Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([C:11](=O)[CH3:12])[C:8]([OH:14])=[C:7]([CH3:15])[C:6]=1[CH3:16])(=O)C.O.Cl>C1(C)C=CC=CC=1.[Zn].Cl[Hg]Cl>[CH2:11]([C:9]1[C:8]([OH:14])=[C:7]([CH3:15])[C:6]([CH3:16])=[C:5]([OH:4])[CH:10]=1)[CH3:12]
Reactant: CC(=O)Oc1cc(C(C)=O)c(O)c(C)c1C
Agent: Cl
Agent: Cl[Hg]Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(O)c(C)c(C)c1O
Yield: 99.6 %

Procedure:
To a well stirred solution of 5-acetyl-4-hydroxy-2,3-dimethylphenyl acetate (4.7 g) in 100 mL of toluene were added Zn dust (5.0 g), HgCl2 (480 mg), water (9 mL) and concentrated HCl (9 mL). The heterogeneous mixture was allowed to reflux for 2 days. The mixture was cooled, filtered, and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 and water, and dried over anhydrous Na2SO4. Evaporation of the organic solvents gave 3.5 g of 5-ethyl-2,3-dimethylbenzene-1,4-diol as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][CH2:13][C@@H:14]3[CH2:16][O:15]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:17]1[C:29]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][C:18]=1[N:30]1[CH2:37][C@H:36]2[NH:38][CH2:39][C@@H:31]1[CH2:32][CH:33]=[CH:34][CH2:35]2.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][CH2:13][C@@H:14]([OH:15])[CH2:16][N:38]3[CH2:39][CH:31]4[N:30]([C:18]5[CH:19]=[CH:20][C:21]6[C:22]7[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=7)[CH2:28][C:29]=6[CH:17]=5)[CH2:37][CH:36]3[CH2:35][CH:34]=[CH:33][CH2:32]4)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(OC[C@@H]3CO3)ccnc2c1
Reactant: C1=CC[C@H]2CN[C@@H](C1)CN2c1ccc2c(c1)Cc1ccccc1-2
Agent: C1=C\C[C@H]2CN[C@@H](C/1)CN2c1ccc2c(c1)Cc1ccccc1-2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H](COc1ccnc2cc(Cl)ccc12)CN1CC2CC=CCC1CN2c1ccc2c(c1)Cc1ccccc1-2
Temperature: 95 °C

Procedure:
(S)-7-Chloro-4-oxiranylmethoxy-quinoline (20 mg, 0.084 mmol) and Z-(1S,6S)-7-(9H-fluoren-2-yl)-7,9-diaza-bicyclo[4.2.2]dec-3-ene (22 mg, 0.073 mmol) were placed in a μW tube with ethanol (3 ml), DIPEA (15 μL, 0.086 mmol) and heated to 95° C. for 900 sec. The solvent was evaporated from the reaction mixture and the residue was purified via reverse phase chromatography (gradient 20% to 90% CH3CN/water for 12 min) to yield the title compound as a residue.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH:13]=[N:12][CH:11]=1>C1COCC1>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[CH:15]=[C:10]([CH2:9][OH:8])[CH:11]=[N:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cncc(-c2ccc(Cl)c(Cl)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cncc(-c2ccc(Cl)c(Cl)c2)c1
Reaction time: 2 h
Yield: 27 %

Procedure:
To a suspension of LiAlH4 (161 mg, 4.2 mmol) in THF (20 ml) at 0° C. was added dropwise 5-(3,4-dichloro-phenyl)-nicotinic acid methyl ester (2.0 g, 7.0 mmol) in THF (20 ml) and stirred for a further 2 h at this temperature. The reaction was quenched by careful addition of THF/H2O (9:1) and then dried directly with Na2SO4, filtered and the solvent was evaporated. The residue was chromatographed [silica, elution with CH2Cl2/(2M NH3 MeOH)=97:3] to afford the title compound (480 mg, 27%) as an orange solid. MS: m/e=254.0 (M+H+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][S:10]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[N:29]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:28]=[C:27]([C:36]([F:39])([F:38])[F:37])[CH:26]=3)=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11]>>[Br:1][C:26]1[C:27]([C:36]([F:39])([F:38])[F:37])=[N:28][N:29]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:25]=1[C:22]1[CH:23]=[CH:24][C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([S:10]([CH3:9])(=[O:11])=[O:12])[CH:14]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)Cn1nc(C(F)(F)F)c(Br)c1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1

