Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CC(O)C.[C:7]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([OH:44])=[C:23]([CH:43]=2)[C:24]([NH:26][C:27]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][C:28]=2[C:29]([O:31]C)=[O:30])=[O:25])[CH2:12][CH2:11]1)(=[O:9])[CH3:8].[ClH:45]>O>[ClH:45].[C:7]([N:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([OH:44])=[C:23]([CH:43]=2)[C:24]([NH:26][C:27]2[CH:36]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][C:28]=2[C:29]([OH:31])=[O:30])=[O:25])[CH2:14][CH2:15]1)(=[O:9])[CH3:8]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(C(C)=O)CC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)N1CCN(CCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.24 mL) was added to a 2-propanol (1.5 mL) suspension of the obtained methyl 2-(5-(2-(4-acetylpiperazin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoate (0.083 g), followed by stirring at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and water was added thereto. After adjusting the pH to 6.5 with 1.0 mol/L hydrochloric acid, the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the solid substance was collected by filtration. Ethyl acetate (2.0 mL) and a 4.0 mol/L hydrogen chloride-dioxane solution (0.10 mL) were added to the obtained solid substance, followed by stirring at room temperature for 3 hours and 30 minutes. The solid substance was collected from the reaction mixture by filtration to obtain 0.038 g of 2-(5-(2-(4-acetylpiperazin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoic acid hydrochloride as a light yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][CH:7]=[CH:8][C:9]=1[C:10]([O:12]C)=O)=O.CCO.O.[NH2:18][NH2:19]>O>[O:6]1[C:5]2[C:3](=[O:2])[NH:18][NH:19][C:10](=[O:12])[C:9]=2[CH:8]=[CH:7]1
Reactant: NN
Reactant: COC(=O)c1ccoc1C(=O)OC
Solvent: O
Solvent: CCO
Product: O=c1[nH][nH]c(=O)c2occc12

Procedure:
Furan-2,3-dicarboxylic acid dimethyl ester (1.6 g, 8.69 mmol) is added to EtOH (10 mL) and hydrazine hydrate (1.46 mL, 55% in water). Heat the reaction to reflux for 5-6 h. Cool and concentrate in vacuo to form a slurry. Dilute the material with additional H2O and filter the precipitate. Wash with additional H2O. Transfer material from filter to a round bottom flask and add HCl (7.2 mL, 2N in H2O). Heat reaction mixture to reflux for 4 h. Cool and filter the precipitate washing with H2O, to yield the title compound without further purification (930 mg, 70%)
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[F:5][C:6]1[CH:7]=[C:8](I)[CH:9]=[CH:10][CH:11]=1>[Cu](I)I.C(NCC)C>[F:5][C:6]1[CH:11]=[C:10]([C:3]#[C:2][CH2:1][OH:4])[CH:9]=[CH:8][CH:7]=1
Reactant: C#CCO
Reactant: Fc1cccc(I)c1
Agent: I[Cu]I
Solvent: CCNCC
Product: OCC#Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.5 %

