Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:10][N:9]=[C:8]([CH2:11][OH:12])[CH:7]=2)=[CH:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>ClCCl>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:10][N:9]=[C:8]([CH:11]=[O:12])[CH:7]=2)=[CH:2]1
Reactant: OCc1cc(-c2ccsc2)on1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1cc(-c2ccsc2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
To a solution of 30 mg of (5-(3-thienyl)isoxazol-3-yl)methanol in 5 mL of dichloromethane, 84 mg of Dess-Martin periodinane was added under cooling with ice, and the mixture was stirred at room temperature for 1 hour 30 minutes. Thereto was further added 40 mg of Dess-Martin periodinane, and the mixture was stirred at room temperature for 1 hour 30 minutes. Diethyl ether was added to the reaction mixture, the insoluble substance was filtered off, and the solvent was distilled off under reduced pressure to obtain 30 mg of 5-(3-thienyl)isoxazole-3-carbaldehyde as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C@@H:9]([OH:13])[CH2:8][CH2:7][CH2:6]2>C(Cl)Cl.CC#N.O=[Mn]=O>[OH:13][C@H:9]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:4]=[C:3]([CH:2]=[O:1])[CH:12]=[CH:11][C:10]1=2
Reactant: OCc1ccc2c(c1)CCC[C@@H]2O
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CC#N
Product: O=Cc1ccc2c(c1)CCC[C@@H]2O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (S)-6-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-ol (2.5 g, 14 mmol) in CH2Cl2/MeCN (1:1, 80 mL) was added MnO2 (6.1 g, 70. mmol). The reaction mixture was stirred for 16 h at RT. The solid was filtered off, and the filtrate was concentrated to afford the title compound. MS (m/z): 277.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH2:18][OH:19])=[C:7]([CH3:17])[CH:8]=2)[N:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:9]2[C:4](=[CH:5][C:6]([CH:18]=[O:19])=[C:7]([CH3:17])[CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)c2cc(C)c(CO)cc2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cc(N2CCCC2)c2cc(C)c(C=O)cc2n1
Yield: 82 %

Procedure:
A mixture of (2,6-dimethyl-4-pyrrolidin-1-yl-quinolin-7-yl)-methanol (example 59, 140 mg, 0.585 mmol) and manganese dioxide (509 mg, 5.85 mmol) was stirred in dichloromethane (3 mL) at r.t. for 16 h, then insoluble material was removed by filtration through a dicalite pad, and the filtrate was evaporated to yield the title compound (122 mg, 82%). Yellow solid, ISP-MS: m/e=255.2 ([M+H]+).
Reaction SMILES: [CH2:1]([O:15][CH2:16][CH:17]([CH2:19][OH:20])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>CN(C=O)C>[CH2:1]([O:15][CH2:16][CH:17]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCCCCCCCCOCC(O)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
A mixture of rac-1-O-tetradecylglycerol (57.7 g, 0.2 mol), tert-butyldimethylsilyl chloride (33.2 g, 0.22 mol), imidazole (30.0 g, 0.44 mol), and DMF (300 ml) was stirred at room temperature for 1 day. The solvent was evaporated to dryness in vacuo at 70° C. and the residue was partioned between H2O and diethyl ether (500 ml each). The organic layer was dried over Na2SO4 and then evaporated to dryness. The oily residue was further evaporated by using a high vacuum at 70° C. The crude product, essentially homogeneous by TLC, was used for the next step without further purification (100% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=O)[CH2:6][CH3:7].[CH3:10][NH2:11]>>[CH3:1][O:2][C:3](=[O:9])[CH:4]=[C:5]([NH:11][CH3:10])[CH2:6][CH3:7]
Reactant: CCC(=O)CC(=O)OC
Reactant: CN
Product: CCC(=CC(=O)OC)NC

Procedure:
Prepared according to the procedure described in Example 1, Step 1, using 3-oxo-pentanoic acid methyl ester and methylamine.
Reaction SMILES: [C:1]([C:3]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)([CH2:10][CH3:11])[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:2]>O=[Pt]=O.C(O)C>[C:1]([C:3]([C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)([CH2:10][CH3:11])[CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: CCC(C#N)(CCC(=O)OC)c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCC(C#N)(CCC(=O)OC)c1ccc(N)cc1
Yield: 101 %

