Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[CH2:25]([O:24][C:22](=[O:23])[C:21]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])=[O:27])[CH3:26]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1ccc(CN)c(OC)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)NCc1ccc(OC)cc1OC
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A clean and dry jacketed reactor was equipped with a condenser, a Claisen adapter, a temperature probe, and an addition funnel or head column. The reactor was flushed with nitrogen gas for at least 15 minutes. The reactor was then charged with 1,396 g (1 equiv., 8.3 mol) of 2,4-dimethoxybenzylamine, 1,693 g (2 equiv., 16.7 mol) of triethylamine, and 25,086 mL of THF. The mixture was cooled to from 0 to 5° C. Ethyl chlorooxoacetate (1140 g, 1 equiv., 8.3 mol) was added to an addition funnel or head column and charged to the batch at such a rate that the internal temperature did not exceed 10° C. Solids formed approximately ⅓ into the addition. After the addition was complete, the cooling was turned off and the slurry was allowed to stir for 30 minutes at from 5° C. to 15° C. When complete, the reaction was warmed to from 20° C. to 25° C. The organic phase was washed twice with 22,580 mL of 1 N HCl. The organic phase was then washed with 12,600 mL saturated sodium bicarbonate. Next, the organic phase was washed with 12,463 mL of brine and dried over magnesium sulfate. The mixture was filtered through a thin pad of celite and concentrated at from 40° C. to 45° C. to a yellow oil. A total of 2,052 g (7.7 mol, 92%) of the crude N-(2,4-dimethoxy-benzyl)-oxalamic acid ethyl ester was isolated.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([C:15]1[CH:31]=[CH:30][C:18]([CH2:19][NH:20][C:21](=[O:29])[CH:22]([O:26][CH2:27][CH3:28])[C:23]([OH:25])=O)=[CH:17][CH:16]=1)#[N:14].[C:32](=[N:40]O)([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:13]([C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:20][C:21](=[O:29])[CH:22]([O:26][CH2:27][CH3:28])[C:23]2[O:25][N:40]=[C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:39]=2)=[CH:30][CH:31]=1)#[N:14]
Reactant: NC(=NO)c1ccccc1
Reactant: CCOC(C(=O)O)C(=O)NCc1ccc(C#N)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1nc(-c2ccccc2)no1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
To a solution under N2 of 1,1′-carbonyldiimidazole (272 mg) in THF (10 ml) was added a solution of (RS)-N-(4-cyano-benzyl)-2-ethoxy-malonamic acid (400 mg) in THF (10 ml). The mixture was stirred for 30 min before addition of a solution of benzamidoxime (228 mg) in THF (20 ml). After stirring 18 h the solvent was evaporated. The crude product was dissolved in EtOAc and extracted with HCl 0.1 N, NaHCO3 and brine. After drying (MgSO4) the solvent was evaporated. The resulting white powder was redissolved in DMF (15 ml) and this solution was heated 5 min in a sealed tube at 140° C. using microwave radiation. DMF was removed, the residue was diluted with EtOAc and washed twice with water. The aqueous phases were extracted with more EtOAc. The combined organic phases were dried over MgSO4 and the solvent was evaporated. Flash chromatography (MeCl2/Et2O, from 100:0 to 95:5) yielded (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-(3-phenyl-[1,2,4]oxadiazol-5-yl)-acetamide, 305 mg (55%); lightly yellow oil. MS 363.1 (100, [M+H]+), 380 (53, [M+NH4]+).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12.[C-:24]#N.[K+]>CC(O)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16]([O:18][CH:19]([CH3:24])[CH3:20])=[O:17])=[C:5]2[C@@H:4]2[CH2:21][CH2:22][CH2:23][N:3]12
Reactant: [C-]#N
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2

