Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]([OH:16])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].CCOC(C)=O>CN(C=O)C.O>[CH3:34][O:33][C:31](=[O:32])[CH2:30][O:16][C:7]1[C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)COc1c(-c2ccccc2)cc([N+](=O)[O-])cc1-c1ccccc1
Yield: 99.1 %

Procedure:
To a stirred solution of 5′-nitro-[1,1′;3′,1″]terphenyl-2′-ol (0.250 g, 0.858 mmol) and K2CO3 (0.130 g, 0.944 mmol) in DMF (9 mL) at room temperature was added dropwise methyl bromoacetate (0.162 mL, 1.72 mmol). After 72 h at this temperature, it was diluted with H2O (20 mL) followed by excess EtOAc (200 mL). The organic layer was washed with 1 N HCl (50 mL), sat. aq. NaHCO3 (50 mL), and brine (50 mL) and then dried (MgSO4). After concentration, the residue was purified by flash chromatography (5 to 30% acetone/hexane gradient) to afford the product (0.309 g, 99%) as a clear oil; 1H NMR (DMSO-d6) δ 3.37 (s, 3H), 4.03 (s, 2H), 7.43–7.53 (m, 6H), 7.60–7.64 (m, 4H), 8.14 (s, 2H); IR (film) 3420, 3080, 2950, 1770, 1745, 1590, 1530, 1500, 1455, 1440, 1410, 1350, 1305, 1210, 1110, 1070, 910, 745, and 700 cm−1; mass spectrum [EI], m/z 363 (M)+; Anal. Calcd. for C21H17NO5.0.75H2O: C, 66.93; H, 4.95; N, 3.72. Found: C, 66.89; H, 4.67; N, 3.51.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])(=O)=O.[CH2:18]([O:22][C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30](O)=[O:31])=[CH:25][N:24]=1)[CH2:19][CH2:20][CH3:21].C(=O)([O-])O.[Na+]>O>[CH2:18]([O:22][C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]([O:10][CH2:11][CH2:12][C:13]([CH3:17])=[C:14]([F:16])[F:15])=[O:31])=[CH:25][N:24]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Reactant: CCCCOc1ncc(C(=O)O)c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1ncc(C(=O)OCCC(C)=C(F)F)c(C)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To 50 ml of N,N-dimethylformamide were dissolved 6.6 g (33 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate and 7.6 g (36 mmol) of 2-butoxy-4-methylpyrimidine-5-carboxylic acid, followed by the addition of 3.6 g (43 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 2 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 3.3 g (yield: 32%) of 4,4-difluoro-3-methyl-3-butenyl 2-butoxy-4-methylpyrimidine-5-carboxylate.
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl[CH2:20][C:21]#[C:22][CH2:23][S:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].O>CO>[C:26]([O:28][CH3:29])(=[O:27])[CH2:25][S:24][CH2:23][C:22]#[C:21][CH2:20][S:18][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCS
Reactant: COC(=O)CSCC#CCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCSCC#CCSCC(=O)OC
Reaction time: 0.5 h

Procedure:
460 μl of a 30% solution of sodium methoxide in methanol were added to a solution of 665 μl of tetradecanethiol in a 5 ml methanol/2 ml THF mixture, under an inert atmosphere. The mixture was maintained under stirring for 30 min and then 0.47 g of methyl 7-chloro-3-thia-5-heptynoate in 5 ml of methanol was added, under an inert atmosphere. The mixture was maintained under stirring for 8 hours at room temperature and then the reaction medium was poured over 100 ml of acid water (98 ml of water+2 ml concentrated H2SO4) and then extracted 3 times with ethyl ether. The combined organic phases were washed 3 times with water and then with a saturated aqueous solution of NaCl before being dried (Na2SO4), filtered and concentrated under vacuum in a rotary evaporator. The wax thus obtained was chromatographed on a silica gel column (CH2Cl2) providing 1.05 g of methyl 3,8-dithia-5-docosynoate in the form of an oil. (Quantitative yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:13][C:14]([CH:16]1[S:20][CH2:19][NH:18][C@@H:17]1[C:21](O)=[O:22])=[O:15])[CH2:7]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:13][C:14]([CH:16]1[S:20][CH2:19][NH:18][C@@H:17]1[C:21]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:22])=[O:15])[CH2:7]2
Reactant: C1CCNC1
Reactant: Cc1cc(C)c2c(c1)CC(CC(=O)C1SCN[C@@H]1C(=O)O)CC2
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: Cc1cc(C)c2c(c1)CC(CC(=O)C1SCN[C@@H]1C(=O)N1CCCC1)CC2
Yield: 60 %

