Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br>C1COCC1.CN(C=O)C>[C:4]([O:3][C:1]([NH:8][CH:9]([CH2:10][O:11][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=1[F:21])[C:12]([OH:14])=[O:13])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: Fc1ccc(CBr)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(COCc1ccc(F)cc1F)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of N-Boc-(D)-serine (452 9, 2.2026 mol) in a mixture of THF (7 L) and DMF (3 L) at about 0° C. was added potassium tert-butoxide solution (515.8 g, 4.5963 mol). The reaction mixture was stirred at about 0° C. for about 30 min., then 2,4-difluorobenzyl bromide (456.5 g, 2.2051 mol) was added. After warming to room temperature, the reaction mixture was concentrated in vacua to remove the THF. Partitioned the reaction mixture between 4.5 L H2O and 4.5 L IPE. Separated the layers and adjusted the pH of the aqueous layer with 1 N HCl to about 3. The aqueous layer was extracted twice with 4 L each of IPE. The organic solution was dried over Na2SO4, and concentrated in vacuo to yield a yellow waxy solid (518.0 g, yield: 70.9 %). 1H-NMR (CDCl3) δ1.44 (s, 9H), 3.73 (m, 1H), 3.94 (d, 1H), 4.44 (br s, 1H), 4.54 (s, 2H), 5.34 (m, 1H), 6.78 (m, 1H), 6.84 (m, 1H), 7.30 (m, 1H).
Reaction SMILES: [CH:1]1[C:6](C2C=C[C:10]3[C:13]([O:15][C:16](=[O:17])[C:9]=3C=2)=[O:14])=C[C:4]2C(O[C:21](=O)[C:3]=2[CH:2]=1)=O.C1C2C(OC(=O)C=2C=C2C(OC(=O)C=12)=O)=O.CC([N:42](C)C)=O>>[C:13]([O:15][C:16](=[O:17])[CH3:9])(=[O:14])[CH3:10].[N:42]1[CH:6]=[CH:1][CH:2]=[C:3]([CH3:21])[CH:4]=1
Reactant: CC(=O)N(C)C
Reactant: O=C1OC(=O)c2cc(-c3ccc4c(c3)C(=O)OC4=O)ccc21
Agent: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Product: CC(=O)OC(C)=O
Product: Cc1cccnc1

Procedure:
Polymer was made at room temperature by adding 3,4′-ODA, PPD, BPDA, and PMDA with stirring in DMAc in quantities to make polymers with compositions between 5 and 14 mole % BPDA and between 5 and 21 mole % PPD. The remaining monomers were PMDA as the dianhydride and 3,4′-ODA as the diamine. The polymers were each cast on a substrate and converted in a bath of 50 volume % acetic anhydride and 50 volume % beta-picoline, at room temperature, to form a gel film. The gel film was restrained and heated in an oven to dry and cure at 300° C. for 60 minutes, and then heated in 400° C. oven for 5 minutes. The properties were as follows:
Reaction SMILES: C[CH2:2][CH:3]([C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[C:14]([CH:16]=1)[OH:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O=[C:19]1[CH2:24][CH2:23][CH2:22][S:21][CH:20]1[C:25](OC)=[O:26].Cl.[CH2:30](O)C>>[OH:17][C:12]1[C:13]2[C:19]3[CH2:24][CH2:23][CH2:22][S:21][C:20]=3[C:25](=[O:26])[O:15][C:14]=2[CH:16]=[C:10]([CH:3]([CH:4]([CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2])[CH:11]=1
Reactant: CCO
Reactant: COC(=O)C1SCCCC1=O
Reactant: CCCCCCC(CC)c1cc(O)cc(O)c1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)SCCC3
Reaction time: 48 h