Procedure:
934 mg (3 mmol) of ethyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate are stirred at 60° C. for 48 hours with 198 mg (3 mmol) of potassium cyanide in 30 ml of dry 2-propanol. The mixture is evaporated in vacuo. The residue is treated with 30 ml of 2-propanol and 198 mg (3 mmol) of potassium cyanide and heated to boiling under reflux for 22 hours. After evaporation in vacuo, the residue is treated with water and extracted three times with 30 ml of chloroform each time. The combined chloroform phases was washed three times with 20 ml of water each time, dried over magnesium sulphate and evaporated. After recrystalisation from ethyl acetate/n-hexane, there is obtained isopropyl (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 207°-208° C.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]2)=[CH:11][CH:10]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>C(O)=O.[Pd].CO>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC#Cc1ccc(C2CCC(=O)C2)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CCCCCCCCc1ccc(C2CCC(=O)C2)cc1
Reaction time: 48 h

Procedure:
Several drops of formic acid and catalytic amount 5% Pd/C was added to a 25 mL flask charged with 10 mL methanol and 1.34 g (5 mmol) of 2. The reaction vessel was flushed with H2, 3 times, and then mounted with a H2 balloon. After two days of hydrogenolysis, the solute was filtered through a pad of silica, and concentrated to provide a yellow oil. 1.32 g (98%) product was collected. 1H NMR (CDCl3) δ 7.18 (s, 4H, ArH), 3.38 (m, 1H, ArCHCC), 2.60 (t, 2H, CCCH2CH2), 2.45-1.91 (m, 6H, cyclo-pentyl), 1.64-1.15 (m, 12H, CH2), 0.90 (t, 3H, CH3); 13C NMR (CDCl3) δ 220, 142, 140, 129, 127, 46, 42, 39, 36, 32, 32, 32, 30, 30, 29, 23, 14.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][N:30]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC[C@H]1O
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f16) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][NH:20]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28]>O1CCOCC1>[ClH:28].[NH2:20][CH2:19][CH2:18][O:17][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]#[N:14]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(C#N)ccc1OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(OCc2ccccc2)c(OCCN)c1
Reaction time: 8 h

Procedure:
3.4 g (9.2 mmol) of 4-benzyloxy-3-[2-(t-butoxycarbonylamino)ethoxy]benzonitrile was dissolved in 40 ml of 4 N solution of hydrogen chloride in dioxane, and the obtained solution was stirred overnight. The solvent was evaporated to obtain hydrochloride of the crude title compound.
Reaction SMILES: C[Li].[N:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[CH:4]=1.[C:11]1(C)C=CC=CC=1>CCOCC>[CH3:11][C:4]1[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][N:3]=1.[N:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[CH3:11]
Reactant: Cc1ccccc1
Reactant: Cc1cncc(C)c1
Agent: [Li]C
Solvent: CCOCC
Product: Cc1cnc(C)c(C)c1
Reaction time: 4 h

Procedure:
To 500 ml of a 5% solution of methyl lithium in ether were added dropwise at room temperature under argon 1200 ml of ether, subsequently 35.6 g of 3,5-lutidine (3,5-dimethylpyridine) and finally 400 ml of toluene. The ether was distilled off completely, whereupon the solution was stirred at 100° for 4 hours. Ice was then added portionwise thereto while cooling with methanol/ice until the evolution of heat no longer occurred. The toluene phase was separated from rhe precipitated solid and was extracted wirh 66 ml of semi-concentrated hydrochloric acid. The separated aqueous phase was adjusted to a pH of about 10 with 3N sodium hydroxide solution while cooling and extracted twice with 300 ml of ether. The ether extracts were dried over sodium sulfate and evaporated. The residue was distilled in vacuo at 20 mm/ 72-74° ; there was obtained 2,3,5-collidine 2,3,5-trimethylpyridine) which had a 99.15% purity in accordance with gas chromatography.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH2:3].C[O-].[Na+].[C:15](O)(=[O:17])C>CO>[CH3:15][O:17][CH2:3][CH:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:1]([O:10][CH3:11])=[O:9]
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCC(CC(=O)OC)C(=O)OC
Reaction time: 96 h
Yield: 80.3 %