Procedure:
Following bromination with N-bromosuccinimide, the title compound 37 is prepared starting from ethyl 2-(5-(3′-(methylsulfonyl)biphenyl-4-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate 36.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:35]=[C:36](\[C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=2)/[C:37]([OH:39])=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[CH:28]1(/[CH:35]=[C:36](\[C:40]2[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=2)/[C:37]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:39])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A solution of triphenylphosphine (341 mg, 1.3 mmol) in methylene chloride (7 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (231 mg, 1.3 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-3-cycloheptyl-2-(4-(methanesulfonyl)-3-(trifluoromethyl)-phenyl)-acrylic acid (255 mg, 0.65 mmol). After 15 min at 0° C., the reaction mixture became clear. The clear solution was then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (193 mg, 1.95 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (50 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30) mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 to 2/1 hexanes/ethyl acetate) afforded the pure (E)-3-cycloheptyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-acrylamide (133 mg, 43%) as an amorphous solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][C@@H:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[C:13]=3[CH:12]=[CH:11]2)[CH2:7][C@H:6]1[CH2:29][OH:30])(=[O:3])[CH3:2].Cl[S:32]([NH2:35])(=[O:34])=[O:33]>C(C#N)(C)=O>[C:1]([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][C@@H:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[C:13]=3[CH:12]=[CH:11]2)[CH2:7][C@H:6]1[CH2:29][O:30][S:32]([NH2:35])(=[O:34])=[O:33])(=[O:3])[CH3:2]
Reactant: NS(=O)(=O)Cl
Reactant: CC(=O)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CO
Agent: CC(=O)C#N
Product: CC(=O)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1COS(N)(=O)=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
(1S,2S,4R)-4-{4-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]-pyrimidin-7-yl}-2-(hydroxymethyl)cyclopentyl acetate (2.30 g, 5.38 mol) was dissolved in AcCN (108 mL) and TEA (3.75 mL, 26.9 mmol) was added. The solution was cooled to 0° C. and a 2.00 M solution of chlorosulfonamide in AcCN (5.38 mL, 10.8 mmol, as prepared above) was added. The mixture was stirred at rt for 45 min. TLC indicated 50% conversion. Additional 2.00 M chlorosulfonamide in AcCN solution (5.38 mL, 10.8 mmol) was added and the mixture was stirred at rt for 15 min. At this time, TLC indicated complete conversion. The mixture was quenched with MeOH (3.00 mL), and the solvent was removed in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in EtOAc to afford the title compound (2.45 g, 94%). LC/MS: Rt=1.68 min, ES+ 486 (AA standard).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[C:17](=O)[O:16][CH2:15][CH:14]2[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:19]([NH2:21])[CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:17][NH:21][CH2:19][CH3:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]2[CH2:15][OH:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN
Reactant: O=C1OCC2CCCCC12c1ccc(Cl)c(Cl)c1
Product: CCNCC1(c2ccc(Cl)c(Cl)c2)CCCCC1CO