Procedure:
A solution of 14.2 g. (0.06 mole) of 5-(methyl-2-octyl)resorcinol and 11.1 g. (0.063 mole) of methyl 3-oxo-2,3,4,5-tetrahydro-6H-thiopyran-2-carboxylate in 90 ml. of absolute ethanol was cooled in an ice-salt bath and saturated with anhydrous hydrogen chloride. After standing for 2 days at room temperature, the ethanol was removed on a rotary evaporator. The residue was dissolved in ether, washed with sodium bicarbonate solution and dried over sodium sulfate. Evaporation of the solvent gave 28.0 g. of residue which was chromatographed using Florisil (60-100 mesh) and graded methanol/chloroform solvent mixtures. A total of 10 g. of crude solid was obtained from the 1% methanol/chloroform fractions. The material was recrystallized twice from ethyl acetate/hexane to give 8.5 g. (40%) colorless crystals, m.p. 131°-133°C. The proposed structure was confirmed by IR and NMR spectra.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].O=S(Cl)Cl.[CH3:14]O>>[CH3:14][O:8][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Br:1])=[O:9]
Reactant: O=C(O)c1sccc1Br
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1sccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromothiophene-2-carboxylic acid (5.0 g, 24 mmol, 1 eq.) was dissolved in MeOH (100 mL) and the mixture was degassed and purged with nitrogen (2×). SOCl2 (15 mL, 0.2 mol, 8.3 eq.) was added dropwise and the resulting mixture was stirred overnight at room temperature. The mixture was then concentrated and DCM (150 mL) was added. Saturated NaHCO3 (20 mL) was added, and the resulting mixture was stirred at room temperature for 15 minutes. The organic layer was washed with saturated NaHCO3 (20 mL), water (20 mL), and saturated aqueous NaCl (20 mL), then dried over Na2SO4, filtered and concentrated to yield 3-bromothiophene-2-carboxylic acid methyl ester (4.0 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[C:7]3[C:11](=[CH:12][CH:13]=[C:5]2[S:4][CH:3]=1)[NH:10][C:9]1[CH2:14][CH2:15][NH:16][CH2:17][C:8]3=1.CN(C)P(=O)(N(C)C)N(C)C.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH2:37][CH2:38][CH2:39]I)=[CH:32][CH:31]=1>CN(C)C=O>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH:36]([C:41]2[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=2)[CH2:37][CH2:38][CH2:39][N:16]2[CH2:15][CH2:14][C:9]3[NH:10][C:11]4[C:7]([C:8]=3[CH2:17]2)=[C:6]2[C:2]([CH3:1])=[CH:3][S:4][C:5]2=[CH:13][CH:12]=4)=[CH:34][CH:35]=1
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Reactant: Cc1csc2ccc3[nH]c4c(c3c12)CNCC4
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1csc2ccc3[nH]c4c(c3c12)CN(CCCC(c1ccc(F)cc1)c1ccc(F)cc1)CC4
Temperature: 80 °C

Procedure:
2.4 g of 1-methyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole are dissolved in 50 ml of dimethylformamide and 10 ml of hexamethylphosphoric acid triamide 4.5 g of 4,4-bis-(4-fluorophenyl)butyl iodide are added and the mixture is warmed to 80° C. under N2 for 5 hours. The solvent is then evaporated off; the residue is taken up in chloroform, the chloroform mixture is washed with water, dried and evaporated, the residue is chromatographed on Al2O3 with chloroform and the product is recrystallised from isopropanol. Melting point: 158° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C-:13]#[N:14].[Na+]>[Zn].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(C)=O)C>[F:10][C:9]([F:12])([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[N:14])=[CH:3][CH:4]=1
Reactant: FC(F)(F)Oc1ccc(Cl)cc1
Reactant: [C-]#N
Agent: [Na+]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCC(C)=O
Product: N#Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
Under an atmosphere of nitrogen, a mixture of 6.5 g of bis-triphenylphosphine-nickel dichloride, 5 g of triphenylphosphine and 120 ml of MEK was stirred at room temperature for 10 minutes. 1.9 g of activated zinc powder were then added, and the reaction mixture was stirred at 70° C. for 30 minutes. Following this, the mixture was allowed to cool to 25° C., and 93.25 g of 1-chloro-4-trifluoromethoxybenzene were added dropwise. The mixture was stirred for 10 minutes, 24 g of sodium cyanide were added, and the reaction mixture was stirred at from 65 to 70° C. for 20 h. The conversion was then approximately 75% (GC). After cooling to room temperature, the mixture was filtered, the solid filter residue was washed 2× with 50 ml of MEK and the combined organic phases were concentrated under reduced pressure. Vacuum distillation gave 58.5 g (66% of theory) of 4-trifluoromethoxybenzonitrile as a colourless liquid (boiling point at 120 mbar: 80° C.). 2.6% of coupling products had formed.
Reaction SMILES: CS(O[CH2:6][C:7]1([CH3:28])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([CH3:27])[C:11]([CH3:26])=[C:12]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH3:17])[O:8]1)(=O)=O.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:19]([O:18][C:12]1[C:13]([CH3:17])=[C:14]2[C:9](=[C:10]([CH3:27])[C:11]=1[CH3:26])[O:8][C:7]([CH2:6][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:28])[CH2:16][CH2:15]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(COS(C)(=O)=O)O2
Reactant: C1CNCCN1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CN1CCNCC1)O2
Yield: 47.8 %

