]oxepin, m.p. 133°-134.5° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:14])[CH:11]=2)[C:6]1=[O:15]>CN(C)C=O.O>[C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:14])[CH:11]=2)[C:6]1=[O:15])#[N:2]
Reactant: [C-]#N
Reactant: O=C1c2ccc(Cl)cc2CC1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1Cc2cc(Cl)ccc2C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
10.4 g of sodium cyanide were dissolved in a mixture of 100 ml of dimethylformamide and 6 ml of water and initially charged. This solution was heated with stirring to 50° C., and 20.4 g of 2,5-dichloroindan-1-one, dissolved in 100 ml of dimethylformamide, were then added dropwise over a period of 60 minutes. After the addition had ended, stirring was continued at 50° C. for 1 hour. The mixture was then allowed to cool to room temperature and the solvent was stripped off using a rotary evaporator. The resulting crystal slurry was mixed with 200 ml of water and acidified to pH 4.5 using 10% by weight strength aqueous hydrochloric acid. The precipitated solid was filtered off with suction, washed with water, recrystallized from toluene and dried in a vacuum drying cabinet. This gave 18.5 g of 2-cyano-5-chloroindan-1-one (yield: 97% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=O.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:15]3[C:10]([CH:11]=[N:12][C:13]([NH:16][C:17]4[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=4)=[N:14]3)=[C:8]([CH3:9])[N:7]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Br)c4)n3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.9 %

Procedure:
To a solution of 3-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 18) (490 mg, 1.0 mmol) and 1,2,4-triazole (210 mg, 3.0 mmol) in pyridine (10 mL) was added phosphorus oxychloride (0.14 mL, 1.5 mmol). The mixture was stirred at room temperature for 24 hours. The excess phosphorus oxychloride was quenched with methanol and ammonium hydroxide. The product was extracted into ethyl acetate (100 mL) and washed with 0.1N hydrochloric acid (3×50 mL). The solution was dried with magnesium sulfate and filtered. Silica gel (2.5 g) was added, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (25:75) to ethyl acetate:hexanes (75:25) using a RediSep silica gel cartridge (12 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine (0.23 g) as a yellow solid. 1H NMR (CD3OD): δ9.01 (s, 1H) 8.51 (dd, J=1.9, 1.6 Hz, 1H), 8.33 (ddd, J=7.9, 1.4, 1.1 Hz, 1H), 7.57 (ddd, J=7.9, 1.9, 1.1 Hz, 1H), 7.38 (dd, J=8.1, 7.9 Hz, 1H), 6.99 (s, 2H), 3.76 (s, 6H), 3.75 (s, 3H), 2.56 (s, 3H). MS m/z 470, 472 (M+1, M+3).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:39][C:40]1([C:46]2[CH:51]=[CH:50][C:49]([S:52]([NH:55][C:56]3[S:57][CH:58]=[CH:59][N:60]=3)(=[O:54])=[O:53])=[CH:48][CH:47]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]([N:43]2[CH2:42][CH2:41][C:40]([C:46]3[CH:51]=[CH:50][C:49]([S:52]([NH:55][C:56]4[S:57][CH:58]=[CH:59][N:60]=4)(=[O:53])=[O:54])=[CH:48][CH:47]=3)([OH:39])[CH2:45][CH2:44]2)=[O:14])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(C2(O)CCNCC2)cc1
Reactant: O=C(O)Cn1ccc2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: O=C(Cn1ccc2ccc(Cl)cc21)N1CCC(O)(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1
Reaction time: 16 h
Yield: 52.6 %

