Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCOc1cccc(OCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 3-(benzyloxy)phenol (2.002 g), 2-chloro-N,N-dimethylethanamine (1.459 g) in N,N-dimethylformamide (50 mL) was treated with cesium carbonate (3.91 g) and stirred at 50° C. overnight. The mixture was diluted with ethyl acetate and 1N aqueous NaOH and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (5% 7N NH3 in methanol-dichloromethane) to give the desired product.
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])([C:21]#[N:22])[CH2:17][CH2:16]1)=O)(C)(C)C>>[ClH:29].[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:18]1([C:21]#[N:22])[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(c2ccccc2Cl)CCNCC1
Yield: 200 %

Procedure:
A solution of HCl in dioxane (4M, 200 mL, 800 mmol) was added to the Boc-protected amine 18.15 (18.4 g, 57.4 mmol). After 1.5 h the solvent was evaporated and the residue dried in vacuo, giving 14.8 g (57.4 mmol, 100%) of 7.15, colorless solid, mp 241-243° C. (decomp.). 1H NMR (200 MHz, CDCl3): δ=2.5-2.8 (brm, 4H), 3.4-3.6 (brm, 2H), 3.6-3.8 (brm, 2H), 7.33-7.39 (m, 3H), 7.48-7.53 (m, 1H), 10.01 (brs, 2H). C12H14Cl2N2 (257.16): calcd. C 56.05, H 5.49, Cl 27.57, N 10.89; found C 55.67, H 5.48, Cl 27.86, N 10.61.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23]O)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23][Cl:27])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CO)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Yield: 82.4 %

Procedure:
To a solution of 4-butoxy-7-fluoro-3-hydroxymethyl-2-neopentyl-1(2H)-isoquinolinone (2.35g, 7 mmol) in tetrahydrofuran (10 ml) and toluene (10 ml) was added thionyl chloride (1.0 ml, 14 mmol) and the obtained mixture was refluxed under heating for 2 h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with brine dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-butoxy-7-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (2.04 g, 82.6%) as an oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]#[CH:21]>C(#N)C.O>[CH2:21]([O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1])[C:20]#[CH:19]
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCOc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 168 h
Yield: 107.6 %

Procedure:
To a solution of 2-trifluoromethoxyphenol (10.0 g, 56.1 mmol) in acetonitrile (120 mL) was added potassium carbonate (9.31 g, 67.4 mmol) and propargyl bromide (80% in toluene, 10.0 g, 7.70 mL, 67.4 mmol). The reaction was stirred at ambient temperature for seven days, then diluted with water (150 mL) and extracted with diethyl ether (300 mL). The organic layer was separated and concentrated to obtain the title compound (13.05 g) which was used without further purification in the next step. 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.19-7.13 (m, 1H), 7.04-6.95 (m, 1H), 4.77 (d, J=2.4 Hz, 2H), 2.53 (t, J=2.4 Hz, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)Cc1ccc2c(c1)CCN2C(C)=O
Agent: [Pd]
Product: COC(=O)Cc1ccc2c(ccn2C(C)=O)c1
Yield: 41.2 %