Procedure:
The title compound (7 g, 47%) was prepared as a syrupy liquid from (2RS)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ylmethyl methanesulphonate (15 g) and piperazine (19 g) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([O:13][CH3:14])=[C:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=O.ClC(Cl)(O[C:19](=[O:25])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:34]1([C@@H:40]([NH2:42])[CH3:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:14][O:13][C:4]1[S:3][C:2]2[NH:1][C:19](=[O:25])[N:42]([C@H:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH3:41])[C:7](=[O:9])[C:6]=2[C:5]=1[CH3:12]
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)c1c(N)sc(OC)c1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1sc2[nH]c(=O)n([C@@H](C)c3ccccc3)c(=O)c2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
To a solution (30 mL) of ethyl 2-amino-5-methoxy-4-methylthiophene-3-carboxylate (1.0 g) in methylene chloride were added triphosgene (1.8 g) and triethylamine (3.0 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added (1S)-1-phenylethanamine (1.7 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (15 mL), sodium methoxide (1.0 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.43 g, 29%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH:5]([C:8]([F:11])([F:10])[F:9])[CH2:4][NH:3]1.CC(N(C)C)=O.CCN(C(C)C)C(C)C.Br[CH2:28][C:29]1[CH:38]=[C:37]2[C:32]([C:33]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)=[CH:34][C:35]([C:39]#[N:40])=[N:36]2)=[CH:31][CH:30]=1>CCOC(C)=O>[F:47][C:44]1[CH:45]=[CH:46][C:41]([C:33]2[C:32]3[C:37](=[CH:38][C:29]([CH2:28][N:3]4[CH2:4][CH:5]([C:8]([F:11])([F:9])[F:10])[NH:6][CH2:7][C@@H:2]4[CH3:1])=[CH:30][CH:31]=3)[N:36]=[C:35]([C:39]#[N:40])[CH:34]=2)=[CH:42][CH:43]=1
Reactant: C[C@H]1CNC(C(F)(F)F)CN1
Reactant: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@H]1CNC(C(F)(F)F)CN1Cc1ccc2c(-c3ccc(F)cc3)cc(C#N)nc2c1
Temperature: 50 °C

Procedure:
To the solution of (2S)-2-methyl-5-(trifluoromethyl)piperazine (4-20) was added DMA (1.76 ml), DIEA (0.614 ml, 3.52 mmol) followed by 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (300 mg, 0.879 mmol). The reaction was heated to 50° C. for 4 hours. The reaction was diluted with EtOAc and then washed with H2O, brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel eluting with hexanes to EtOAc to provide 4-(4-fluorophenyl)-7-(((2S)-2-methyl-5-(trifluoromethyl)piperazin-1-yl)methyl)quinoline-2-carbonitrile as a colorless solid. LRMS m/z (M+H)+ 429.2 found, 429.4 required.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].CN(C=O)C>CC#N.O>[OH:8][C:3]1[CH:4]=[CH:5][C:6]([N:7]2[CH2:16][CH2:17][CH2:18][C:19]2=[O:20])=[CH:1][CH:2]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCN1c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 19.3 %