Procedure:
A mixture of propargyl alcohol (0.200 g, 5.4 mmol), 3-fluoro iodobenzene (0.63 ml, 5.4 mmol), copper iodide (0.103 g, 0.54 mol), dichlorobis (triphenylphosphine) palladium (II) (0.190 g, 0.3 mmol), diethylamine (10 ml) was degassed for 10 min. and stirred for 20 hrs at 25-25° C. Excess of diethyl amine was distilled off under vacuum. The residue was diluted with water (10 ml) and extracted with ethyl acetate. The organic layer was washed with brine solution and dried over Na2SO4. The solvent was evaporated and the crude product was purified by column chromatography (10% Ethyl acetate in hexane) to obtain pure 3-(3-fluoro-phenyl)-prop-2-yn-1-ol (0.750 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Yield: 71.8 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (compound 42.1, 9.00 g, 28.9 mmol) in pyridine (50 mL). With stirring, phosphoroyl trichloride (7.93 mL, 84.8 mmol) was added drop-wise. The resulting mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL) and carefully quenched by slow addition of aqueous sodium bicarbonate. The layers were separated and the organic layer was washed with aqueous sodium bicarbonate (2×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:100 to 1:10) to yield the title compound as a colorless oil (6.1 g, 72%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C@:11]1([C:31]2([OH:35])[CH2:34][CH2:33][CH2:32]2)[CH2:15][C@H:14]([N:16]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[C@@H:17]2[C@H:22]([O:23][CH3:24])[CH2:21][O:20][CH2:19][CH2:18]2)[CH:13]=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>CN(C1C=CN=CC=1)C.ClCCl>[C:45]([O:35][C:31]1([C@@:11]2([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:15][C@H:14]([N:16]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[C@@H:17]3[C@H:22]([O:23][CH3:24])[CH2:21][O:20][CH2:19][CH2:18]3)[CH:13]=[CH:12]2)[CH2:32][CH2:33][CH2:34]1)(=[O:47])[CH3:46]
Reactant: CC(=O)Cl
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(O)CCC2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(OC(C)=O)CCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
To a stirred solution of 3.58 g (7.2 mmol) of 1,5-anhydro-3-{[(1S,4R)-4-[(benzyloxy)carbonyl]-4-(1-hydroxycyclobutyl)cyclopent-2-en-1-yl](trifluoroacetyl)amino}-2,3-dideoxy-4-O-methyl-D-erythro-pentitol, 1.6 mL (9.2 mmol) of diisopropylethylamine, and 100 mg (0.82 mmol) of DMAP in 10 mL of dichloromethane was added dropwise 5.1 mL (72 mmol) of acetyl chloride. The solution was stirred at ambient temperature for 18 h, then cooled in ice and quenched with aqueous NaHCO3. The aqueous phase was extracted with additional dichloromethane, and the combined organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 8-10% ethyl acetate in dichloromethane provided 2.63 g (68%) of the title compound as a viscous yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35-1.48 (m, 1H) 1.54-1.61 (m, 1H) 1.82-1.94 (m, 1H) 1.88 (s, 3) 2.17-2.26 (m, 1H) 2.34 (dd, J=14.7, 9.9 Hz, 1H) 2.43-2.64 (m, 5H) 3.32 (d, J=12.6 Hz, 1H) 3.37-3.43 (m, 1H) 3.43 (s, 3H) 3.46-3.55 (m, 1H) 3.84-3.94 (m, 1H) 4.09-4.15 (m, 1H) 4.19 (d, J=13.0 Hz, 1H) 4.98-5.05 (m, 1H) 5.08 (d, J=12.3 Hz, 1H) 5.23 (d, J=12.3 Hz, 1H) 5.75 (dd, J=5.8, 2.0 Hz, 1H) 6.16 (dd, J=5.8, 2.4 Hz, 1H) 7.28-7.43 (m, 5H). TLC Rf 0.39 (10% ethyl acetate-dichloromethane). LC-MS ES+ 540.2.
Reaction SMILES: [NH:1]1[C:31](=[O:32])[C@H:18]([CH2:19][CH2:20][C:21](=[O:30])[O:22]CC2C=CC=CC=2)[NH:17][C:15](=[O:16])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C(O)C(F)(F)F.[Pd]>[NH:1]1[C:31](=[O:32])[C@H:18]([CH2:19][CH2:20][C:21](=[O:22])[OH:30])[NH:17][C:15](=[O:16])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H]1NC(=O)[C@H](CCC(=O)OCc2ccccc2)NC1=O
Agent: [Pd]
Solvent: OCC(F)(F)F
Product: CC(C)(C)OC(=O)NCCCC[C@@H]1NC(=O)[C@H](CCC(=O)O)NC1=O
Reaction time: 48 h