Procedure:
A 3-necked round-bottomed flask was charged with methyl 4-cyano-4-(4-nitrophenyl)hexanoate (20.0 g), 90% ethanol (1000 ml) and PtO2 (1.0 g). The vessel was then evacuated and charged with nitrogen. The mixture was stirred vigorously and subjected to H2 at atmospheric pressure supplied via a balloon. The catalyst was removed by filtration through celite and the solvent removed under reduced pressure to give methyl 4-cyano-4-(4-aminophenyl)-hexanoate (18 g, 100%) as a viscous, brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N:19]([CH3:21])[CH3:20])[C:15]=1[N:16]([CH3:18])[CH3:17])[CH:6](O)CS(C)(=O)=O.C[O-].[Na+].[NH:26]([CH2:33][CH2:34][C:35]#[N:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O>[NH:26]([CH:33]=[C:34]([CH2:6][C:5]1[CH:13]=[C:14]([N:19]([CH3:20])[CH3:21])[C:15]([N:16]([CH3:18])[CH3:17])=[C:3]([N:2]([CH3:1])[CH3:22])[CH:4]=1)[C:35]#[N:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N#CCCNc1ccccc1
Reactant: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C)c1N(C)C

Procedure:
A mixture of 8.96 g. of 3,4,5-tris(dimethylamino)-α-[(methylsulfonyl)methyl]benzyl alcohol, 2.56 g. of sodium methylate and 6.6 g. of β-anilinopropionitrile in 70 ml. of dimethylsulfoxide was stirred at room temperature under nitrogen for 50 minutes. The mixture was poured into 500 ml. of ice water, the separated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethanol, there was obtained α-(anilinomethylene)-3,4,5-tris(dimethylamino)hydrocinnamonitrile having a melting point of 179°-181° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:7]=1)[CH3:2].[CH3:24][C@@H:25]1[C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[C@H:25]([CH3:24])[C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:7]=1)[CH3:2]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: CCOC(=O)Cc1cc(F)cc(Oc2ccc(Br)cc2CBr)c1
Product: CCOC(=O)Cc1cc(F)cc(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-5-fluoro-phenyl]-acetic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: C(N(CC)CC)C.[CH:8](Br)=[CH2:9].[CH3:11][CH:12]1[CH2:16][CH2:15][C:14](=[CH:17][N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:26].CCCC[O-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2N(C)C)CCCCC1.C1(C)C=CC=CC=1>[CH3:11][C:12]1([CH:8]=[CH2:9])[CH2:16][CH2:15][C:14](=[CH:17][N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:26]
Reactant: CC1CCC(=CN(C)c2ccccc2)C1=O
Reactant: C=CBr
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[O-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CC1(C)CCC(=CN(C)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 93.6 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was purged with argon. The septum was removed, and the tube was charged with palladium acetate (2.2 mg, 0.01 mmol, 2 mol %) and (+)-2-(dicyclohexylphosphino)-2′-(dimethylamino)-1,1′-binaphthyl (10.9 mg, 0.011 mmol 2.2 mol %). The tube was capped with the septum, purged with argon, and toluene (2 mL) and triethylamine (5 mg, 0.05 mmol) were added through the septum. The mixture was stirred at room temperature for 3 min, then vinyl bromide (1.0 mL 1.0 mmol) was added through septum. The septum was removed and 2-methyl-5-(N-methyl-anilinomethylene)cyclopentanone (108 mg, 0.5 mmol) and sodium 1-butoxide (96 mg, 1.0 mmol) were added. The tube was capped with the septum and purged with argon. Additional toluene (4 mL) was added and the mixture was stirred at room temperature for 2 h. The mixture was quenched with saturated aqueous ammonium chloride (5 mL), diluted with ether (20 mL) and poured into a separatory funnel. The layers were separated and the aqueous layer was extracted with ether (20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 113 mg (94%) of the title compound. The ee was determined to be 85% by chiral HPLC analysis.
Reaction SMILES: [CH2:1]([N:8](C)[C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C1C=CC=CC=1.[H][H]>[Pd].CO>[C:19]([O:18][C:16]([NH:15][C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]1[NH:8][CH3:1])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(Cc1ccccc1)[C@@H]1CCCC[C@@H]1NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN[C@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Yield: 92.3 %