Procedure:
A colorless oil of 1-[3-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 3-(5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioproline prepared in Reference Example 25 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 60%).
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](/[C:19](/[C:38]2[NH:43][C:42](=[O:44])[C:41]([CH2:45][CH3:46])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[N:22]2CC2C=CC(OC)=CC=2OC)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>FC(F)(F)C(O)=O>[C:9]([C:13]1[CH:14]=[CH:15][C:16](/[C:19](/[C:38]2[NH:43][C:42](=[O:44])[C:41]([CH2:45][CH3:46])=[CH:40][CH:39]=2)=[CH:20]\[C@H:21]2[CH2:25][CH2:24][C:23](=[O:26])[NH:22]2)=[CH:17][CH:18]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CCc1ccc(/C(=C/[C@H]2CCC(=O)N2Cc2ccc(OC)cc2OC)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCc1ccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Temperature: 65 °C
Reaction time: 7 h
Yield: 57.6 %

Procedure:
Anisole (0.25 mL) was added to a solution of 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-3-ethylpyridin-2(1H)-one (49 mg) in trifluoroacetic acid (0.5 mL), and the mixture was stirred at 65° C. for seven hours. Trifluoroacetic acid (0.5 mL) was added and the mixture was stirred for further five hours, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=1:0→9:1). The resulting crystals (25 mg) were recrystallized from ethyl acetate-hexane to give the title compound as a colorless powder (20 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.S(=O)(=O)(O)O.[OH-].[Na+].[CH2:21](O)[CH3:22]>>[CH2:21]([O:12][C:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:13])[CH3:22]
Reactant: CCO
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Yield: 90 %

Procedure:
A mixture of 5.0 g (28.5 mmols) of indole-3acetic acid, 250 ml of ethanol and 5 ml of conc. sulfuric acid was heated under reflux for 2 hours. After cooling to 0° C., the mixture was neutralized with a 2 normal aqueous sodium hydroxide solution. The solvent was evaporated under reduced pressure, and then water was added to the residue followed by extraction of the solution with chloroform. The chloroform layer was washed with an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dried to afford 5.2 g (yield: 90%) of the title compound.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[CH2:5](O)[CH2:6][O:7]CCO.[CH3:12][O-:13].[Na+]>CO>[CH2:1]([OH:4])[CH:2]([OH:3])[CH2:5][CH2:6][OH:7].[C:1](=[O:4])([O:13][CH3:12])[O:7][CH3:6]
Reactant: OCCOCCO
Reactant: C[O-]
Reactant: OCCO
Agent: [Na+]
Solvent: CO
Product: COC(=O)OC
Product: OCCC(O)CO