Procedure:
Cyclo-L-Lys(Boc)-L-Glu(OBzl) (22.2 g, 0.05 mol) was dissolved in 200 ml of trifluorethanol and 1.5 g of palladium black was added. Hydrogen was bubbled through the suspension with stirring for 48 hours. The reaction was monitored by TLC. After the reaction was complete, the catalyst was filtered off and the solvent was evaporated in vacuum. The residual peptide was dissolved in 200 ml of distilled water and the impurities were extracted with 3×100 ml of EtOAc. The water phase was combined and evaporated in vacuum. The precipitate was washed with ether and hexane and dried in air. The yield was 16.7 g (90%). Rf=0.4 (CHCl3:EtOAc:MeOH:32% AcOH=6:3:1:0.1); HPLC data: retention time 12.7 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][CH:12]2[CH2:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH2:13]2)[CH:10]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[N:14]1[C:15](=[O:17])[CH2:16][CH:12]([CH2:11][N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH2:13]1
Reactant: CCOC(=O)c1cnn(CC2CC(=O)N(c3ccc(F)cc3F)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn(CC2CC(=O)N(c3ccc(F)cc3F)C2)c1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.222 g, 0.62 mmol) was dissolved in a mixture of solvents Methanol:water (3:1, 5 ml) and KOH (0.07 g, 125 mmol) was added to the reaction mixture and then stirred at 50-55° C. for 3 hours. Solvents were removed and the residue was diluted with water (3 ml) and washed with DCM (3×10 ml) and acidified with dil. HCl. It was extracted with ethyl acetate (3×15 ml), organic layers were mixed and washed with brine (20 ml), dried over Na2SO4 and evaporated to dryness to obtain 1-[1-(2,4-Difluoro-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazole-4-carboxylic acid (0.18 g, 90%) as a brownish sticky mass.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH:6]1[CH2:9][NH:8][CH2:7]1.C(N(CC)CC)C.Cl[C:21]1[N:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH:6]1[CH2:9][N:8]([C:21]2[N:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])[CH2:7]1
Reactant: Fc1cccc(OC2CNC2)c1
Reactant: O=C(O)c1cc(C(F)(F)F)cnc1Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2cccc(F)c2)C1

Procedure:
To a mixture of 3-(3-fluorophenoxy)azetidine) (D50) (106.73 mg, 0.638 mmol) and triethylamine (0.11 ml, 0.798 mmol) in methanol (3 ml), 2-Chloro-5-(trifluoromethyl)nicotinic acid (120 mg, 0.532 mmol) was added and the mixture was heated 10 min (2 cycles of 5 min each) under microwave irradiation at 150° C. After solvent evaporation the residue was purified by SPE-Si cartridge (25 g) eluting with a mixture dichloromethane/methanol from 100/0 to 50/50. Collected fraction after solvent evaporation afforded the title compound (D121) (83 mg)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@@H:18]([CH2:34][CH2:35][CH3:36])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31]CC)=[O:30])=[CH:24][CH:23]=2)=[S:20])(=[O:16])=[O:15])=[CH:10][CH:9]=1>O.CO>[C:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19](=[S:20])[C@@H:18]([NH:17][S:14]([C:11]2[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=2)(=[O:16])=[O:15])[CH2:34][CH2:35][CH3:36])=[CH:23][CH:24]=1)([OH:31])=[O:30]
Reactant: CCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCC[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=S)Nc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
A solution of K2CO3 (3.2 g) in water (40 ml) was added to a solution of (S)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-methylthiobutanamide (3.75 g) in methanol (80 ml), and the whole was stirred at room temperature overnight under argon. The reaction mixture was concentrated under reduced pressure. It was repeated 3 times in order to remove methanol completely that a small amount of purified water was added to the residue, and then the product was concentrated under reduced pressure. The residue was dissolved in purified water and washed with ethyl acetate. The aqueous layer was acidified with 1N HCl, and then extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution, and dried over Na2SO4. Then, the solvent was evaporated under reduced pressure, and the resulting crude product was recrystallized from acetonitrile to obtain (S)-N-(4-(carboxymethyl)phenyl)-2-(4-chlorobenzenesulfonylamino)-4-methylthiobutanamide (2.84 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([OH:26])(=O)[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][C:17]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:10]([O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:16])=[O:26])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(O)CCCCC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 100.3 %

Procedure:
Using General Procedure A with 1.0 g (4.1 mmol) L-Proline benzyl ester hydrochloride and 300 mg (2.1 mmol) adipic acid afforded, after flash chromatography (EtOAc), 1.07 g (100%) of the title compound as a colorless oil. MS m/e (%): 521 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][N:19]=[C:20]=[S:21]>>[CH3:18][NH:19][C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[S:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CN=C=S
Product: CNC(=S)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 85.8 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 9.56 mg (0.098 mMol) methyl isothiocyanate, 17.0 mg (86%) of the title compound were recovered.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12][CH2:11]1.[CH3:20][C:21]([S:24](Cl)=[O:25])([CH3:23])[CH3:22].Cl>C(OCC)(=O)C>[CH3:20][C:21]([S:24]([NH:9][C@@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:15]1)=[O:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)S(=O)Cl
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@@H](NS(=O)C(C)(C)C)CC1