Procedure:
To a solution of p-aminophenol (0.545 g, 5.00 mmol) in dry MeCN (5 mL) at 0° C. was added K2CO3 (1.38 g, 10.0 mmol), followed by dropwise addition of 4-chlorobutanoyl chloride (0.56 mL, 5.0 mmol). The mixture was stirred at rt for 40 min and then brought to reflux. Dry DMF (5 mL) was added after 90 min and heating was continued for an additional 2 h. The mixture was cooled, poured into water, and extracted with EtOAc (×8). Combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.171 g of the title compound as a colorless solid: MS (APCI) m/z 177 (M+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:46][C:47]1[O:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1.N1C=CC=CC=1>C(Cl)Cl.O>[O:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[NH:46][C:35](=[O:37])[CH:34]([C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)[CH2:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nc2ccccc2o1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1nc2ccccc2o1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 75.8 %

Procedure:
A solution of triphenylphosphine (274 mg, 1.04 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (211 mg, 1.18 mmol). The resulting brownish-purple mixture was stirred at 0° C. for 5 min until the reaction mixture became homogeneous. The reaction mixture was then treated with 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 1, 200 mg, 0.70 mmol). The reaction mixture was stirred at 0° C. for 20 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminobenzoxazole (140 mg, 1.04 mmol) and pyridine (0.17 mL, 2.09 mmol), and the reaction mixture was allowed to stir at 25° C. for 20 h. The resulting reaction mixture was diluted with water (15 mL) and then extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 80/20 hexanes/ethyl acetate) afforded N-benzoxazol-2-yl-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (214 mg, 76%) as a light yellow foam: EI-HRMS m/e calcd for C21H20Cl2N2O2 (M+) 402.0902, found 402.0908.
Reaction SMILES: Cl.[C:2](=[NH:7])(OCC)[CH3:3].CCN(CC)CC.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:24]([C:32]([NH:34][NH2:35])=[O:33])=[CH:25][N:26]([CH3:31])[C:27](=[O:30])[C:28]=2[F:29])=[C:18]([F:36])[CH:17]=1.Cl>CN(C=O)C.C1COCC1>[NH:7]=[C:2]([NH:35][NH:34][C:32]([C:24]1[C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][C:18]=2[F:36])=[C:28]([F:29])[C:27](=[O:30])[N:26]([CH3:31])[CH:25]=1)=[O:33])[CH3:3]
Reactant: Cn1cc(C(=O)NN)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reactant: CCOC(C)=N
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=N)NNC(=O)c1cn(C)c(=O)c(F)c1Nc1ccc(Br)cc1F
Reaction time: 1.5 h

Procedure:
Ethyl acetimidate HCl salt (40 mg, 0.32 mmol) and Et3N (0.049 mL, 0.35 mmol) were added to a stirred suspension of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydrazide (0.10 g, 0.27 mmol) in 2:1 THF:DMF (3 mL) at 0° C. After 1.5 hours at 0° C. and 17 hours at room temperature, the reaction mixture was poured onto water, neutralized with dilute aqueous HCl and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. Trituration with methylene chloride gave the desired product.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([NH:23][NH2:24])=O.[Cl-].ClC1N(C)C=C[N+]=1C.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[O:15][C:21]([C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)=[N:23][N:24]=1
Reactant: NNC(=O)c1cccs1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2cccs2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.8 %