Procedure:
(±)-cis-N1-Benzyl-N2-tert-butoxycarbonyl-N1-methyl-1,2-cyclohexanediamine (1.92 g) was added to methanol (50 ml), 10% palladium on carbon (containing 50% of water, 900 mg) was added, and the mixture was stirred for 20 hours in a hydrogen atmosphere. After separating the catalyst by filtration, the filtrate was concentrated to obtain the title compound (1.27 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:5][CH2:4][CH2:3]1.N1C=CN=C1.[CH:31]([Si:34](Cl)([CH:38]([CH3:40])[CH3:39])[CH:35]([CH3:37])[CH3:36])([CH3:33])[CH3:32]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:22]=[C:21]([O:23][Si:34]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:31]([CH3:33])[CH3:32])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(-c2cc(O)ccc2F)c(C2=CCCC2(C)C)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2F)c(C2=CCCC2(C)C)c1
Reaction time: 4 h
Yield: 80.2 %

Procedure:
To 66.14B (77.0 mg, 226 μmol) in DMF (10 mL) was added imidazole (30.8 mg, 452 μmol) and then triisopropylsilyl chloride (58.1 μL, 271 μmol). The resulting mixture was then stirred for 4 hours. The reaction was diluted with EtOAc and washed with 1N HCl, water, and brine. The organic phase was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (0 to 10% EtOAc/Hexanes) to provide 66.14C (90.0 mg, 80.1% yield).
Reaction SMILES: O=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:12]=1[C:13]#[N:14].Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:4]([C:3]1[C:2]([CH3:9])=[N:10][C:11]2[C:12]([C:13]=1[NH2:14])=[C:15]([O:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH:16]=[CH:17][CH:18]=2)=[O:5])[CH3:8]
Reactant: N#Cc1c(N)cccc1OC1CCCCC1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCCC3)c2c1N
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 85.1 %

Procedure:
A solution of ethyl 3-oxobutanoate (29.9 g, 0.230 mol) in anhydrous toluene (200 mL) was added to a solution of 2-amino-6-(cyclohexyloxy)benzonitrile (Example 36b, 49.8 g, 0.230 mol) in anhydrous toluene (1000 mL) under nitrogen in a 3 L round bottom flask sitting in an oil bath at room temperature. SnCl4 (53.9 mL, 0.461 mol) was added slowly over a period of approximately 1 h. The oil bath temperature was then raised to 110° C. and the reaction mixture was stirred at that temperature for 2.5 h. It was then cooled down to 5° C., still under nitrogen, and the toluene was decanted away from the immiscible viscous oil at the bottom of the flask. The viscous oil was further concentrated under vacuum at 60° C., re-dissolved in boiling ethyl acetate (1 L), and transferred to a 4 liter Erlenmeyer flask. The solution was diluted with more EtOAc (1.5 L), cooled down to −15° C., and neutralized with NaOH (3 N, 500 mL). The organic layer was separated, and the aqueous emulsion was extracted once more with ethyl acetate. The insoluble tin salts were filtered out from the aqueous layer, then both the salts and aqueous filtrate were washed once more with ethyl acetate. The combined organic layers were dried over MgSO4, concentrated, and passed through a silica column using 0% to 60% ethyl acetate in hexanes. The product was purified by recrystallization from EtOAc to give the title compound as an off-white solid (64.3 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 1.28-1.34 (m, 1H), 1.32 (t, 3H), 1.37-1.45 (m, 2H), 1.51-1.63 (m, 3H), 1.67-1.71 (m, 2H), 1.99-2.03 (m, 2H), 2.54 (s, 3H), 4.28-4.33 (q, J=6.8 Hz, 2H), 4.64 (m, 1H), 6.95-6.97 (d, J=7.6 Hz, 1H), 7.19-7.21 (d, J=8.4 Hz, 1H), 7.65 (t, J=8.4 Hz, 1H), 8.15 (brs, 2H). MS 329 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][N:31]2C(OC(C)(C)C)=O)=[O:29])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][CH2:25][OH:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@@H:9]([NH:27][C:28]([C@@H:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][NH:31]2)=[O:29])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][CH2:25][OH:26])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2CCO)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2CCO)CC1)[C@@H]1Cc2ccccc2CN1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-[N-((1R)-1-[(4-chlorophenyl)methyl]-2-(4-[2-(hydroxyethyl)phenyl]-piperidyl]-2-oxoethyl)carbamoyl]-(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Step f) (323 mg, 0.5 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by reverse phase preparative HPLC (Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white solid (145 mg). MS (ESI, pos. ion) m/z: 546 (M+1); (ESI, neg. ion) m/z: 544 (M−1). Calc'd for C32H36ClN3O3: 545.24.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([CH2:13][SH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[C:31]3[C:26](=[C:27]([Cl:33])[CH:28]=[C:29]([Cl:32])[CH:30]=3)[CH2:25][N:24]([CH3:34])[CH2:23]2)=[CH:18][CH:17]=1>C1(C)C(C)=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:13]([S:14][C:16]1[CH:17]=[CH:18][C:19]([CH:22]2[C:31]3[C:26](=[C:27]([Cl:33])[CH:28]=[C:29]([Cl:32])[CH:30]=3)[CH2:25][N:24]([CH3:34])[CH2:23]2)=[CH:20][CH:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(Br)cc2)C1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1C
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(SCc3ccccc3)cc2)C1
Temperature: 0 °C
Yield: 33.6 %