Procedure:
Triethylamine (272 mL) was added dropwise to a suspension of methyl cis-4-amino-1-cyclohexane carboxylate hydrochloride (7) (151 g, 0.78 mol) and 2-methylpropane-2-sulfinyl chloride (3) (120.8 g, 1.1 eq) in ethyl acetate (755 mL) at 6 to 9° C. The mixture was stirred for an hour at the same temperature and poured into diluted hydrochloric acid. The mixture was extracted with ethyl acetate (750 mL×2) and each of organic layers was washed with water, 5% aqueous solution of sodium bicarbonate, water and brine, successively. The solvent was concentrated under reduced pressure to obtain oily (14) (222.7 g, 1.09%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]O.S(Cl)(Cl)=O.[CH3:16][NH:17][CH3:18]>C(Cl)Cl>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][N:17]([CH3:18])[CH3:16]
Reactant: COc1ccc(N)c(CO)c1
Reactant: CNC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(N)c(CN(C)C)c1

Procedure:
2-Amino-N,N-dimethyl-5-methoxy-benzylamine was prepared from 2-amino-5-methoxy-benzyl alcohol, thionyl chloride and dimethylamine analogous to Example 1. Proof of structure by IR-, UV- and NMR-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:12]([NH2:21])[CH2:13][N:14]([CH2:18][CH2:19][NH2:20])[CH2:15][CH2:16][NH2:17].[K+].[Br-]>>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([CH:12]([NH2:21])[CH2:13][N:14]([CH2:18][CH:19]([NH2:20])[C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH2:15][CH:16]([NH2:17])[C:1](=[O:10])[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])=[O:10]
Reactant: COC(=O)c1ccccc1O
Reactant: NCCN(CCN)CCN
Agent: [Br-]
Agent: [K+]
Product: NC(CN(CC(N)C(=O)c1ccccc1O)CC(N)C(=O)c1ccccc1O)C(=O)c1ccccc1O
Temperature: 100 °C
Yield: 47 %

Procedure:
Methyl salicylate (78 mmol) was mixed with distilled TREN (17 mmol). The mixture was sealed and heated to 100° C. overnight. The thick resulting oil was purified on a silica column eluted with 0-4% MeOH in CH2Cl2, resulting in a white powder after removal of solvent. Overnight drying in vacuo gave a colorless glass. Yield: 47%. IR (KBr) 1543, 1590, 1636 cm31 1. 1H NMR(300 MHz, CD3OD, 25 C) 2.78 (t, 3J=6.2 Hz, 6H, CH2), 3.49 (t, 3J=6.2 Hz, 6H, CH2), 6.68 (t, 3J=7.2 Hz, 3H, ArH), 6.80 (d, 3J=7.4 Hz, 3H, ArH), 7.23 (t, 3J=5.8 Hz, 3H, ArH), 7.63 (d, 3J=6.4 Hz, 3H, ArH), 8.44 (t br, 3H, NH). 13C NMR (400 MHz, CD3OD, 25 C) 39.0 (CH2), 54.6 (CH2), 117.1 (Ar), 118.4 (Ar), 120.2 (Ar), 129.0 (Ar), 134.7 (Ar), 160.9 (ArCO), 170.9 (C═O). Anal. Calcd (Found) for C27H30N4O6: C, 64.02 (63.94); H, 5.97 (5.97); N, 11.06 (11.01).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[N:13]=[C:14]([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([CH:54]=[CH:55][CH:56]=2)[C:23]([NH:25][C:26]2[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][S:44]([C:47]3[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[CH:38]=[CH:37][C:27]=2[O:28][CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])=[O:24])[S:15][CH:16]=1)([CH3:11])([CH3:10])[CH3:9].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:8]([C:12]1[N:13]=[C:14]([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([CH:54]=[CH:55][CH:56]=2)[C:23]([NH:25][C:26]2[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][S:44]([C:47]3[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=3)(=[O:45])=[O:46])[CH:38]=[CH:37][C:27]=2[O:28][CH2:29][C:30]([OH:32])=[O:31])=[O:24])[S:15][CH:16]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCCc2nc(C(C)(C)C)cs2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1csc(CCOc2cccc(C(=O)Nc3cc(CCCS(=O)(=O)c4ccc(Cl)cc4)ccc3OCC(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
Under ice-cooling, trifluoroacetic acid (1.2 ml) was added to a mixture of tert-butyl 2-[3-[2-(4-tert-butyl-2-thiazolyl)ethoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (185 mg, 0.25 mmol) and dichloromethane (2 ml), and the resulting reaction solution was stirred at room temperature for 3 hours and then concentrated under reduced pressure. Saturated sodium bicarbonate aqueous solution was added to the resulting residue and the product formed was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in water, and the solution obtained was adjusted to pH 2 by adding 10% citric acid aqueous solution. Thereafter, the solid material formed was collected by filtration and purified by silica gel column chromatography (eluent=chloroform:methanol=50:1) to give 2-[3-[2-(4-tert-butyl-2-thiazolyl)ethoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetic acid 0.5 hydrate (58 mg, 0.086 mmol, 34%).
Reaction SMILES: [Na].[CH3:2][C:3]1[NH:4][O:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].IC[CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:2][C:3]1[N:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[O:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(C)[nH]oc1=O
Reactant: CC(C)CCI
Agent: [Na]
Product: CCOC(=O)c1c(C)n(CC(C)C)oc1=O

