Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH:3]([NH2:14])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([S:24](Cl)(=[O:26])=[O:25])[CH:23]=1>N1C=CC=CC=1.C(O)(=O)C.C(OCC)(=O)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([O:28][CH3:29])=[C:22]([S:24]([NH:14][CH:3]([CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[C:2]([F:1])([F:15])[F:16])(=[O:25])=[O:26])[CH:23]=1
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(Br)cc1S(=O)(=O)NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Temperature: 65 °C
Reaction time: 16 h
Yield: 31.4 %

Procedure:
A mixture of 100 mg (0.44 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine and 143 mg (0.50 mmol) of 5-bromo-2-methoxybenzenesulfonyl chloride in 4 mL of pyridine was warmed at 65° C. After 16 hours, the mixture was cooled and concentrated to afford a thick oily residue. The residue was diluted with 10% acetic acid and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, decanted, and concentrated in vacuo. The crude material was purified by preparative TLC using ethyl acetate-hexanes (15:85). Material from the plate was isolated by suspending the silica gel in ethyl acetate followed by filtration. The filtrate was concentrated in vacuo to afford 66 mg (32%) of the title compound as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([C@@H:9]([NH:20][C:21](=[O:36])[C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:29])=[C:24]([CH3:35])[CH:23]=3)[CH2:10][CH2:11][NH:12][S:13]([CH2:16][CH2:17][CH2:18]Cl)(=[O:15])=[O:14])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([C@@H:9]([NH:20][C:21](=[O:36])[C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:29])=[C:24]([CH3:35])[CH:23]=3)[CH2:10][CH2:11][N:12]3[CH2:18][CH2:17][CH2:16][S:13]3(=[O:14])=[O:15])=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCNS(=O)(=O)CCCCl)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)N[C@@H](CCN2CCCS2(=O)=O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
130 mg (0.22 mmol) of N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(3-chloropropylsulfonylamino)propyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is dissolved in 5 mL of dimethylformamide and, after the addition of 21 mg (0.45 mmol) of sodium hydride (50% in oil), stirred for 2 hours at ambient temperature. Then it is combined with water and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulfate and concentrated by evaporation. Yield: 90 mg (70%); Rf value: 0.40 (silica gel: dichloromethane/ethanol=9:1); C26H30ClN5O4S (544.077); mass spectrum: (M+H)+=545/547 (chlorine isotope).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[CH2:6]([NH:13][CH:14]([CH3:18])[CH2:15][C:16]#[N:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([N:13]([CH:14]([CH3:18])[CH2:15][C:16]#[N:17])[CH2:1][CH:2]([OH:3])[CH2:4][OH:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCC1CO1
Reactant: CC(CC#N)NCc1ccccc1
Solvent: CCO
Product: CC(CC#N)N(Cc1ccccc1)CC(O)CO
Yield: 26.6 %

Procedure:
A solution of glycidol (70 ml, 1.05 mol) and 3-(benzylamino)butyronitrile (111 g, 0.64 mol) in ethanol (800 ml) was heated to reflux for 18 hours. Additional glycidol (50 ml, 0.75 mol) was added, and the mixture was heated at reflux for an additional 24 hours. Removal of solvent in vacuo left a residue which was partitioned between water and ethyl acetate. The organic layer was washed with water, washed with saturated sodium chloride solution and dried over sodium sulfate. Filtration and concentration in vacuo provided an oil, which was purified by column chromatography (eluant: 5% methanol in chloroform) to give the title product as an oil (42 g, 0.17 mol, 27% yield). 1H NMR (CDCl3): 7.31 (m, 5H), 3.77 (d, J=13.4 Hz, 1H), 3.67 (m, 3H), 3.49 (d, J=13.5 Hz, 1H), 3.43 (m, 1H), 3.18 (m, 1H), 2.55 (m, 4H), 2.30 (m, 1H), 1.16 and 1.08 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.CCOC(C)=O.O>[CH2:20]([O:13][C:4]1[C:3]([CH:1]=[O:2])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C=O)c1OCc1ccccc1
Yield: 62.1 %

Procedure:
A slurry of methyl 3-formyl-2-hydroxybenzoate (640 mg, 3.56 mmol), K2CO3 (982 mg, 7.12 mmol), and benzyl bromide (0.63 mL, 5.34 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours and diluted with EtOAc (100 mL) and water (40 mL). The layers were separated and the organic phase dried over MgSO4. After filtration and concentration in vacuo, the residue was purified via silica gel chromatography, eluting with 0-15% EtOAc in isohexane, to give the title compound as a white solid (598 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:26])[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1>C(OCC)C>[NH2:23][C:19]1[CH:18]=[C:17]([NH:16][C:14](=[O:15])[C:13]([N:10]2[CH2:11][CH2:12][CH:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[O:26])[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccc(F)cc3)CC2)c1