Procedure:
An intimate mixture of 1-acetyl-2,3-dihydro-1H-indole-5-acetic acid, methyl ester (2.96 g) and 10% palladium on charcoal (50% moistened with water) (6.18 g) was heated at 200° for 11/2 h and the resulting solid was continuously extracted with chloroform (Soxhlet) for 2 h. Evaporation of the solvent gave an oil (1.21 g), which was purified by column chromatography on silica (Merck 7734; 138 g). Elution with ether-petroleum ether (1:1) gave the title compound (0.99 g) as an oil which was used in the next stage without further purification.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6](=[O:18])[CH2:5]1)=[N+:2]=[N-:3].[BH4-].[Na+]>C1COCC1.O.O>[N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:7][CH:6]([OH:18])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC(O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To as solution of (Z)-tert-butyl 3-oxo-2,3,6,7-tetrahydro-1H-azepine-1-carboxylate (2.0 g, 9.5 mmol) in acetonitrile (3 mL), was added trimethylsilyl azide (3.76 mL, 28.4 mmol) followed by AMBERLITE® IRA 900F resin (loading: 2-3 mmolg-1, 2.4 g) and the resulting mixture was heated at 60° C. behind a blast shield for 16 hr. After cooling to room temperature, the solution was filtered washing the resin with acetonitrile and the filtrate was concentrated under reduced pressure (temperature of bath<40° C.) to give tert-butyl 5-azido-3-oxoazepane-1-carboxylate as a yellow liquid (2.21 g). To a solution of the azide (2.2 g, 8.70 mmol) in THF/water (1/1, 40 mL), was added portionwise NaBH4 (0.82 mg, 21.8 mmol) and the mixture was stirred at room temperature for 2 hr. The mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave tert-butyl 5-azido-3-hydroxyazepane-1-carboxylate as an oil (2.01 g). To a solution of this oil (2.0 g, 7.8 mmol) in MeOH (20 mL), was added HCl (4 M in 1,4-dioxane, 43 mL, 173 mmol) and the solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the crude residue was dissolved in MeOH and passed through an SCX column, washing with MeOH and eluting with 7 N ammonia in MeOH to give 5-azidoazepan-3-ol as a yellow oil. To this oil in dry DMSO (20 mL) was added potassium fluoride (1.68 g, 28.9 mmol) and 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (1.17 g, 7.2 mmol) and the mixture heated at 65° C. for 16 hr. The mixture was diluted with water (300 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (3×20 mL), separated, dried over MgSO4 and the solvents removed under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol as a viscous yellow oil (1.9 g, 72% over four steps). 1H NMR (400 MHz, CDCl3) δ 8.06 and 8.02 (2s, 1H), 4.15-3.97 (m, 2H), 3.95-3.83 (m, 4H), 3.58-3.46 (m, 1H), 3.39-3.16 (m, 3H), 2.29-1.91 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[F:17])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+]>[Fe].O>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:12]([F:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[F:17])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(Oc2ccc(Cl)cc2)c(F)c1
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cc(F)c(Oc2ccc(Cl)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 114.2 %

Procedure:
A mixture of 4-(4-chlorophenoxy)-3,5-difluoronitrobenzene (10.6 g, 37 mmol), toluene (150 ml), H2O (150 ml), iron powder (6.9 g, 124 mmol), and ammonium acetate (9.3 g, 120 mmol) was heated to reflux with stirring for 2-3 hrs. After cooling to room temperature, the reaction mixture was filtered through Celite with thorough washing with H2O and EtOAc. The filtrate was transferred to a separatory funnel and the phases separated. The aqueous phase was further extracted with EtOAc (2×). The combined organic phases were washed with H2O (1×), sat'd NaCl (1×), dried over Na2SO4, and concentrated in vacuo to give 4-(4-chlorophenoxy)-3,5-difluoroaniline (10.8 g, 113%) which was used in the next step without further purification. 1H NMR (CDCl3): δ 3.81 (s, 2H), 6.27 (d, 2H, J=9.2 Hz), 6.85 (d, 2H, J=9.2 Hz), 7.21 (d, 2H, J=9.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:11]OS(C2C=CC(C)=CC=2)(=O)=O)[C:9]#[N:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[SH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH2:10])=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[S:30][N:11]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)ON=C(C#N)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)CS
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1snc(-c2ccc(F)cc2)c1N
Temperature: 5 °C
Reaction time: 16 h
Yield: 41.3 %

Procedure:
Under a nitrogen atmosphere, a stirred suspension of 2-(4-fluorophenyl)-2-(4-methylphenylsulfonyloxy)iminoacetonitrile (64.0 g, 0.2 mole) and triethylamine (61.8 g, 0.61 mole) in 1 l of absolute ethanol was cooled to 5° C. Ethyl 2-mercaptoacetate (26.8 g, 0.22 mole) was added dropwise over a four hour period. The reaction mixture was then stirred for 16 hours and warmed to room temperature. The reaction mixture was concentrated and poured into 2 l of ice water. The resultant precipitate was collected by filtration. The solid filter cake was washed with water and dried. The solid was dissolved in 1.5 l of boiling heptane, and the solution was slurried with silica gel. The hot mixture was filtered; on cooling the filtrate, the solid recrystallized and was collected by filtration, washed with heptane, and dried to give ethyl 3-(4-fluorophenyl)-4-amino-5-isothiazolecarboxylate (22.0 g, mp 137°-139° C.).
Reaction SMILES: ClC1C2C=C(F)C=CC=2SC=1C(Cl)=O.[Cl:15][C:16]1[C:17]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:18]=2[S:19][C:20]=1[C:21](Cl)=[O:22].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:15][C:16]1[C:17]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:18]=2[S:19][C:20]=1[CH2:21][OH:22]
Reactant: O=C(Cl)c1sc2c(F)cccc2c1Cl
Agent: O=C(Cl)c1sc2ccc(F)cc2c1Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1sc2c(F)cccc2c1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 11.7 %