Procedure:
The title compound was prepared by alkylation of ethyl 3-methyl-5-oxo-2,5-dihydroisoxazole-4-carboxylate sodium salt with 1-iodo-3-methylbutane in a manner similar to step 1 of example 28. 1H NMR (CDCl3) δ ppm 4.12 (q, 2H, J=7.1 Hz), 3.47 (t, 2H, J=6.8 Hz), 2.35 (s, 3H), 1.97-2.07 (m, 1H), 1.16 (t, 3H, J=7.0 Hz), 0.77 (d, 6H, J=6.8 Hz). LCMS (APCI, M+H+): 228.2.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:19][C:18]=1[CH2:17][CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH:5]([CH2:6][CH3:7])[C:4]([OH:30])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(CC)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Temperature: 55 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Under N2, a solution of 2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}butyric acid ethyl ester (216 mg, 0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a white solid (155 mg, 77%): 1H NMR (400 MHz, CDCl3) δ 1.05 (t, 3H, J=7.57 Hz), 1.92-1.96 (m, 2H), 2.35 (s, 3H), 2.94 (t, 2H, J=6.35 Hz), 4.16 (t, 2H, J=6.60 Hz), 4.41 (t, 1H, J=6.11 Hz), 6.76-6.83 (m, 4H), 7.39-7.41 (m, 3H), 7.97-7.99 (m, 2H); MS (ES) m/e 382.0 (M+1).
Reaction SMILES: S([O-])([O-])(=O)=O.[Cl:6][C:7]1[CH:20]=[CH:19][C:18]2[C:9](=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:11]3[C:16]([N+:17]=2[CH3:21])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=1.O.[BH4-].[K+]>CO>[Cl:6][C:7]1[CH:20]=[CH:19][C:18]2[N:17]([CH3:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=2[CH:8]=1
Reactant: COC(=O)c1c2ccccc2[n+](C)c2ccc(Cl)cc12
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)C1c2ccccc2N(C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.4 gm of the metho sulfate of 2-chloro-9-methoxycarbonyl-10-methyl-acridinium were suspended in 50 cc of methanol and 2.5 cc of water and after the addition of 5 gm of potassium borohydride, the temperature maintained at 35- 40°C and the mixture was then stirred for 30 minutes at room temperature. The mixture was added to a mixture of ice and water and then filtered. The precipitate was washed with water and then iced methanol and dried to obtain 3.45 gm of 2-chloro-9-methoxycarbonyl-10-methyl-acridane melting at 166°C. The product occurred as a colorless solid soluble in alcohol and chloroform, slightly soluble in ether and insoluble in water. For analysis, the product was recrystallized from methyl ethylketone.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[C:27]([CH3:28])=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[N:25]2)=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:28][C:27]1[C:18]([N:17]=[C:8]=[S:9])=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2
Reactant: Cc1c(N)ccc2cccnc12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2cccnc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (DPT) (2.29 g) (Aldrich) and 4-dimethylaminopyridine (DMAP)(0.02 g) in CH2Cl2 (50 mL) is added dropwise a solution of 7-amino-8-methylquinoline (1.3 g) in CH2Cl2 (50 mL). The mixture is stirred for 5 hours at room temperature then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 25% ethyl acetate/hexane to afford 8-methyl-7-quinolinylisothiocyanate as a pale yellow solid.