Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][C:17]([OH:23])=[CH:16][CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:37]([CH:39]1[O:41][CH2:40]1)Cl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][C:17]([O:23][CH2:37][CH:39]1[O:41][CH2:40]1)=[CH:16][CH:15]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1CO1
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2ccc(OCC3CO3)cc12

Procedure:
Reaction of 3′,4′-dibenzyloxy-6-hydroxy-flavone, 24 (4.5 g, 10 mmol), 50% sodium hydride (1.4 g, 60 mmol) and epichlorohydrin (4.7 mL, 60 mmol) in dry dimethyl formamide (120 mL) using identical procedure as described for 28 furnished 30. Yield 4.2 g (81%); mp 147-149° C.; MS (FAB) 507 (M++1); IR (KBr) 1610; 1H NMR (200 MHz, CDCl3) δ 7.57-7.29 (m, 15H), 7.02 (d, J=8.6 Hz, 1H), 6.66 (s, 1H), 5.25 (s, 4H), 4.39 (dd, J=11.0 Hz, 2.6 Hz, 11H), 3.98 (dd, J=11.0 Hz, 6.0 Hz, 1H), 3.40-3.39 (m, 1H), 2.93 (t, J=4.5 Hz, 4.5 Hz 1H), 2.78 (dd, J=4.8 Hz, 2.6 Hz, 1H).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[S:10](Cl)(=[O:12])=[O:11].Cl.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]#[CH:23])[C:17]1=[O:24]>>[O:24]=[C:17]1[C@@H:16]([NH:15][S:10]([C:2]2[S:1][C:9]3[C:4](=[N:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)(=[O:12])=[O:11])[CH2:20][CH2:19][N:18]1[CH2:21][C:22]#[CH:23]
Reactant: C#CCN1CC[C@H](N)C1=O
Reactant: O=S(=O)(Cl)c1cc2ncccc2s1
Agent: Cl
Product: C#CCN1CC[C@H](NS(=O)(=O)c2cc3ncccc3s2)C1=O

Procedure:
The title compound is prepared as described in EXAMPLE 1, Part K using thieno[3,2-b]pyridine-2-sulfonyl chloride and 3-(S)-amino-1-prop-2-ynyl-pyrrolidin-2-one hydrochloride as starting material. The crude product is isolated as a white solid and used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:4].[CH3:18][O:19]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:16])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH:18]=[O:19])[CH:9]=1)=[O:4]
Reactant: COc1ccc(CCNC(=O)C(F)(F)F)cc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C(F)(F)F)cc1C=O
Temperature: 25 °C
Yield: 87.2 %

Procedure:
The product from step (a) (24.7 g, 0.1 mole) was dissolved in dry dichloromethane (500 ml) and the solution cooled to -15°. A solution of titanium tetrachloride (57.0 g, 21.6 ml, 0.3 mole) in dry dichloromethane (200 ml) was added dropwise with stirring and cooling. To the yellow-orange solution was added -dichloromethyl methyl ether (27.9 g, 22.0 ml, 0.24 mole) in dry dichloromethane (200 ml). The solution was stirred at -15° for 0.5 hr and warmed to room temperature over a period of 2 hr. The reaction mixture was poured onto ice/2N hydrochloric acid (21/500 ml) and stirred vigorously. The dichloromethane layer was separated and the aqueous layer extracted with dichloromethane (2×200 ml). The combined organic extracts were washed with water, dried (Na2SO4) and evaporated. The crude product was recrystallised from 50% aqueous methanol to give an off-white solid (24.0 g) mp 105°-6°.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[C:11]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:12]=3)[C:7](=[O:34])[C:6]([C:35]([O:37]CC3C=CC(OC)=CC=3)=[O:36])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[K+]>CO.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([O:24][CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)=[C:11]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[CH:12]=3)[C:7](=[O:34])[C:6]([C:35]([OH:37])=[O:36])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(COC(=O)c2cn(C3CC3)c3cc(OCc4ccc(OC)cc4)c(OCc4ccc(OC)cc4)cc3c2=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(COc2cc3c(=O)c(C(=O)O)cn(C4CC4)c3cc2OCc2ccc(OC)cc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a suspension of 4-methoxybenzyl 1-cyclopropyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylate (14 g, 22.52 mmol) in a mixture of Methanol (100 mL) and Water (50.0 mL) was added KOH (2.53 g, 45.0 mmol) portionwise. The resulting mixture was stirred at 90° C. for 2 h. LCMS indicated completion of the reaction. The reaction mixture was cooled down to r.t. and concentrated, and was then diluted with water and adjusted pH to 1 using 2 N HCl (aq.). The precipitates were collected by filtration and dried to afford 1-cyclopropyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (11 g, 21.93 mmol, 97% yield) as pale yellow solid. LCMS: [M+H]+: 502.3.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17]C)=[O:16])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([OH:17])=[O:16])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)(C)C(=O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2.10 g; 8.23 mmol), 1 N LiOH (15 ml), and methanol (50 ml) was stirred at 0° C. for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 ml of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87%) of snow-white solid which did not require further purification, 1H NMR (CDCl3): δ 0.87 (t, 3H); 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m, 1H); 3.53 (dd, 2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[F:24][C:25]1[C:26]([O:35][CH3:36])=[CH:27][C:28]([CH3:34])=[C:29](B(O)O)[CH:30]=1>>[F:24][C:25]1[C:26]([O:35][CH3:36])=[CH:27][C:28]([CH3:34])=[C:29]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)[CH:30]=1
Reactant: COc1cc(C)c(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: COc1cc(C)c(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)cc1F