Procedure:
To an ice-cold suspension of a 6:1 mixture of 3-chloro-5-fluoro-benzo[b]thiophene-2-carbonyl chloride and 3-chloro-7-fluoro-benzo[b]thiophene-2-carbonyl chloride (5.46 g, 23.6 mmol) in THF (120 mL) was added lithium aluminum hydride (11.8 mL of a 1.0 M solution in THF, 11.8 mmol) dropwise. The mixture was stirred for 4 h then quenched with NaOH (0.35 N solution in H2O). The mixture was diluted with Et2O and the solution filtered. The filtrate was dried (Na2SO4) and concentrated. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 9:1 to hexanes/EtOAc 8:2) gave the title compound (600 mg, 4% (2 steps), 7-fluoro isomer) as a light, yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.0 Hz, 1H), 7.41 (ddd, J=8.0, 8.0, 4.9 Hz, 1H), 7.10 (dd, J=9.1, 9.1 Hz, 1H), 5.00 (d, J=6.2 Hz, 2H), 2.04 (t, J=6.5 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@@H:5](/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[OH:6])[NH2:4]>ClCCl>[CH3:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]/[CH:8]=[CH:7]/[C@@H:5]([OH:6])[C@@H:3]([NH:4][C:2]([CH2:3][CH2:5][CH2:7][CH2:8][CH3:9])=[O:1])[CH2:2][OH:1]
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Solvent: ClCCl
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO)NC(=O)CCCCC
Reaction time: 0.25 h

Procedure:
2a (0.1 g(acid)) was dissolved in dichloromethane (3 mL) at room temperature under an atmosphere of nitrogen. A model compound from sphingosine derivatives (Ceramide (C2:0), (C4:0), (C6:0), (C8:0), (C10:0), (C12:0), (C14:0), (C16:0), (C17:0), (C18:0), (C18:1), (C20:0), (C24:0), (C24:1)) (0.1 g) was dissolved in dichloromethane (3 mL). When completely in solution this mixture was added drop-wise, over 15 minutes, to the oligofluoro (2a) in solution. The reaction mixture was sealed and left under N2 for two hours. The excess solvent was removed under pressure to allow the formation of the final product. The release/dissociation of the sphingosine compound (ceramide family) was confirmed using HPLC (0.5 mg/mL, injected 6 times, retention time 14.062 minutes) (FIG. 2l). This reaction procedure was further analyzed by polarized light microscopy and scanning electron microscopy. The polarized light microscopy results indicated that when the two components were simply mixed together and left at room temperature to allow the solvent to evaporate, a heterogenous matrix was formed (FIGS. 2a, 2b, 2c and 2d). This was further confirmed by scanning electron microscopy (FIGS. 2e, 2f, 2g and 2h). The homogeneity of the sample was further examined by using stainless steel unpolished metallic platforms. These platforms were coated with the product as a thin layer and then examined using scanning electron microscopy (FIGS. 2i and 2j). The results were indicative of a homogenous coating. Furthermore, the reaction procedure was analyzed to confirm that during the reaction and isolation of the final product the overall structure of the active compound was unaltered. Differential scanning electron microscopy (FIG. 2k) and NMR analysis confirmed the primary structure of the active compound remained intact. This composition was used to coat prototype devices which relates to endo-vascular devices. No phase separation was observed using Scanning Electron Microscopy (SEM) (FIGS. 2n, 2m, 2o and 2p).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:3]=1[CH3:29].[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:32][CH2:31]1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[CH3:39][O:38][C:36]([CH:33]1[CH2:34][CH2:35][N:30]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:3]=2[CH3:29])[CH2:31][CH2:32]1)=[O:37]
Reactant: COC(=O)C1CCNCC1
Reactant: Cc1c(Cl)ncnc1NC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ncnc(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)c2C)CC1
Yield: 25 %