Procedure:
The title compound was prepared from racemic 7a-(3,4-dichlorophenyl)hexahydroisobenzofuran-1(3H)-one and ethylamine according to General Procedures AA, followed by General Procedure E. The racemic aminol was separated using a chiral column (Chiracel OD column; 95:5:0.1 hexanes:IPA:DEA, λ=254 nm, 1 mL/min) to give the fast moving enantiomer 169 E1 (Rt=7.5 min) and the slow moving enantiomer 169 E2 (Rt=9.7 min). LCMS Rt=7.88 min, m/z=316 (M+1). 1H NMR (CDCl3, δ): 7.4 (m, 2H), 7.17 (dd, J=2.4, 8.5 Hz, 1H), 3.7 (m, 2H), 3.10 (d, J=12.3 Hz, 1H), 2.71 (d, J=12.3 Hz, 1H), 2.6 (m, 2H), 2.3 (m, 1H), 1.9-1.3 (m, 8H), 1.04 (t, J=7.2 Hz, 3H). 13C NMR (CDCl3, δ, mult): 146.5(0), 133.1(0), 130.8(1), 130.0(0), 128.5(1), 125.7(1), 63.2(2), 53.6(br, 2), 45.4(0), 43.9(2), 41.9(1), 39.8(br, 2), 26.1(2), 24.8(2), 22.0(2), 14.5(3).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH2:34])[CH:32]=[CH2:33]>>[CH2:31]([NH:34][CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH:32]=[CH2:33]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: C=CCN
Product: C=CCNCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and allylamine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.96 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.81 (s, 1H), 5.95 (m, 1H), 5.55 (m, 2H), 3.25-3.8 (m, 14H); MS (DCI) m/z 392 (M+H)+;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([O:25][CH3:26])=[O:24].[Na+].[CH3:28][S:29]([O-:31])=[O:30]>CS(C)=O.[Cu]I>[CH3:22][C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:8][C:9]2[C:4]([C:5]=1[C:23]([O:25][CH3:26])=[O:24])=[CH:3][C:2]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:11][CH:10]=2
Reactant: COC(=O)c1c(C)c(-c2ccc(C(F)(F)F)cc2)nc2ccc(Br)cc12
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1c(C)c(-c2ccc(C(F)(F)F)cc2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Methyl 6-bromo-3-methyl-2-[4-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.1 g, 12.02 mmol) was dissolved in dimethyl sulfoxide (60 mL) and copper(I) iodide (4.58 g, 24.04 mmol) and methanesulfinic acid sodium salt (2.455 g, 24.04 mmol) were added. The reaction vessel was evacuated and flushed with N2 three times, and heated at 120° C. overnight. The reaction mixture was diluted with CH2Cl2 and H2O, stirred for 30 min, filtered through the Celite, and washed with CH2Cl2. The filtrate was extracted three times with CH2Cl2, and the combined organic extracts were washed twice with brine, and dried over Na2SO4. The residue was purified via silica gel flash chromatography (0%-20% EtOAc/CH2Cl2) to afford the desired product as an off white solid (3.3 g, 65%). MS (m/z) 424.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Product: CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1
Yield: 93.9 %

Procedure:
Beginning with 1.00 gm (7.4 mMol) 5-fluoro-1H-indole and 1.82 mL (14.8 mmol) 1-methyl-4-piperidone, 1.60 gm (94%) of the title compound were recovered as a crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]([O:18]C)=O)=[CH:10][C:11]([CH2:14][OH:15])=[CH:12][CH:13]=1.[C:20]([Li])([CH3:23])([CH3:22])[CH3:21].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=1[C:16](=[O:18])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1cc(CO)ccc1-c1ccccc1F
Reactant: [Li]C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1cc(CO)ccc1-c1ccccc1F
Reaction time: 5 h
Yield: 78 %

Procedure:
To a stirred solution of 66.32C (0.850 g, 3 mmol) in THF (33 mL) at −78° C. was added tert-butyllithium (6 mL, 10 mmol, 1.7M). The reaction was stirred for 5 hours and then a saturated solution of ammonium chloride was added and the mixture was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-40% EtOAc in hexanes) to yield 66.32D as a colorless oil (0.670 g, 72% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][C:3]=1[OH:10].[Yb+3].F[C:13](F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.C(OC)(OC)OC>CCO.CC(=O)OCC.CCCCCC>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]2[N:1]=[CH:13][O:10][C:3]=2[CH:4]=1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: Cc1cc(N)c(O)cc1Br
Agent: [Yb+3]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc2ncoc2cc1Br
Temperature: 90 °C
Yield: 1344.1 %