Procedure:
Into a 1-liter flask provided with a distilling column, 12 g (0.2 mol) of ethylene glycol, 41 g (0.4 mol) of diethylene glycol, 53 g (0.5 mol) of 1,2,4-butane triol, 450 g (5.0 mol) of dimethyl carbonate and 0.5 g (0.003 mol) of a 28 wt % methanol solution of sodium methoxide were charged, and heated under ordinary pressure at 110 to 150° C. for 8 hours to remove the methanol produced during the reaction from the mixture by evaporation. Thereafter, by elevating the temperature up to 180° C. under reduced pressure, the residual dimethyl carbonate was removed by evaporation.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][O:5][C:6]1[CH:17]=[CH:16][C:9]2[C@H:10]([CH2:13][CH2:14]O)[CH2:11][O:12][C:8]=2[CH:7]=1.C1COCC1.CS(Cl)(=O)=O.[C:33](=[S:36])([O-:35])[CH3:34].[K+]>CN(C=O)C.CCN(CC)CC>[C:33](=[O:35])([S:36][CH2:14][CH2:13][C@H:10]1[C:9]2[CH:16]=[CH:17][C:6]([O:5][CH2:4][C:3]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=3[Cl:1])=[CH:7][C:8]=2[O:12][CH2:11]1)[CH3:34]
Reactant: OCC[C@@H]1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Reactant: CC([O-])=S
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SCC[C@@H]1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a mixture of 2-((3S)-6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)ethanol (678 mg) and THF (dry) (20 mL) were added methanesulfonyl chloride (0.310 mL) and Et3N (0.279 mL). The mixture was stirred at room temperature for 30 min. And then DMF (dry) (20.00 mL) and potassium ethanethioate (228 mg) were added to the mixture. The volatiles (THF) were removed by evaporation. The resulting mixture was stirred at 70° C. for 2 h. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (570 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)NCCc2ccc(-c3ccc(C(C)CNS(=O)(=O)C(C)C)cc3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 13 mL (0.11 mmol) 4-methoxybenzoyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [BH4-].[Na+].C(N)CN.[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][N:16]1[CH:21](/[CH:22]=[CH:23]/[C:24](=[O:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19][CH2:18][C:17]1=[O:33].[H][H]>C(O)C.[Ni](Cl)Cl>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][N:16]1[CH:21](/[CH:22]=[CH:23]/[C:24](=[O:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19][CH2:18][C:17]1=[O:33]
Reactant: COC(=O)CCCC#CCN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Reactant: [H][H]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: NCCN
Product: COC(=O)CCC/C=C\CN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A round bottom flask was charged with nickel (II) chloride (68 mg, 0.52 mmol) and sodium borohydride (9.9 mg, 0.26 mmol), then 95% ethanol (1.0 mL) was added. The mixture immediately turned black. After 15 min at rt, ethylene diamine (56 μL, 0.84 mmol) was added. After another 15 min at rt, 7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester (40 mg, 0.10 mmol) in 95% ethanol (1.0 mL) was added via cannula. A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 18 h. The reaction mixture was filtered through celite, washing with ethanol, and the filtrate was concentrated in vacuo. Purification of the resulting residue by flash column chromatography (CH2Cl2→30% EtOAc/CH2Cl2, gradient) afforded 28 mg (70%) of the title compound.
Reaction SMILES: Cl.[CH2:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[O:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:23]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[C:24]([CH3:26])=[CH2:25].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:29]([O:28][C:23](=[O:27])[CH:24]([CH3:26])[CH2:25][N:19]1[CH2:20][CH2:21][O:22][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:16][CH:15]=2)[CH2:18]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Reactant: C=C(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C2CN(CC(C)C(=O)OC(C)(C)C)CCO2)cc1
Temperature: 140 °C
Yield: 50.7 %