Procedure:
The title compound is prepared from 2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-N-(3-nitro-phenyl)-2-oxo-acetamide (Example 15) according to the method described in Example 11. Melting Point: 117-120° C. (diethylether)
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][CH:23]([NH2:26])[CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:23]([NH:26][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH2:24][CH3:25])[CH3:22]
Reactant: CCC(C)N
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCC(C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), butan-2-amine (193 mg, 2.64 mmol, 6.00 equiv), potassium carbonate (181.6 mg, 1.32 mmol, 3.00 equiv), toluene (3 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 109 mg (crude) of methyl 3-(sec-butylamino)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:10]([NH:12][CH:13]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14]([O:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:37][CH2:38][C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40]>CCOC(C)=O.C(#N)C>[Cl-:37].[C:1]([O:5][C:6]([NH:8][CH:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:10]([NH:12][CH:13]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:14]([O:16][C@@H:17]1[CH:22]2[CH2:21][CH2:20][N+:19]([CH2:38][C:39](=[O:40])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([CH2:24][CH2:23]2)[CH2:18]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)c1ccccc1
Reactant: O=C(CCl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC(C(=O)NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 24 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(2-(tert-butoxycarbonylamino)-2-phenylacetamido)-2-phenylacetate (210 mg, 0.42 mmol) in EtOAc (3 ml) and acetonitrile (3 ml), was added 2-chloro-1-phenylethanone (65.8 mg, 0.42 mmol), and the reaction was stirred at RT for 15 hours. More 2-chloro-1-phenylethanone (19.7 mg, 0.13 mmol) was added, and the reaction was stirred at RT for 24 hours. The solvent was evaporated, and the crude was purified by flash chromatography (DCM/MeOH=94/6 to 93/7) to obtain (3R)-3-(2-(2-(tert-butoxycarbonylamino)-2-phenylacetamido)-2-phenylacetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (65.3 mg, 23.7% yield).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=2)=[CH:4][CH:3]=1.[F-].[K+].[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])[CH2:26][OH:27].O>O1CCOCC1>[CH2:30]([O:29][C:25]([CH2:26][O:27][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=2)=[CH:4][CH:3]=1)=[O:28])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOC(=O)CO
Reactant: Cn1c(C(F)(F)F)cnc(-c2ccc(F)c([N+](=O)[O-])c2)c1=O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCOC(=O)COc1ccc(-c2ncc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 84 %

Procedure:
Then, 1.10 g of 3-(4-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-13) was dissolved in 4.0 ml of 1,4-dioxane, to which 0.812 g of potassium fluoride and 0.925 g of butyl glycolate, and the mixture was heated under reflux for 1.5 hours. After completion of the reaction, the reaction mixture was left cooling to room temperature. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 1.25 g (yield, 83%) of 3-[4-(butoxycarbonylmethoxy)-5-nitrophenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (the present compound depicted below).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7]Br)([CH3:4])([CH3:3])[CH3:2].[CH3:10][CH:11]([CH3:22])[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][CH:11]([CH3:22])[CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)CCOc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc(NCC(=O)OC(C)(C)C)cc1
Reaction time: 14 h
Yield: 98 %

Procedure:
t-Butylbromoacetate (1.12 g, 0.85 mL, 5.76 mmol) was added drop wise over 5 min to a stirred suspension of {4-[(3-methylbutyl)oxy]phenyl}amine (intermediate 5, 0.85 g, 4.8 mmol) and potassium carbonate (0.66 g, 4.8 mmol) in dimethylformamide (23.4 mL) at room temperature under a nitrogen atmosphere. After stirring for 14 h the volatiles were evaporated and the residue partitioned between dichloromethane (50 mL) and water (50 mL). The phases were separated and the aqueous phase washed with dichloromethane (2×50 mL). The organic phases were combined, dried (magnesium sulfate) then the solvent evaporated. The residue was chromatographed on silica gel (10% diethyl ether:cyclohexane) to give the title compound (inseparable 10:1 mixture of mono- to di-substitution) as a colourless oil (1.38 g). Mono-product: LC/MS: 3.77 min; z/e 294, calcd (M+1) 294. 1H NMR (400 MHz; CDCl3): 0.90 (6H), 1.45 (9H), 1.65 (2H), 1.85 (1H), 3.75 (2H), 3.90 (2H), 6.55 (2H), 6.80 (2H).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[C:3](O)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=1>>[OH:1][CH:2]([CH2:6][CH3:7])[C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=1)=[O:4]
Reactant: CCC(O)C(=O)O
Reactant: Cc1ccc(N)nc1
Product: CCC(O)C(=O)Nc1ccc(C)cn1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A8, starting from 2-hydroxy-butyric acid and 2-amino-5-picoline,
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:19][C:15]1[N:14]=[C:13]([NH:12][C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nccc2cccnc12
Reactant: Cc1cccc(N)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1cccc(Nc2nccc3cccnc23)n1
Temperature: 150 °C
Reaction time: 0.83 h