Procedure:
A mixture of 2-amino-5-bromo-4-methylphenol (42) (290 mg), trifluoromethanesulfonic acid Ytterbium (III) salt (20 mg) and trimethyl orthoformate (185 μl, 1.5 eq.) in 2 ml EtOH was heated at 90° C. for 2 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine, dried over Na2SO4, concentrated to dryness. The resulting brown solid was dissolved in DCM and subjected to silica gel column purification using 0-60% B (A: hexane; B: 50% EA in hexane) to furnish 91.9 mg 6-bromo-5-methylbenzoxazole (43) as yellow solid (yield: 38%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=2)[C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[CH3:5].[CH3:33][C:34]1[C:39]([C:40](O)=[O:41])=[C:38]([CH3:43])[N:37]=[CH:36][N:35]=1>>[C:31]([C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][N:12]([C:13]1[CH:14]=[CH:15][C:16]([S:19](=[O:21])(=[O:20])[NH:22][CH3:23])=[CH:17][CH:18]=1)[CH:9]1[CH2:10][CH2:11][N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:40]([C:39]2[C:34]([CH3:33])=[N:35][CH:36]=[N:37][C:38]=2[CH3:43])=[O:41])[CH2:7][CH2:8]1)#[N:32]
Reactant: CNS(=O)(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCN)CC2)cc1
Reactant: Cc1ncnc(C)c1C(=O)O
Product: CNS(=O)(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Yield: 87.2 %

Procedure:
Using general procedure E, 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-N-methyl-benzenesulfonamide (see EXAMPLE 151) (63 mg, 0.14 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (23 mg, 0.15 mmol) gave COMPOUND 152 as a white solid (72 mg, 89%). 1H NMR (CDCl3) δ 1.00-1.17 (m, 2H), 1.02 (d, 3H, J=5.4 Hz), 1.55 (m, 1H), 1.74-1.78 (m, 3H), 2.21 (t, 1H, J=10.5 Hz), 2.50 (s, 6H), 2.58-2.62 (m, 4H), 2.75-2.85 (m, 3H), 3.34 (m, 1H), 3.77 (m, 2H), 4.05 (s, 2H), 4.44 (d, 1H, J=4.2 Hz), 6.56 (d, 2H, J=8.1 Hz), 7.47-7.72 (m, 5H), 8.35 (br s, 1H), 8.90 (s, 1H). 13C NMR (CDCl3) δ 13.52, 21.97, 28.92, 29.32, 30.31, 31.00, 39.75, 43.60, 48.08, 51.64, 55.73, 59.82, 112.00, 112.78, 118.79, 125.81, 129.25, 129.48, 129.64, 130.70, 130.88, 130.95, 140.36, 151.29, 157.53, 163.15, 166.30. ES-MS m/z 590 (M+H). Anal. Calcd. for C31H39N7O3S.0.6CH2Cl2: C, 59.24; H, 6.32; N, 15.30; S, 5.00. Found. C, 59.35; H, 6.37; N, 15.18; S, 4.87.
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)/[C:10](=[N:23]\[NH:24][C:25]([NH2:27])=[O:26])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Reactant: NNC(N)=O
Agent: Cl
Product: Cc1ccc2c(c1)/C(=N\NC(N)=O)C(=O)N2CCN(C(C)C)C(C)C
Yield: 53.9 %