Procedure:
To a suspension of 2-(4-octyloxy-phenyl)-morpholine hydrochloride (0.17 g; 0.5 mmol) in DMF (5.00 mL) was added tert-butyl methacrylate (0.17 mL; 1.0 mmol) and DBU (0.23 mL; 1.5 mmol) The resulting mixture was heated at 140° C. in a sealed flask overnight. After cooling to RT the reaction mixture was partitioned between 5% aqueous NaHCO3 solution and EtOAc. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 2-methyl-3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-propionic acid tert-butyl ester (0.11 g).
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:7]CCC(C)(C)N1.C(=O)=O.[Li]CCCC.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=1.C(=O)CC>C1COCC1>[Cl:19][C:20]1[N:21]=[CH:22][C:23]2[C:24](=[O:26])[O:25][CH:1]([CH2:2][CH3:7])[C:27]=2[CH:28]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCC=O
Product: CCC1OC(=O)c2cnc(Cl)cc21
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (5 ml, 30 mmol) in a 100 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 20 ml of dry THF is added. The reaction mixture is cooled to −50° C. by adding a controlled amount of dry ice to an acetone bath. The cooled reaction mixture is treated dropwise with nBuLi solution (16 mL of a 2.5 M solution in hexanes, 40 mmol) and the reaction is let stir at that −50 C for 0.5 h. A solution of 6-chloro-nicotinic acid (1.58 g, 10 mmol) in THF (20 mL) is added dropwise to the reaction at −50° C. The reaction is stirred at −50° C. for 1.5 h and then cooled to −78° C. The reaction mixture is treated with propionaldehyde (4.2 ml, 58 mmol) dropwise at −50° C. The reaction is stirred at −78° C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated to remove solvent and water and ether are added. The aqueous layer is extracted with ether (6×50 ml). The aqueous phase is treated with aqueous 1N HCl solution, until the pH of aqueous layer is ˜6 and is then extracted with ether (3×40 mL). The aqueous solution is treated with aqueous 1N HCl solution until the pH ˜2 and solution is heated at 100° C. overnight. An oily residue separates from solution. Dichloromethane is added to the aqueous phase which dissolves the oily residue. Without extracting, the solution is poured into a separatory funnel and the organic phase is collected. The organic phase is washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered and concentrated to give the title compound (1.45 g, 73%) as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[O:7][CH2:8][CH2:9][CH:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11]([O-:13])=[O:12])(=[O:3])C.[Se](=O)=O.[C:28](=[O:31])([OH:30])[O-].[Na+].[C:33](OCC)(=O)C>N1C=CC=CC=1>[C:18]([O:17][C:15]([NH:14][CH:10]([C:11]([O:13][CH3:33])=[O:12])[CH2:9][CH2:8][O:7][C:6]1[CH:5]=[C:4]([C:1](=[O:3])[C:28]([OH:30])=[O:31])[CH:24]=[CH:23][CH:22]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(C)=O
Reactant: CC(=O)c1cccc(OCCC(NC(=O)OC(C)(C)C)C(=O)[O-])c1
Reactant: O=C([O-])O
Agent: O=[Se]=O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)C(CCOc1cccc(C(=O)C(=O)O)c1)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
Methyl DL-4-(m-acetylphenoxy)-2-tert-butoxycarbonylaminobutyrate (2.21 g.) was dissolved in pyridine (10 ml.), and to the solution was added selenium dioxide (1.11 g.), whereafter the solution was stirred at 90° C. for 4.5 hours. The reaction mixture was filtered and the filter cake was washed with ethyl acetate. These washings and the filtrate were combined and evaporated to dryness under reduced pressure to give a residue, which was poured into a mixture of an aqueous sodium bicarbonate and ethyl acetate. The insoluble materials were removed by filtration and the filtrate was adjusted to pH 2 with 10% hydrochloric acid. This aqueous solution was extracted twice with ethyl acetate, and the extract was washed with water and then dried over magnesium sulfate. The ethyl acetate was removed by evaporation from the solution under reduced pressure to give DL-m-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenylglyoxylic acid (1.35 g.).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.[SH:19][CH:20]([CH2:24][C:25]([OH:27])=[O:26])[C:21](O)=[O:22].C(OC)(OC)OC>CCOC(C)=O>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]1[N:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21](=[O:22])[CH:20]([CH2:24][C:25]([OH:27])=[O:26])[S:19]1
Reactant: O=C(O)CC(S)C(=O)O
Reactant: O=Cc1ccccc1F
Reactant: NCCc1ccccc1
Solvent: CCOC(C)=O
Solvent: COC(OC)OC
Product: O=C(O)CC1SC(c2ccccc2F)N(CCc2ccccc2)C1=O