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl (6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH) carboxylate (189 mg, 0.5 mmol) and corresponding 5-fluoro-4-methoxy-2-methylphenyl boronic acid (184 mg, 1.0 mmol) to afford after chromatographic purification the title compound (130 mg, 60%). 1H NMR (CDCl3, 300 MHz) δ6.94 (d, 1H, J=12.5 Hz), 6.84 (s, 1H), 6.79-6.82 (m, 2H), 4.02-4.22 (m, 1H), 3.90 (s, 3H), 3.82-3.92 (m, 1H), 3.64-3.74 (m, 1H), 3.24-3.54 (m, 4H), 2.86-3.22 (m, 3H), 2.22 (s, 3H), 1.82-1.94 (m, 2H), 1.48 (s, 9H) ppm. MS-ApCI: 439 [M+H+].
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][CH:17]=[O:18])[C:3]([NH:5][C:6]1[S:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][N:10]=1)=[O:4].Cl>O>[C:11]([C:8]1[S:7][C:6]([N:5]2[CH:17]([OH:18])[CH2:16][CH2:15][N:2]([CH3:1])[C:3]2=[O:4])=[N:10][N:9]=1)([CH3:13])([CH3:14])[CH3:12]
Reactant: CN(CCC=O)C(=O)Nc1nnc(C(C)(C)C)s1
Agent: Cl
Solvent: O
Product: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O

Procedure:
The dimethyl acetal of 3-[1-methyl-3-(5-t-butyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (16 grams), concentrated hydrochloric acid (10 ml) and water (500 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is filtered while hot and the filtrate is then cooled, resulting in the formation of a precipitate. The precipitate is recovered by filtration, dried and is recrystallized to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[C:13](O)(=[O:17])[C:14]([CH3:16])=[CH2:15]>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[C:1]([C:5]1[CH:10]=[C:9]2[C:8]([CH2:15][CH:14]([CH3:16])[C:13]2=[O:17])=[CH:7][C:6]=1[O:11][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C(C)C(=O)O
Reactant: COc1ccccc1C(C)(C)C
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1cc2c(cc1C(C)(C)C)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 1-tert-butyl-2-methoxybenzene (32.8 g, 0.2 mol) and methacrylic acid (21.5 g, 0.25 mol) was added at 60° C. to a well stirred Eaton reagent (55 g P2O5 and 280 ml of methanesulfonic acid). After 1 h of stirring the reaction mixture was cooled, poured into ice water, and extracted with benzene (3×200 ml). The combined organic layer was washed with water, aq. NaHCO3, dried over MgSO4, evaporated and distilled at 145-150° C./0.7 Torr. Yield 20 g (43%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:34]=[CH:33][CH:32]=[C:7]2[C:8]([N:10]([CH:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH:19]=3)[CH2:14][C:15](O)=[O:16])[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:48][OH:49]>C1COCC1>[C:1]([NH:4][C:5]1[CH:34]=[CH:33][CH:32]=[C:7]2[C:8]([N:10]([CH:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[CH:19]=3)[CH2:14][C:15]([NH:48][OH:49])=[O:16])[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2]
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1OC1CCCC1
Yield: 69.3 %