Procedure:
8-Chloro-[1,7]naphthyridine (Example A) (0.2 g, 1.2 mmol) and 2-amino-6-methylpyridine (0.13 g, 1.2 mmol) were dissolved in 8 ml dry dioxane. 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (145 mg, 0.24 mmol), cesium carbonate (0.63 g, 1.95 mmol) and tri(dibenzylideneacetone)dipalladium chloroform complex (0.13 g, 0.12 mmol) were added and the reaction mixture was stirred under microwave irradiation for 50 minutes at 150° C. The reaction mixture was then evaporated and purified by flash chromatography on silica gel (heptane/ethyl acetate 95:5->70:30 gradient). The desired product was obtained as a light yellow solid (98 mg, 34%),
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[Mg].CN([CH:15]=[O:16])C.Cl>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:9])[C:7]=1[F:8])[CH:15]=[O:16]
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)cc(F)c1F
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc(F)c(F)c(F)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
In a nitrogen atmosphere, a solution prepared by dissolving 50 g of 3,4,5-trifluorobromobenzene in 50 mL of THF was added dropwise at a rate that caused gentle reflux to a mixed solution of 6.34 g of magnesium and 60 mL of THF. After dropwise addition, the mixture was stirred at 40° C. for 1 hour. Then, a solution prepared by dissolving 34.64 g of DMF in 60 mL of THF was added dropwise under ice cooling at such a rate that the inside temperature did not exceed 20° C., followed by stirring at room temperature for 1 hour. Then, 10% hydrochloric acid was added until the reaction system became acidic, and the mixture was stirred at room temperature for 1 hour. Then, hexane was added to the mixture to separate an organic layer, and an aqueous layer was subjected to extraction with hexane. The hexane extract was combined with the organic layer and washed with a saturated aqueous sodium bicarbonate solution and saturated brine. The resultant mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure to yield 37.91 g of 3,4,5-trifluorobenzaldehyde.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:19]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:20]>ClCCl>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[C:19]([C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:20]
Reactant: CNCCN1CCOCC1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C(=O)N(C)CCN2CCOCC2)c1
Temperature: 2.5 °C

Procedure:
Into a 100-mL round bottom flask, was placed a solution of N-methyl-2-morpholinoethanamine (2.1 g, 13.12 mmol, 1.00 equiv, 90%) in dichloromethane (20 mL), and triethylamine (1.47 g, 14.55 mmol, 1.00 equiv). This was followed by dropwise addition of a solution of methyl 3-(chlorocarbonyl)benzoate (3.3 g, 15.00 mmol, 1.20 equiv, 90%) in dichloromethane (10 mL) with stirring at 0-5° C. The resulting solution was stirred for 3 h at room temperature. The resulting solution was diluted with 100 mL of dichloromethane. The resulting mixture was washed with 1×30 mL of 10% sodium bicarbonate and 1×30 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane:methanol (20:1). This resulted in 4.4 g (99%) of methyl 3-(methyl(2-morpholinoethyl)carbamoyl)benzoate as a brown solid.
Reaction SMILES: CC(=C)C[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.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:35]C)C=C4)N(CC2)C1.[CH3:72][C:73]([OH:76])([CH3:75])[CH3:74].O>>[CH2:6]([O:5][CH2:4][CH2:72][C@:73]([CH3:75])([OH:76])[CH2:74][OH:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
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=C(C)CCOCc1ccccc1
Reactant: CC(C)(C)O
Solvent: O
Product: C[C@@](O)(CO)CCOCc1ccccc1

Procedure:
Compound 1 was added to a solution of AD-mix-α in tBuOH/H2O (1:1) cooled in an ice bath. After TCL monitoring showed the disappearance of the starting material, the reaction was quenched by adding Na2SO3. The aqueous phase was extracted with ethyl acetate three times and the combined organic phase was washed with brine and dried (Na2SO4). The solid was filtered and the solvent was removed. The residue was purified by column chromatography to give compound 2.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[OH:16].C(N(CC)CC)C>C(OCC)C>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:16][C:7]1[CH:8]=[CH:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cl)Oc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 88 %