Procedure:
A solution of phenylethylamine (85 μl), 2-fluorobenzaldehyde (143 μl) and mercaptosuccinic acid (306 mg) and trimethyl orthoformate (0.5 mL) in THP (3 mL) was heated at 80° C. for 4 hrs. The reaction mixture was cooled, diluted with EtOAc (2 mL) and washed twice with 2 ml of 1N HCl. The organic layer was concentrated to give a residue that was used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][OH:6])#[N:2].C(N(CC)CC)C.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO>ClCCl>[C:14]([O:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: N#CCCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 3-cyano-1-n-propanol (16.85 g, 198 mmol, prepared by method of Blicke, et al., J. Org. Chem. 1961, 26, 3685) in dichloromethane (250 mL) were added triethylamine (80.1 g, 792 mmol) and trityl chloride (82.8 g, 297 mmol) at room temperature and the mixture was stirred for 16 h. To the reaction mixture was added methanol (25 mL) and stirred for 1 h. After concentration, the residue was purified on a column of silica gel using ethyl acetate and hexanes as eluent to give 40 g (61.7%) of the desired product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[C:9]#[N:10]>OS(O)(=O)=O>[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([N+:1]([O-:4])=[O:2])[C:13]=1[OH:14])[C:9]#[N:10]
Reactant: O=[N+]([O-])O
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=S(=O)(O)O
Product: N#Cc1cc(F)c(O)c([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Fuming HNO3 (1.8 mL; 44 mmol) was added dropwise to a solution of 3-fluoro-4-hydroxybenzonitrile (4.0 g; 29 mmol) in conc. H2SO4 (10 mL) at −10° C. The mixture was stirred at −10° C. for 1 h and thereafter slowly poured into ice. The precipitate was filtered off and the filtrate was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was combined with the precipitate and crystallized from EtOAc/PE to give the sub-title compound.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[CH:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:28](=O)[C:27]5[C:26]([C:37]([O:39]C)=O)=[CH:25][CH:24]=[CH:23][C:22]=5[NH:21]4)=[CH:16][CH:15]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:42][NH2:43]>>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[NH:21][C:22]5[C:27]6[C:28](=[N:42][NH:43][C:37](=[O:39])[C:26]=6[CH:25]=[CH:24][CH:23]=5)[CH:29]4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1ccc(C(=O)N3CCN(C(=O)C4CC4)CC3)cc1)N2
Reactant: NN
Solvent: O
Product: O=C(c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1)N1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
A mixture of methyl 2-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (300 mg, 0.55 mmol) and hydrazine monohydrate (3 mL) was stirred room temperature for 3 h. The resulting mixture was evaporated under reduced pressure to 10 mL and then filtered; the filtrate was concentrated to give the crude product. The crude product was purified by pre-HPLC to give 8-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a white solid (4 mg, yield 19%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm); 0.71-0.74 (m, 4H), 1.97 (t, 1H), 3.46-3.76 (m, 8H), 4.36 (dd, 1H), 4.83 (dd, 1H), 7.13-7.23 (m, 6H), 7.30 (d, 2H), 7.38 (t, 3H), 7.47 (s, 1H), 7.59 (t, 1H), 12.17 (s, 1H); LC-MS (ESI) m/z: 520 (M+1)+.
Reaction SMILES: O[CH:2]([C:6]1[C:14]2[O:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]([CH3:24])=[C:8]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:7]=1[CH3:33])[CH2:3][CH2:4][CH3:5]>CCCCCC.C(OCC)(=O)C>[CH2:2]([C:6]1[C:14]2[O:13][CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]([CH3:24])=[C:8]([NH:25][C:26](=[O:32])[CH2:27][C:28]([CH3:29])([CH3:31])[CH3:30])[C:7]=1[CH3:33])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCc1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Yield: 33 %

Procedure:
Using a diastereo mixture of N-(7-(1-hydroxybutyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Examples 90 and 91, the title compound was synthesized in the same manner as in Example 23. Yield: 33%. Melting point: 149-151° C. (hexane-ethyl acetate).