Procedure:
200 g of dimethyl itaconate are dissolved, together with 5.9 g of sodium methoxide, in 650 ml of methanol and the solution is left to stand for four days. The solution is then acidified with acetic acid and fractionally distilled. 240 g (83.4% of the theoretical yield) of dimethyl 2-methoxymethylsuccinate are obtained, at a boiling range of from 109° to 112° C. After the ester has been hydrolyzed with 2N HCl, the free acid is obtained in a yield of 80.3% of the theoretical yield.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:14](O)[CH3:15])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>C(Cl)Cl>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:14]([Cl:19])[CH3:15])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1Cc2ccc(C(C)O)cc2C1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(=O)NC1Cc2ccc(C(C)Cl)cc2C1
Reaction time: 1 h

Procedure:
25 g (0.11 mol) of 1-(2-acetamido-indan-5-yl)-1-ethanol are suspended in 280 ml of methylene chloride, and 15 g (0.12 mol) of thionyl chloride are added. A clear solution is formed. After 1 hour, this solution is neutralised by washing with a saturated solution of sodium bicarbonate. The desired reaction product is obtained after drying and evaporating.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C:12]1[N:17]=[N:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)(=O)C>O.CO>[CH3:19][O:18][C:15]1[N:16]=[N:17][C:12]([CH2:11][OH:10])=[CH:13][C:14]=1[O:20][CH3:21]
Reactant: COc1cc(COC(C)=O)nnc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(CO)nnc1OC
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A solution of potassium carbonate (0.2 g) in water 2 mL) is added to a solution of 6-acetoxymethyl-3,4-dimethoxypyridazine (0.27 g) in methanol (6 mL) and the mixture stirred at 60-70° C. for 2 hours. After evaporating to dryness the residue is partitioned between ethyl acetate (10 mL) and brine (10 mL). The ethyl acetate phase is evaporated to dryness and the residue purified by flash chromatography (ethyl acetate as eluent on silica) to give 3,4-dimethoxy-6-hydroxymethylpyridazine as a white solid, m.p. 151-3° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[OH:9][CH2:8][C:3]1[C:2]([NH:1][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1CO
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1CO)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of (3-amino-pyridin-2-yl)-methanol (0.310 g, 2.54 mmol) and Et3N (0.570 g, 5.33 mmol) in dry CH2Cl2 (20 mL) was added benzoyl chloride (0.700 g, 5.08 mmol) dropwise. After the mixture was stirred for 18 h CH2Cl2 was removed, and then MeOH (5 mL) and saturated aqueous K2CO3 (25 mL) were added. The mixture was stirred for 2 h, and then extracted with CH2Cl2 (5×50 mL). The combined extracts were dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (2:1 CH2Cl2/Et2O), affording N-(2-hydroxymethyl-pyridin-3-yl)-benzamide as a white solid. The white solid was dissolved in CH2Cl2 (15 mL), and activated MnO2 (0.660 g, 7.68 mmol) was added. The suspension was stirred for 64 h, and then filtered through a celite cake. The filtrate was concentrated by evaporation under vacuum, and a brown residue was purified by flash chromatography on a silica gel column (4:1 CH2Cl2/Et2O), affording N-(2-formyl-pyridin-3-yl)-benzamide as a pale yellow solid (0.139 g, 24% two steps). 1H NMR (CDCl3) δ 7.54-7.62 (m, 4H), 8.07 (d, 2H, J=7.2 Hz), 8.54 (d, 1H, J=4.2 Hz), 9.32 (d, 1H, J=8.7 Hz), 10.19 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([Cl:18])=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][OH:22].[H-].[Na+].Br[CH2:26][C:27]#[C:28][CH3:29]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH3:17])=[CH:13][CH:14]=2)[C:5]([Cl:18])=[CH:4][C:3]=1[CH2:19][CH2:20][CH2:21][O:22][CH2:26][C:27]#[C:28][CH3:29]
Reactant: CC#CCBr
Reactant: CCOc1ccc(Cc2cc(Br)c(CCCO)cc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC#CCOCCCc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1Br
Reaction time: 0.67 h
Yield: 65.6 %