Procedure:
Prepared using general procedure 20. A solution of 2-(6-chloro-1H-indol-1-yl)acetic acid (184 mg, 0.88 mmol) and HATU (335 mg, 0.88 mmol) in DMF (3 mL) was stirred under an N2 atmosphere at 0° C. for 1 h. To this mixture, 4-(4-hydroxypiperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (300 mg, 0.88 mmol) and NaHCO3 (148 mg, 1.76 mmol) were added under an N2 atmosphere at RT, and the reaction was stirred for 16 h. The reaction mixture was filtered and purified by Gilson preparative HPLC (5-99% CH3CN—H2O) to isolate 4-(1-(2-(6-chloro-1H-indol-1-yl)acetyl)-4-hydroxypiperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (246 mg, 52%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=531.3; tR=2.98 min. 1H NMR (400 MHz, DMSO-d6) δ, 7.78 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.6 Hz, 2H), 7.29 (dd, J=28.5, 3.9 Hz, 2H), 7.03 (dd, J=9.3, 0.9 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 6.47 (d, J=3.1 Hz, 1H), 5.23 (q, J=14.8 Hz, 2H), 4.27 (d, J=12.1 Hz, 1H), 3.87 (d, J=12.6 Hz, 1H), 3.51 (t, J=11.9 Hz, 1H), 3.02 (t, J=11.6 Hz, 1H), 2.04-1.97 (m, 1H), 1.81 (m, 1H), 1.67-1.61 (m, 2H).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][C:9](=[CH:11]/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][C:17]([CH3:39])([CH3:38])[CH2:18]/[CH:19]=[CH:20]\[C:21]([O:30][Si](CC)(CC)CC)([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH2:8][C@@H:7]([O:40]C(=O)C)[CH2:6]1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[F:23][C:22]([F:24])([F:25])[C:21]([OH:30])([C:26]([F:28])([F:29])[F:27])/[CH:20]=[CH:19]\[CH2:18][C:17]([CH3:39])([CH3:38])[CH2:16][CH2:15][CH2:14]/[CH:13]=[CH:12]/[CH:11]=[C:9]1[CH2:10][C@@H:5]([OH:4])[CH2:6][C@H:7]([OH:40])[CH2:8]1
Reactant: CC[Si](CC)(CC)OC(/C=C\CC(C)(C)CCC/C=C/C=C1C[C@@H](OC(C)=O)C[C@H](OC(C)=O)C1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C/C=C\C(O)(C(F)(F)F)C(F)(F)F)CCC/C=C/C=C1C[C@@H](O)C[C@H](O)C1
Reaction time: 8 h

Procedure:
To a solution of 50 mg of acetic acid (1R,3R)-3-acetoxy-5-[(2E,9Z)-12,12,12-trifluoro-7,7-dimethyl-11-triethylsilanyloxy-11-trifluoromethyl-dodeca-2,9-dienylidene]-cyclohexyl ester in 1.5 ml of CH3OH was added at 22° a solution of 37 mg of K2CO3 in 0.25 ml of water and stirring was continued for 8 h after which time t.l.c. indicated completion of the reaction. The mixture was evaporated and the residue was partitioned between dichloromethane and aqueous sat. NaCl, the organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica with hexane/AcOEt 2:1 to give 34 mg of the pure (t.l.c.) title compound as a colorless resin. IR (neat): 3345s (OH), 1661w and 1622w (C═C); MS (EI): 444/10 (M), 426/8 (M−H2O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2c[nH]c3ccccc23)cc1
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1ccc(-c2cn(-c3ccncc3)c3ccccc23)cc1
Reaction time: 18 h

Procedure:
3-(4-Fluorophenyl)-1H-indole 1a (39.3 g), 4-chloropyridine hydrochloride (55.8 g), K2CO3 (102.8 g), CuBr (15 g) and N-methylpyrrolidinone (1.2 l) were refluxed under stirring for 18 h. The reaction mixture was cooled, poured into water (1.0 l) and extracted with diethyl ether (2×1 l). The combined organic phases were washed with brine (3×1.5 l), dried (Na2SO4) and treated with activated carbon. Evaporation of the solvent gave the title compound which was crystallized from diethyl ether. Yield: 42.0 g, mp 115°-118° C.
Reaction SMILES: ClC1C(Cl)=CC2O[C@@H](C)C[C@H](C([O-])=O)C=2C=1.C(ON1CCC2(C3C=C(F)C=CC=3OC(C)C2)C1=O)C1C=CC=CC=1.C([O:49][N:50]1[CH2:54][CH2:53][C:52]2([C:59]3[CH:60]=[C:61]([Cl:65])[C:62]([Cl:64])=[CH:63][C:58]=3[O:57][CH:56]([CH3:66])[CH2:55]2)[C:51]1=[O:67])C1C=CC=CC=1>>[OH:49][N:50]1[CH2:54][CH2:53][C:52]2([C:59]3[CH:60]=[C:61]([Cl:65])[C:62]([Cl:64])=[CH:63][C:58]=3[O:57][CH:56]([CH3:66])[CH2:55]2)[C:51]1=[O:67]
Reactant: CC1CC2(CCN(OCc3ccccc3)C2=O)c2cc(Cl)c(Cl)cc2O1
Agent: CC1CC2(CCN(OCc3ccccc3)C2=O)c2cc(F)ccc2O1
Agent: C[C@H]1C[C@H](C(=O)[O-])c2cc(Cl)c(Cl)cc2O1
Product: CC1CC2(CCN(O)C2=O)c2cc(Cl)c(Cl)cc2O1