Procedure:
To a suspension of 5-methyl-3-phenylisoxazole-4-carboxylic acid (357 mg, 1.76 mmol) in dichloromethane (7 mL) was added thiophene-2-carboxylic acid hydrazide (250 mg, 1.76 mmol) and 2-chloro-1,3-dimethylimidazolium chloride (654 mg, 3.87 mmol). After the solution was stirred for 15 min at ambient temperature triethylamine (1.2 mL, 8.79 mmol) was added at 0° C. and the light brown suspension was stirred for 18 h while warming to ambient temperature. It was washed with water (25 mL) and aqueous sodium carbonate (half saturated, 25 mL). The aqueous layers were extracted with dichloromethane and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 70:30) afforded the title compound (233 mg, 43%) as a light yellow semisolid. MS: m/e=310.3 [M+H]+.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CC(C)=O.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Mg+2].C([O-])(=O)C>C(O)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Mg+2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-acetoacetyl-L-aspartic acid, 21.7 parts, was slurried with 20 parts by volume of dry acetone and 10.7 parts acetic anhydride. Anhydrous magnesium acetate, 0.20 parts, was dissolved in 2.0 volumes glacial acetic acid and the solution was added to the stirred slurry of N-acetoacetyl-L-aspartic acid. The mixture was stirred for 3 hours at room temperature and the solid was then collected on a filter under nitrogen. The solid was rinsed with dry ethyl acetate and then dried at 0.1 mm to afford 17.3 parts of N-acetoacetyl-L-aspartic anhydride.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].C([N-]C(C)C)(C)C.[Li+].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH2:27]Br)[CH:20]=1.CO>C1COCC1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH2:27][CH2:1][C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]([OH:9])=[O:8])[CH:20]=1
Reactant: COc1ccc(Br)cc1CBr
Reactant: Cc1sccc1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Br)cc1CCc1sccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
To a solution of 2-methyl-thiophene-3-carboxylic acid (8.01 g, 56.0 mmol, 1.0 equiv) in THF (56 mL) at −78° C. was added a solution of lithium diisopropylamide (LDA; 2M, 56 mL, 112.0 mmol, 2 equiv). The orange solution was allowed to stir for 1 hr and then a solution of 4-bromo-2-bromomethyl-1-methoxybenzene (17 g, 73 mmol, 1.3 equiv) in THF (50 mL) was added dropwise via cannula. The solution was allowed to stir at −78° C. for one hour and then warmed to room temperature. The reaction was quenched by the addition of water and ethyl acetate. The phases were separated and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give a yellow oil. Addition of methanol caused precipitation of a white solid, which was filtered and dried to give 2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-thiophene-3-carboxylic acid (5.3 g, 15.5 mmol, 27%). 1H NMR (300 MHz, d6-DMSO) δ 12.59 (s, 1H), 7.31 (dd, J=8.7, 5.7 Hz, 1H), 7.26 (dd, J=6.6, 5.4 Hz, 2H), 7.21 (d, J=2.4 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 3.71 (s, 3H), 3.27-3.35 (m, 2H), and 2.79-2.88 (m, 2H). LCMS ES− 339 (M−1), 341 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.N#N.[H-].[Na+].I[CH2:19][CH3:20]>CN(C)C=O.CCOC(C)=O>[CH2:19]([CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH3:20]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: CCI
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C

Procedure:
A solution of 6-methoxy-3,4-dihydro-1(2H)-naphthalenone (5.0 g, 28 mmol) in anhydrous N,N-dimethylformamide (DMF, 60 mL) was purged with N2, cooled in an ice bath, stirred, and treated with NaH (1.2 g of a 60% dispersion in mineral oil, 30 mmol). The cooling bath was removed and the mixture was stirred at room temperature for 10 minutes. The mixture was re-cooled in an ice bath, treated with iodoethane (3.35 mL, 42 mmol), and then stirred under a N2 atmosphere while gradually warming to room temperature. After stirring for 2.9 days, the mixture was diluted with EtOAc (250 mL) and washed with water (200 mL), and the aqueous phase was back-extracted with EtOAc (100 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40M (4×15 cm) silica gel column, eluting successively with 1000 mL portions of 0.2%, 1%, 2%, and 5% EtOAc in hexane. The product-containing fractions were combined and evaporated under vacuum to afford 2-ethyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone as an oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20]([O:23][C@@H:24]1[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:35]([O:41][C:42](=[O:44])[CH3:43])[C@@H:34]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[O:33][C@@H:25]1OC(=N)C(Cl)(Cl)Cl)(=[O:22])[CH3:21]>ClCCl>[C:20]([O:23][C@@H:24]1[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:35]([O:41][C:42](=[O:44])[CH3:43])[C@@H:34]([CH2:45][O:46][C:47](=[O:49])[CH3:48])[O:33][C@H:25]1[O:1][C:2]1[C:7]2[C:8]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Cc1ccc(CCc2coc3cccc(O)c23)cc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(C)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of 4-hydroxy-3-[2-(4-methylphenyl)ethyl]-benzofuran (0.13 g) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (0.27 g) in dichloromethane (5 mL) was added boron trifluoride-diethyl ether complex (0.069 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-3/2) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-[2-(4-methylphenyl)ethyl]benzofuran (0.25 g). This material was dissolved in methanol (4 mL). To the solution was added sodium methoxide (28% methanol solution, 0.082 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.14 g).