Procedure:
3-(3-Acetoamidophthalimido)-3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxypropionamide was prepared by the procedure of Example 1 from 3-(3-acetoamidophthalimido)-3-(3-cyclopentyloxy-4-methoxyphenyl)propanoic acid (3.0 g, 6.5 mmol), carbonyldiimidazole (1.16 g, 7.12 mmol) and hydroxylamine hydrochloride (0.56 g, 8.07 mmol) in THF (20 mL) to afford 3-(3-acetoamidophthalimido)-3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxypropionamide as a white solid (2.17 g, 70%): mp, 156.5–158.0° C.; 1H NMR (DMSO-d6) δ 1.55–1.87 (m, 8H, C5H8), 2.19 (s, 3H, CH3), 3.11 (d, J=7.8 Hz, 2H, CH2), 3.70 (s, 3H, OCH3), 4.50–4.84 (m, 1H, OCH), 5.64 (t, J=7.8 Hz, 1H, CH), 6.80–6.90 (m, 3H, Ar), 7.56 (d, J=7.3 Hz, 1H, Ar), 7.77 (t, J=7.9 Hz, 1H, Ar), 8.44 (d, J=8.4 Hz, 1H, Ar), 8.81 (s, 1H, NH), 9.72 (s, 1H, OH), 10.95 (s, 1H, CONH); 13C NMR (DMSO-d6) δ 23.5, 24.2, 32.2, 34.1, 50.0, 55.6, 79.6, 112.1, 114.2, 117.9, 119.7, 125.9, 130.9, 131.4, 135.8, 136.4, 146.7,;149.2, 165.9, 167.1, 168.2, 169.2; Anal. Calcd. for C25H27N3O7: C, 61.10; H, 5.76; N, 8.55. Found: C, 61.43; H, 5.62; N, 8.50.
Reaction SMILES: O.NN.[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Ni].CO>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccccc1OCc1ccccc1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: Nc1ccccc1OCc1ccccc1

Procedure:
Hydrazine hydrate (5 ml) was added dropwise over 20 minutes to a stirred suspension of Raney nickel in a solution of 2-(benzyloxy)nitrobenzene in methanol (200 ml) causing gentle reflux. The stirred mixture was heated under reflux for a further 30 minutes, cooled, filtered and evaporated. The residue was distilled under vacuum to give a pale oil, b.p. 146°-150°/0.5 mm.
Reaction SMILES: [C:1]([O:9][CH3:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:11][C:12](C)([CH3:15])[CH2:13]O.O>C1(C)C=CC=CC=1>[CH3:13][C:12]1([CH3:15])[CH2:10][O:9][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:11]1
Reactant: COC(=O)c1cccnc1
Reactant: CC(C)(N)CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)COC(c2cccnc2)=N1
Reaction time: 8 h

Procedure:
A solution of 69 g (0.500 mol) of methyl nicotinoate and 45 g (0.500 mol) of 2-amino-2,2,dimethyl-ethanol in 600 ml of toluene was refluxed with a water separator overnight. The solvent was removed in vacuo, 300 ml of water added, and the aqueous solution extracted with 3×300 ml of dichloromethane. Drying of the organic phase over magnesium sulphate and evaporation in vacuo gave a red oil which was filtered through silica gel (eluent: methanol/ether=1/19). Removal of solvents in vacuo gave a yellow oil, 86. Yield: 30.0 g (0.170 mol, 34%).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][CH2:6][C:7]([NH2:9])=[S:8])=[O:4].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=O>C(O)C>[CH3:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][CH2:6][C:7]1[S:8][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[N:9]=1)=[O:4]
Reactant: CC(C)(C)C(=O)OCC(N)=S
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Solvent: CCO
Product: CC(C)(C)C(=O)OCc1nc(-c2cccc(C(F)(F)F)c2)cs1
Yield: 103.7 %