Procedure:
Phosphorus oxychloride (3.23 mL, 1 equiv) and β-naphthol (Aldrich, 5 g, 1 equiv) were stirred in anhydrous diethyl ether (25 mL). Anhydrous triethylamine was added (4.84 mL, 1 equiv) at −78° C. and the solution was allowed to warm to room temperature after 25 min. The triethylamine hydrochloride salt was filtered off and the solvent was removed under reduced pressure to give a clear pale yellow oil (7.95 g, 88%). (oil solidified in the freezer).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)=[CH:4][C:3]=1[O:24][Si](C(C)C)(C(C)C)C(C)C.[C:35](O)(=[O:39])[C:36]#[C:37][CH3:38]>>[OH:24][C:3]1[CH:4]=[C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)[CH:22]=[CH:23][C:2]=1[NH:1][C:35](=[O:39])[C:36]#[C:37][CH3:38]
Reactant: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1N)(C(C)C)C(C)C
Reactant: CC#CC(=O)O
Product: CC#CC(=O)Nc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O

Procedure:
Following the acetylation and desilylation procedure employed for the preparation of (2E)-N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]aminomethyl)phenyl]-2-methylbut-2-enamide, (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-iodoisoquinoline-1,3(2H,4H)-dione (65 mg, 0.11 mmol) is reacted with acid chloride derived from 2-butynoic acid (92 mg, 1.1 mmol). Following desilylation and precipitation, N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]but-2-ynamide is obtained as a solid (20 mg, 36%).
Reaction SMILES: [CH:1]1([O:7][C:8]([CH2:10][O:11][C:12](=[O:16])[CH2:13][CH2:14][NH2:15])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([OH:26])=[O:25])(=[O:20])=[O:19].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([O:7][C:8]([CH2:10][O:11][C:12]([CH2:13][CH2:14][NH:15][S:18]([C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24]([OH:26])=[O:25])(=[O:20])=[O:19])=[O:16])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCCC(=O)OCC(=O)OC1CCCCC1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCNS(=O)(=O)c1cccc(C(=O)O)c1)OCC(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 3-amino-propionic acid cyclohexyloxycarbonylmethyl ester (step 2) (2.30 g, 10.03 mmol) in DCM (200 ml) at RT was treated with 3-chlorosulfonyl-benzoic acid (3.64 g, 16.50 mmol) followed by N,N-diisopropylethylamine (3.04 ml, 17.45 mmol). The resulting mixture was stirred at RT for 1 h. The reaction mixture was washed with 2N HCl (200 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound; LC-MS Rt 1.34 mins; 414.2 [M+H]+, Method 2minLC_v002.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][N:8]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([O:33][CH3:34])[C:27]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:31])=[C:28]([O:33][CH3:34])[C:27]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:26][CH:25]=1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Reactant: COc1c(CNC(=O)C(C)(C)C)ccc(Cl)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(CNC(=O)C(C)(C)C)ccc(Cl)c1C(=O)Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ncnc12
Yield: 32.3 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-8, 60 mg, 0.19 mmol), 6-chloro-2-methoxy-3-(pivalamidomethyl)benzoic acid (Intermediate-43, 88 mg, 0.29 mmol), oxalyl chloride (55 mg, 0.44 mmol), DMF (1 drop) and DIPEA (74 mg, 0.57 mmol) in CH2Cl2 (2 mL) to afford 36 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.49 (s, 1H), 8.92 (d, J=7.8 Hz, 1H), 8.77 (s, 1H), 8.17-8.11 (m, 2H), 7.86 (m, 2H), 7.74 (m, 3H), 7.30 (m, 2H), 4.29 (d, 2H), 3.84 (s, 3H), 1.15 (s, 9H); MS (m/z): 587.17 (M+H)+.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[C:11]=1[CH3:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]([CH:23]=[CH2:24])=[CH2:22]>>[C:1]([O:9][C:10]1[CH:15]=[C:14]2[C:13](=[C:12]([CH3:17])[C:11]=1[CH3:18])[O:16][C:21]([O:20][CH3:19])([CH3:22])[CH2:23][CH2:24]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(O)ccc(OC(=O)c2ccccc2)c1C
Reactant: C=CC(=C)OC
Product: COC1(C)CCc2cc(OC(=O)c3ccccc3)c(C)c(C)c2O1

Procedure:
By the manner of Example 45, 4-benzoyloxy-2,3-dimethylphenol was reacted with 2-methoxybutadiene to give (±)-6-benzoyloxy-2-methoxy-2,7,8-trimethylchroman as a white powder, m.p. 101.5°-102.5°, from ether-30°-60° petroleum ether.