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed K2CO3 (800 mg, 0.50 equiv) and xylene (50 mL). This was followed by the addition of phenylmethanethiol (1.75 g, 1.00 equiv) dropwise with stirring at 0° C. The resulting mixture was then allowed to warm to room temperature and stirred for 1 h. Into another 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-(4-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (4.8 g, 0.80 equiv), Xantphos (200 mg, 0.08 equiv) and Pd2(dba)3 (200 mg, 0.08 equiv) in xylene (30 mL). The mixture was stirred at room temperature for 20 min and transferred to the previously formed potassium thiolate. The dark solution was then purged with nitrogen and heated to 130° C. for 15 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The crude product was then purified by silica gel chromatography with ethyl acetate/petroleum ether (1:80-1:50) to afford 1.8 g (30%) of the title compound as yellow oil. MS (ES, m/z): 414 [M+H]+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:59])[CH2:7][N:8]([CH2:53][C:54]([O:56]CC)=[O:55])[C:9](=[O:52])[C:10]1[CH:15]=[C:14]([NH:16][C:17](=[O:33])[CH2:18][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][CH3:32])[CH:13]=[C:12]([NH:34][C:35](=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:11]=1)C>>[C:6]([CH2:7][N:8]([C:9](=[O:52])[C:10]1[CH:15]=[C:14]([NH:16][C:17](=[O:33])[CH2:18][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][CH3:32])[CH:13]=[C:12]([NH:34][C:35](=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH:11]=1)[CH2:53][C:54]([OH:56])=[O:55])([OH:59])=[O:5]
Reactant: CCCCCCCCCCCCCCCC(=O)Nc1cc(NC(=O)CCCCCCCCCCCCCCC)cc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCC(=O)Nc1cc(NC(=O)CCCCCCCCCCCCCCC)cc(C(=O)N(CC(=O)O)CC(=O)O)c1

Procedure:
Sodium hydroxide hydrolysis of N-(2-ethoxy-2-oxoethyl)-N-[3,5-bis(1-oxohexadecylamino)benzoyl]glycine ethyl ester as in Example 56 and recrystallization from methanol-water gave N-(carboxymethyl)-N-[3,5-bis(1-oxohexadecylamino)benzoyl]glycine, mp 129°-133°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:2]1.[CH3:27][NH:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:28]([CH3:27])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:23])=[CH:20][CH:19]=2)[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[CH:2]1
Reactant: O=C(O)c1ccc(NC(c2csc3ccccc23)C2CCCCC2)cc1
Reactant: CCOC(=O)CCNC
Product: CN(CCC(=O)O)C(=O)c1ccc(NC(c2csc3ccccc23)C2CCCCC2)cc1
Yield: 71.4 %

Procedure:
Using 4-{[1-benzothiophen-3-yl(cyclohexyl)methyl]amino}benzoic acid (250 mg) synthesized in Example A1(3) and ethyl 3-(methylamino)propanoate (108 mg) and in the same manner as in Example A1(4), the title object compound (220 mg, 71%) was obtained as a white solid.
Reaction SMILES: C(OCC)(=O)C.C[O:8][C:9](=[O:35])[C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[C:27]([CH2:28][CH2:29][CH3:30])=[CH:26][C:25]3[C:24]([CH3:32])([CH3:31])[CH2:23][CH2:22][C:21]([CH3:34])([CH3:33])[C:20]=3[CH:19]=2)=[O:17])=[CH:12][CH:11]=1>[OH-].[K+].CO>[CH2:28]([C:27]1[C:18]([C:16]([C:13]2[CH:12]=[CH:11][C:10]([C:9]([OH:35])=[O:8])=[CH:15][CH:14]=2)=[O:17])=[CH:19][C:20]2[C:21]([CH3:34])([CH3:33])[CH2:22][CH2:23][C:24]([CH3:31])([CH3:32])[C:25]=2[CH:26]=1)[CH2:29][CH3:30]
Reactant: CCCc1cc2c(cc1C(=O)c1ccc(C(=O)OC)cc1)C(C)(C)CCC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1cc2c(cc1C(=O)c1ccc(C(=O)O)cc1)C(C)(C)CCC2(C)C