Procedure:
A mixture of 2-amino-2-thioxoethyl 2,2-dimethylpropanoate (7.38 g), 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (7.50 g) and ethanol (150 ml) was heated under reflux for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed successively with diluted aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give crude {4-[3-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl 2,2-dimethylpropanoate (about 10 g) as a colorless solid. The solid was dissolved in ethanol (100 mL) and tetrahydrofuran (100 mL), 2N aqueous sodium hydroxide solution (80 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed successively with diluted aqueous citric acid solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give the title compound (4.90 g) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[N:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:44]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:45])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: O=C(Cl)N1CCOCC1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1ccc(CC2c3cc(OC(=O)N4CCOCC4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 4-morpholinecarbonyl chloride
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16](O)=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2].S(Cl)(Cl)=O.[CH3:34][NH2:35]>C(Cl)(Cl)(Cl)Cl>[CH:1]([C:5]1[CH:6]=[C:7](/[CH:19]=[CH:20]/[C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]2[C:14]=1[O:13][C:12](=[O:15])[C:11]([C:16]([NH:35][CH3:34])=[O:17])=[CH:10]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc2cc(C(=O)O)c(=O)oc12
Reactant: CN
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc2cc(C(=O)NC)c(=O)oc12
Reaction time: 0.67 h

Procedure:
To a suspension of (E)-8-sec-butyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxylic acid of the formula (V) (0.5 g, 1.28 mmol) in CCl4 (15 mL), added thionyl chloride (1.0 mL), was refluxed for 2.5 h. The resulting solution was evaporated to dryness under reduced pressure, and the residue was dispersed in CCl4 (10 mL). The solvent was eliminated under reduced pressure. Dispersion in CCl4 and solvent elimination was repeated twice. The residue was dissolved in CCl4(10 mL) and added with stirring to a solution of the methyl amine (0.04 g, 1.28 mmol). After 40 min at room temperature, the solvent was removed by evaporation under reduced pressure and extracted 3-fold with CHCl3 (25 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides (E)-8-sec-butyl-N-methyl-2-oxo-6-(3-oxo-3-p-tolylprop-1-enyl)-2H-chromene-3-carboxamide (General Formula VI). (0.33 g, 65% yield). White solid, m. p. 215-216° C.; 1H NMR (CDCl3 300 MHz): δ 8.93 (s, 1H), 8.72, (brd, J=4.6 Hz, 1H) 7.96 (d, J=8.1 Hz, 2H), 7.83-7.77 (m, 3H), 7.55 (d, J=15.7 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 3.49-3.37 (m, 1H), 3.04 (d, J=4.9 Hz, 3H), 2.45 (s, 3H), 1.80-1.71 (m, 2H), 1.35 (d, J=6.9 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H); 13C NMR (CDCl3, 75 MHz): δ 189.5, 1610, 161.2, 153.1, 148.5, 144.1, 142.2, 136.5, 135.4, 132.2, 131.4, 129.5, 128.8, 127.1, 123.2, 119.0, 118.8, 33.6, 29.8, 26.7, 21.8, 20.6, 12.1; ESI-MS (m/z): 404 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].[Cl:11][C:12]1[C:13]([F:25])=[C:14]([S:21](Cl)(=[O:23])=[O:22])[C:15]([F:20])=[C:16]([Cl:19])[C:17]=1[F:18]>>[Cl:11][C:12]1[C:13]([F:25])=[C:14]([S:21]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:2]([OH:1])[CH:3]=2)(=[O:23])=[O:22])[C:15]([F:20])=[C:16]([Cl:19])[C:17]=1[F:18]
Reactant: O=S(=O)(Cl)c1c(F)c(Cl)c(F)c(Cl)c1F
Reactant: COc1ccc(N)cc1O
Product: COc1ccc(NS(=O)(=O)c2c(F)c(Cl)c(F)c(Cl)c2F)cc1O