Procedure:
By using 1-(2-diisopropylaminoethyl)-5-methylisatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-1-(2-diisopropylaminoethyl)-5-methylisatin 3-semicarbazone having a melting point of 159°-161° C. (yield: 53.9%, recrystallizing solvent: chloroform-hexane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].COC1C=CC([Mg]Br)=CC=1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32](=O)[C:31]=3[C:40]([O:42]CC)=[O:41])=[CH:24][C:23]=2[O:22]1>CCOCC.C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:30]([C:25]3[CH:26]=[CH:27][C:28]4[O:29][CH2:21][O:22][C:23]=4[CH:24]=3)[CH:31]2[C:40]([OH:42])=[O:41])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)cc1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A solution of 4-bromoanisole (0.89 g, 5.0 mmol) in 9:1 Et2O/THF (10 ml) was added to magnesium turnings (0.105 g, 5.0 mmol), and the resulting mixture was allowed to stir for 30 min. The resultant 4-methoxyphenyl magnesium bromide was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.77 g, 2.4 mmol) in 10:1 Et2O/THF (55 ml) at 0° C. The resulting mtixture was stirred at 0° C. for 1 h and was then partitioned between EtOAc and 1M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow glassy solid (0.80 g, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]([OH:34])[CH2:14][CH2:15][C:16]2[C:17]([O:26]CC3C=CC=CC=3)=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][CH:20]=[CH:19]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1>[Pd].C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@@H:13]([OH:34])[CH2:14][CH2:15][C:16]2[C:17]([OH:26])=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][CH:20]=[CH:19]3)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)CCc2ccc3ncccc3c2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CCc2ccc3ncccc3c2O)cc1

Procedure:
Treatment of (2S)-4-[5-(benzyloxy)quinolin-6-yl]-2-hydroxybutyl 4-methylbenzene sulfonate with palladium on carbon (10 wt. %) in ethanol following the procedure described in Example 9 provides (2S)-2-hydroxy-4-(5-hydroxy-quinolin-6-yl)butyl 4-methylbenzenesulfonate.
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([NH2:16])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[C:22]([O:21][C:17](=[O:20])[CH:18]=[CH:19][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([NH2:16])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Nc1ccc2nc3ccccc3c(N)c2c1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C=Cc1ccc2nc3ccccc3c(N)c2c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
To a 10 mL rbf equipped with a nitrogen bubbler were charged 3-bromo-9-aminoacridine 5 (120 mg, 0.44 mmol), tert-butyl acrylate (75 μL, 0.48 mmol) and anhydrous DMF (1 mL). Tri-(O-tolyl)phosphine (25 mg, 0.08 mmol) and palladium (II) acetate (6 mg, 0.03 mmol) were added. The reaction mixture was stirred at room temperature and degassed by applying nitrogen flow and vacuum successively (3 times). The mixture was finally placed under nitrogen atmosphere and triethylamine (185 μL, 1.32 mmol) was added. The red-orange solution was heated to 110° C. for 3 hours and then cooled to room temperature. The brown-orange solution was filtered through Celite and washed with ethyl acetate. This organic layer was then washed with water and concentrated in vacuo to give the crude product as an orange oil. Purification by Flashmaster II using a gradient elution (DCM→DCM:MeOH 60:40) afforded pure 3-(9-amino-acridin-2-yl)-acrylic acid tert-butyl ester 6 as an orange solid (75 mg, 53%). 1H NMR and LCMS analyses conformed to structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=2[S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].OC1C2C=C([C:30]([F:33])([F:32])[F:31])C=CC=2SC=1C(OC)=O>>[CH3:1][O:2][C:3]1[C:4]2[CH:15]=[C:14]([C:30]([F:33])([F:32])[F:31])[CH:13]=[CH:12][C:5]=2[S:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1sc2ccccc2c1OC
Reactant: COC(=O)c1sc2ccc(C(F)(F)F)cc2c1O
Product: COC(=O)c1sc2ccc(C(F)(F)F)cc2c1OC

Procedure:
When the starting benzthiophene of the above example was replaced by methyl 3-hydroxy-5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, there was obtained methyl 3-methoxy-5-(trifluoromethyl)-benzo[b]thiophene-2-carboxylate as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:5]=1[CH:6]=[O:7])[CH3:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:8]=1)[CH:6]=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOc1ccc(O)cc1C=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(OCc2ccccc2)cc1C=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A mixture of 2-ethoxy-5-hydroxybenzaldehyde (3.72 g), benzyl bromide (5.75 g), anhydrous potassium carbonate (3.10 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (5.06 g, 88%) of 5-benzyloxy-2-ethoxybenzaldehyde from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Redrystallization from ethyl, acetate-hexane gave colorless prism crystals. melting point: 81-82° C.