Procedure:
To a stirred solution of 3-(2-bromo-5-chloro-4-(4-ethoxybenzyl)phenyl)propan-1-ol (BL) (0.268 g, 0.70 mmol) in 5 mL of THF was added NaH (0.034 g, 0.84 mmol, 60%) and stirred for 40 min. 1-bromo-2-butyne (0.094 mL, 1.05 mmol) was added and the mixture was stirred overnight at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, concentrated and purified by preparative TLC (eluting with EtOAc:PE=1:10) to obtain 0.2 g of intermediate BM.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([NH:29][C:30]([C:32]2([C:35](=[O:44])[NH:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:34][CH2:33]2)=[O:31])[C:26]([F:45])=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([CH:14]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[O:13])[CH:6]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH:16]1[CH2:17][CH:14]([C:12]([NH:11][C:7]2[CH:6]=[C:5]([O:4][C:3]3[C:2]([F:1])=[CH:28][C:27]([NH:29][C:30]([C:32]4([C:35]([NH:36][C:37]5[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=5)=[O:44])[CH2:34][CH2:33]4)=[O:31])=[C:26]([F:45])[CH:25]=3)[CH:10]=[CH:9][N:8]=2)=[O:13])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)C1CNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
To a solution of tert-butyl 3-(4-(2,5-difluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-ylcarbamoyl)azetidine-1-carboxylate (220 mg, 0.35 mmol) in CH2Cl2 (4 mL) was added TFA (0.2 mL) at 0° C. and the reaction was stirred at room temperature overnight. Saturated NaHCO3 solution was added drop wise until pH>7 and the mixture with extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by HPLC separation to give N-(4-(2-(azetidine-3-carboxamido)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (16 mg, yield 8.7%). 1H-NMR (400 MHz, MeOH-d4): δ 9.50 (s), 8.46 (d, J=7.2 Hz, 1H), 8.33 (dd, J=7.2 Hz, 12.4 Hz, 1H), 7.53-7.43 (m, 3H), 7.26 (dd, J=7.2 Hz, 2.4 Hz, 1H), 7.10 (t, J=8.4 Hz, 2H), 6.75 (d, J=2.4 Hz, 1H), 4.61-4.54 (m, 1H), 3.63-3.58 (m, 1H), 3.49-3.44 (m, 1H), 3.31-3.29 (m, 1H), 3.27-3.25 (m, 1H), 1.75-1.73 (m, 4H); MS (ESI): m/z 443.2 [M+H]+.
Reaction SMILES: [C:1]1([CH:9]=[CH:10][C:11]2[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=2)[CH:8]=[C:6]([OH:7])[CH:5]=[C:3]([OH:4])[CH:2]=1.[C:18](Cl)(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>N1C=CC=CC=1>[C:18]([O:4][C:3]1[CH:2]=[C:1]([CH:9]=[CH:10][C:11]2[CH:17]=[CH:16][C:14]([O:15][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:13][CH:12]=2)[CH:8]=[C:6]([O:7][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:5]=1)(=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: Oc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)Oc1ccc(C=Cc2cc(OC(=O)CCCCCCCCCCCCCCC)cc(OC(=O)CCCCCCCCCCCCCCC)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 108.4 %