Procedure:
The title compound was prepared in a manner similar to that described in Example 1 by replacing p-anisidine with 3-hydroxy-4-methoxyaniline and replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 3,5-dichloro-2,4,6-trifluorophenylsulfonyl chloride (Example B). 1H-NMR (CDCl3): δ 6.88 (1H, br s), 6.7-6.8 (3H, m), 5.66 (1H, s), 3.85 (3H, s), MS(EI): 402 (15, M+), 401 (20), 138 (100). Anal. Calcd. for C13H8Cl2F3NO4S: C, 38.83; H, 2.00; N, 3.48; S, 7.97. Found: C, 38.66; H, 1.97; N, 3.39; S, 7.86.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:62][CH2:63][C:64]1[CH:65]=[C:66]([F:76])[C:67]2[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=2[CH:75]=1>CN(C=O)C>[F:76][C:66]1[C:67]2[C:71]([CH3:72])([CH3:73])[O:70][B:69]([OH:74])[C:68]=2[CH:75]=[C:64]([CH2:63][NH:62][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([C:11]3[CH2:15][C:14]([C:20]4[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[C:22]([Cl:28])[CH:21]=4)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=3)=[CH:10][C:2]=2[CH3:1])[CH:65]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: CC1(C)OB(O)c2cc(CN)cc(F)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1cc(F)c2c(c1)B(O)OC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a solution of crude 2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzoic acid (0.45 g, 1 mmol) in DMF (5 mL) at rt under N2 was added HBTU (0.76 g, 2 mmol), followed by DIPEA (0.39 g, 3 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was purified by chromatography over silica gel eluted with PE-DCM (1:1) to give an activated intermediate from acid, which was used directly to mix with 6-(aminomethyl)-4-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (0.3 g, 1.44 mmol) in 5 mL of DMF. The reaction mixture was stirred at rt overnight. The reaction was monitored by LC-MS. The reaction solution was purified by pre-HPLC to give the final title compound (260 mg, 40.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H), 8.97 (t, 1H), 7.86 (s, 2H), 7.63-7.62 (m, 2H), 7.53-7.51 (m, 2H), 7.24 (d, 1H), 4.50 (d, J=5.6 Hz, 2H), 4.43-4.31 (m, 2H) 2.42 (s, 3H) 1.53 (s, 6H) ppm; HPLC purity: 97.9% at 220 nm and 99.6 at 254 nm; MS (ESI+): m/z=643 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15]O)[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11].O=S(Cl)[Cl:19].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][Cl:19])[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11]
Reactant: O=S(Cl)Cl
Reactant: C[C@H](Oc1ccc(CO)cc1Cl)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: C[C@H](Oc1ccc(CCl)cc1Cl)C(F)(F)F

Procedure:
A solution of {3-chloro-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}methanol (284 mg) and SOCl2 (179 μL) in DCM (7 mL) was stirred at room temperature for 2 hours. The reaction liquid was poured into water, followed by extraction with chloroform. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure to obtain 2-chloro-4-(chloromethyl)-1-[(1S)-2,2,2-trifluoro-1-methylethoxy]benzene (285 mg) as a colorless liquid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[N:19]1[C:23]([NH2:24])=[N:22][C:21]([NH2:25])=[N:20]1>N1C=CC=CC=1>[NH2:24][C:23]1[N:19]([C:11]2[S:10][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=2)[N:20]=[C:21]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc(N)n(-c2nc3ccccc3s2)n1
Solvent: c1ccncc1
Product: Nc1nc(NC(=O)c2ccccc2)nn1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.7 %

Procedure:
Benzoyl chloride (0.34 mmol) was added dropwise to a stirred solution of 1-benzothiazol-2-yl-1H-[1,2,4]triazole-3,5-diamine (0.34 mmol) in pyridine (3 ml). The reaction mixture was stirred at room temperature for 2 hours then it was concentrated in vacuo. The residue was partitionned between ethyl acetate and 10% aqueous citric acid. At this stage, a white solid was filtered off. The solid was dried in vacuo to afford the pure title compound (10 mg; 15% yield). 1H (400 MHz, DMSO-d6) δ 7.40-7.45 (1H, t), 7.50-7.70 (3H, m), 7.85-8.00 (6H, m), 8.1 (1H, d), 10.95 (1H, s). MS (ES+) m/e=337