Procedure:
3-n-Propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (prepared from Friedel-Crafts alkylation/cyclization of n-propylbenzene with 2,5-dichloro-2,5-dimethylhexane) was combined with monomethylterephthalate acid chloride in dichloromethane and treated portionwise at ambient temperature with aluminum chloride until the spontaneous reflux had subsided and the solution become dark red/brown in color. After stirring at room temperature for 10-15 min, the reaction was poured into ice water and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to give a yellow oil. The crude product was crystallized (CH2Cl2/hexanes) to give 4-[(3-n-propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid methyl ester as white crystals (95%): TLC (20% ethyl acetate: 80% hexanes) Rf 0.7; mp 112-114° C.; 1H-NMR (400 MHz, CDCl3) δ8.19 (½ABq, J=8.0 Hz, 2H, ArH); 7.89 (½ABq, J=8.0 Hz, 2H, ArH), 7.22 (s, 1H, ArH), 7.20 (s, 1H, ArH), 3.95 (s, 3H, OCH3), 2.64 (t, J=8.0 Hz, 2H, CH2), 1.69 (s, 4H, 2CH2), 1.55 (m, 2H, CH2), 1.31 (s, 6H, 2CH3), 1.20 (s, 6H, 2CH3), 0.89 (t, J=7.5 Hz, 3H, CH3), Anal. (C23H32O3) C, H. The ester was hydrolyzed in excess KOH/MeOH at ambient temperature for 24 h. The methanol was removed in vacuo. The residue was taken-up in water and the aqueous layer was adjusted to pH=4-5 with 1 M aqueous HCl. The aqueous solution was extracted 3 times with EtOAc; the organic layers were combined, and washed with water (2×) and brine. The organic solution was dried (Na2SO4), filtered, and concentrated to give 4-[(3-n-propyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid (101). Crystallization gave a white powder (93%): TLC (10% MeOH: 90% CHCl3) Rf 0.3; mp 252-254° C.; 1H-NMR (400 MHz, CDCl3) δ8.20 (½ABq, J=8.0 Hz, 2H, ArH), 7.90 (½Abq, J=8.0 Hz, 2H, ArH), 7.20 (s, 1H, ArH), 7.25 (s, 1H, ArH), 2.64 (t, J=8.0 Hz, 2H, CH2), 1.69 (s, 4H, 2CH2), 1.55 (m, 2H, CH2), 1.31 (s, 6H, 2CH3), 1.20 (s, 6H, 2CH3), 0.89 (t, J=7.5 Hz, 3H, CH3), Anal. (C25H30O3) C, H.
Reaction SMILES: [Cl:1][C:2]1[C:6](C(O)=O)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1>CN(C)C(=O)C.[Cu-]=O>[Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=C(O)c1cn(-c2cccnc2)nc1Cl
Agent: O=[Cu-]
Solvent: CC(=O)N(C)C
Product: Clc1ccn(-c2cccnc2)n1
Temperature: 125 °C
Reaction time: 6 h

Procedure:
To a mixture of 3-chloro-1-(pyridin-3-yl)-1H-pyrazole-4-carboxylic acid (0.223 g, 1.0 mmol) in N,N-dimethylacetamide (3.0 mL) was added copper(I) oxide (0.022 g, 10 wt %). The mixture was heated to 125° C. and stirred for 6 hours. The brown mixture was filtered and washed with N,N-dimethylacetamide (1.0 mL) and acetonitrile (2×2 mL). The light yellow filtrate was analyzed by LC using di-n-propyl phthalate as internal standard (0.124 g, 69% in-pot yield); mp 66-68° C.; 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J=27 Hz, 1H), 8.57 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (ddd, J=8.3, 2.7, 1.5 Hz, 1H), 7.91 (d, J=2.6 Hz, 1H), 7.47-7.34 (m, 1H), 6.45 (d, J=2.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 148.01, 142.72, 140.12, 135.99, 128.64, 126.41, 124.01, 108.0; ESIMS m/z 180 ([M+H]+).