Procedure:
Resveratrol (100 mg; 0.44 mmol) was dissolved in 1 mL of pyridine. Palmitoyl chloride (425 μL; 1.40 mmol; 3.2 equiv) was added with immediate solid formation noted. This mixture was stirred at ambient temperature for 12 h at which point HPLC analysis indicated no resveratrol present. The mixture was partitioned into ethyl acetate and water and the water layer was decanted. The top organic layer was washed sequentially with 1.5 M HCl (10 mL) and 5% sodium bicarbonate (10 mL), dried (MgSO4), and concentrated to afford 0.45 g (99%) of resveratrol tripalmitate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][N:22](C(OCC3C=CC=CC=3)=O)[CH:21]([CH3:35])[CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:44])[N:13]2[C:36]1[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:43].Br.CC(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH:21]([CH3:35])[CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:44])[N:13]2[C:36]1[C:37]([Cl:43])=[CH:38][CH:39]=[CH:40][C:41]=1[Cl:42]
Reactant: CC1CN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CCN1C(=O)OCc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1CN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CCN1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}-2-methylpiperazine-1-carboxylate (105 mg, 0.16 mmol) in methylene chloride (2 mL) at 0° C. was added 30% HBr/HOAc (0.32 mL, 1.62 mmol) slowly. The resulting reaction mixture was stirred at 0° C. for 30 min, and then at rt for 30 min. The reaction was quenched with water, then added 5N NaOH solution to pH ˜1, and extracted with methylene chloride (50 mL×3) and ethyl acetate (50 mL×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by preparative thin layer chromatography using 8% of 2N ammonium in methanol/methylene chloride as eluent provided 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(3-methylpiperazin-1-yl)methyl]-3,4-dihydroquinazolin-2(1H)-one as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.06 (d, 3H, J=4.8 Hz), 1.72 (m, 1H), 2.06 (m, 1H), 2.69 (m, 2H), 2.82 (t, 2H, J=9.3 Hz), 2.98 (d, 1H, J=11.9 Hz), 3.40 (m, 2H), 4.34 (abq, 2H, J=14.4 Hz), 5.10 (s, 1H), 6.17 (s, 1H), 6.84 (s, 1H), 7.30-7.60 (m, 7H). MS (API-ES+): 517 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH:28]=C)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[O:31]1CCCC1>O=[Os](=O)(=O)=O.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH:28]=[O:31])[C:20]([C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: C1CCOC1
Reactant: C=Cc1c(C(F)(F)F)ccc2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)OC
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4C=O)ccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
NaIO4 (1.80 g) and OsO4 (4% in water, 50 μL) are added to a mixture of {(S)-6-[(R)-5-trifluoromethyl-4-vinyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (1.25 g), tetrahydrofuran (16 mL), and water (4 mL) at room temperature. The mixture is stirred at 50° C. overnight. After cooling to room temperature, water is added and the mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. LC (method 4): tR=1.19 min; Mass spectrum (ESI+): m/z=421 [M+H]+.
Reaction SMILES: [BrH:1].C(O)(=O)C.C(OC([NH:13][CH:14]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[C:23]3[C:24]([O:32]C)=[CH:25][N:26]=[CH:27][C:28]=3[CH:29]=[CH:30][CH:31]=2)(=[O:21])=[O:20])[CH2:15]1)=O)(C)(C)C>>[NH2:13][CH:14]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[C:23]3[C:24]([OH:32])=[CH:25][N:26]=[CH:27][C:28]=3[CH:29]=[CH:30][CH:31]=2)(=[O:20])=[O:21])[CH2:15]1.[BrH:1]
Reactant: COc1cncc2cccc(S(=O)(=O)N3CCC(NC(=O)OC(C)(C)C)C3)c12
Agent: Br
Solvent: CC(=O)O
Product: NC1CCN(S(=O)(=O)c2cccc3cncc(O)c23)C1
Reaction time: 0.5 h

Procedure:
30% Hydrogen bromide/acetic acid (1.5 ml, Tokyo Kasei Kogyo) is gradually added with Intermediate 13 (45 mg) obtained in Example 15, Step A at 0° C., and the mixture is stirred at the same temperature for 30 minutes. The solvent is concentrated under reduced pressure, and the obtained solid is collected by filtration to obtain the title compound as hydrobromide (13 mg (predictive yield)).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[CH2:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH2:18][CH3:19]>>[CH2:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=3)[N:6]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH2:18][CH3:19]
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3ccc(NC(C)=O)cc3)cs2)cc1

Procedure:
The title compound was prepared from N-[4-(2-amino-1,3-thiazol-4-yl)phenyl]acetamide and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (1.0 mg) with purity >80%. MS (pos) m/z 416.2.