Procedure:
Prepared from methyl cis and trans 6,7-dichloro-2,3-dihydro-2-methyl-4H-1-benzopyran-4-carboxylate in the same manner as the product of Example 6, part 4 from more polar diastereomer of 1'-benzyloxy-2,3-dihydro-6-fluoro-2-methyl-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'-one, via intermediacy of methyl cis and trans 6,7-dichloro-2,3-dihydro-2-methyl-4-(2-propenyl)-4H-1-benzopyran-4carboxylate (Rf=0.6, 1:1 diethyl ether/hexanes, SiO2), methyl cis and trans 6,7-dichloro-2,3-dihydro-2-methyl-4-(2-benzyloxyaminoethyl)-4H-1-benzopyran-4-carboxylate (Rf=0.4, 1:1 diethyl ether/hexanes, SiO2), and the more polar diasteromer of 1'-benzyloxy-2,3-dihydro-6,7-dichloro-2-methyl-spiro-(4H-1-benzopyran-4,3'-pyrrolidine)-2'one (Rf=0.7, diethyl ether, SiO2).
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.O[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:32])[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=1[N+:29]([O-:31])=[O:30])=[O:20]>O>[CH3:28][O:27][C:23]1[C:22]([N+:29]([O-:31])=[O:30])=[C:21]([C:19]2[O:20][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17](=[O:32])[CH:18]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(C(=O)CC(=O)c2ccccc2O)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(-c2cc(=O)c3ccccc3o2)c1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
A solution of glacial acetic acid (15 mL), concentrated sulfuric acid (180 mL), and 1-(2-hydroxy-phenyl)-3-(3-methoxy-2-nitrophenyl)propane -1,3 -dione (770 mg, 2.43 mmol) is heated at reflux for 2.5 hours. The hot solution is poured onto crushed ice and H2O (200 mL), stirring vigorously for 30 minutes. The solution is cooled in a refrigerator. The resulting solid is filtered and washed with H2O to yield 2-(3-methoxy-2-nitrophenyl)-4-oxo-4H-[1]benzopyran (510 mg, 70%) as a brown solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:25][CH:24]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:25][CH:24]=3)[C@H:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=3)[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1cccc(C(F)(F)F)c1)[C@H]2c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1cccc(C(F)(F)F)c1)[C@H]2c1ccc(OCCN2CCCC2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-4-(4-(2-pyrrolidinoethoxy)phenyl)-3-(3-(trifluoromethyl)phenyl)chromane (0.25 g, 0.50 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white solid.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][C:8]([C:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:32])[C:18]([CH3:31])([S:20]([CH2:23][CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)(=[O:22])=[O:21])[CH3:19])[O:13][N:12]=1)([CH3:10])[CH3:9])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:6][CH2:7][C:8]([C:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:32])[C:18]([CH3:31])([S:20]([CH2:23][CH:24]2[CH2:25][CH2:26][C:27](=[O:30])[CH2:28][CH2:29]2)(=[O:22])=[O:21])[CH3:19])[O:13][N:12]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCC(=O)CC2)on1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCC(=O)CC2)on1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.4 %

Procedure:
To a solution of 0.12 g (0.19 mmol) of N-{3-[2-(tert-butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-isoxazol-5-yl}-2-methyl-2-(4-oxo-cyclohexylmethanesulfonyl)-propionamide in THF (2 mL) is added tetrabutylammonium fluoride (0.65 mL, 0.65 mmol, 1M solution in THF) and the reaction is stirred at room temperature for 48 h. The reaction mixture is quenched by addition of saturated aqueous NH4Cl solution (5 mL) and the mixture is extracted with DCM (8 mL×3). The combined organic extracts are washed with brine (10 mL), dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure and the residue purified twice by column chromatography (silica, eluent: DCM, 20% ethyl acetate, then DCM, 10% ethyl acetate) to afford 0.03 g of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(4-oxo-cyclohexylmethanesulfonyl)-propionamide. Yield: 41%, ES-MS: 401 [M+H]
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C@@H:18]4[O:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20][CH2:19]4)=O)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1COCC1.O.[OH-].[Na+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C@@H:18]4[O:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20][CH2:19]4)[CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCCC(c2ccc3c(c2)OCO3)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OC[C@H](CN1CCCC(c3ccc4c(c3)OCO4)C1)O2
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 83.8 %

Procedure:
(3-Benzo[1,3]dioxol-5-ylpiperidin-1-yl-(R)-2,3-dihydrobenzo[1,4]dioxin-2-ylmethanone (285 mg, 0.77 mmol) was dissolved in dry DMF (2.5 ml) and 1 M BH3 THF (3.10 ml, 3.10 mmol) was slowly added under a nitrogen atmosphere. The reaction mixture was stirred for 4.5 h at RT and then cooled to 0° C. Water was slowly added and the mixture basified with 2.5 M NaOH and extracted three times with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness. The crude product was dissolved in methanol (25 ml) and 5 M HCl (1.5 ml) was slowly added. The mixture was stirred for 1 h at RT and then at 60° C. for 2 h. The reaction mixture was evaporated to dryness, redissolved in EtOAc and washed twice with 1 M Na2CO3 and water. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness to give 228 mg of the title compound.