Procedure:
A mixture of 80 mg (0.19 mmoles) of (1,1-dimethylethyl) 3-[(6-chloro-5-methyl-4-pyrimidinyl)amino]-N-[(phenylmethoxy) carbonyl]alaninate and 3 ml of methyl 4-piperidinylcarboxylate is heated under reflux for 3 hours. After cooling down the reaction medium is taken up in water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent eliminated under vacuum. The residue is chromatographed on silicagel eluting with a gradient of heptane (100%) to heptane-ethyl acetate (50-50). 25 mg (Yield=25%) of the expected product is obtained in the form of oil.
Reaction SMILES: [C:1](=O)([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)OC.ClC[C:14]([O:16][CH2:17][CH3:18])=[O:15].CC1C(CN2CCC(N3CCC(N4C(=O)NC5C4=CC=CC=5)CC3)CC2)=CC=CC=1>>[O:4]([CH2:1][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Oc1ccccc1
Reactant: CCOC(=O)CCl
Agent: Cc1ccccc1CN1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Product: CCOC(=O)COc1ccccc1
Temperature: 120 °C
Yield: 96 %

Procedure:
A mixture of 3.8 g of methyl phenyl carbonate, 3.06 g of ethyl chloroacetate, and 0.42 g of TBPB was heated at 120° C. for 2 hours. Distillation of the resulting reaction mixture provided a 96 percent yield of ethyl phenoxyacetate.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[OH-].[Na+].[CH3:26]I.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][S:2][C:3]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:23])=[CH:12][CH:13]=1)([CH3:26])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CI
Reactant: COC(=O)C(SC)c1ccc(N2Cc3ccccc3C2=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(SC)c1ccc(N2Cc3ccccc3C2=O)cc1

Procedure:
Anhydrous dimethylformamide (7 ml) was added to 256 mg of methyl α-methylthio[p-(1-oxo-2-isoindolinyl)phenyl]acetate. With ice cooling and stirring, 35 mg (65% content) of sodium hydroxide was added. The mixture was stirred for 10 minutes at room temperature and again cooled with ice. Methyl iodide (0.1 ml) was added, and the mixture was stirred for 5 minutes. Addition of an aqueous solution of ammonium chloride (100 mg/30 ml) resulted in the precipitation of colorless crystals. The crystals were collected by filtration, washed with 20 ml of water and then with 10 ml of n-hexane, and dried to afford 191 mg of methyl α-methylthio-α-[p-(1-oxo-2-isoindolinyl)phenyl]propionate. The filtrate and the washing were combined and extracted three times with 20 ml of methylene chloride. The extract was washed with 10 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was wahsed with 10 ml of n-hexane to afford 39 mg of methyl α-methylthio-α-[p-(1-oxo-2-indolinyl)phenyl]propionate. The total amount of the product was 230 mg (yield 86%).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH2:20][C:19]([CH3:22])([CH3:21])[O:18][N:17]=1.O>CN(C)C=O>[CH2:1]([S:8][C:16]1[CH2:20][C:19]([CH3:22])([CH3:21])[O:18][N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(Cl)=NO1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(SCc2ccccc2)=NO1
Temperature: 100 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of 2.8 g (22.5 mmoles) of benzylmercaptan dissolved in 50 ml of dimethylformamide were added, in a nitrogen current, 3.2 g (23.2 mmoles) of anhydrous potassium carbonate and 3.0 g (22.5 mmoles) of 3-chloro-5,5-dimethyl-2-isoxazoline. The mixture was stirred at 100° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, and the residue was purified by silica gel column chromatography to obtain 3.1 g (yield: 62.0%) of 3-benzylthio-5,5-dimethyl-2-isoxazoline as a yellow oily substance (refractive index nD20=1.5521).
Reaction SMILES: CO.[OH-].[Na+].[CH3:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:13]([NH:24][C:25]([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:32]=2)=[O:26])[CH:12]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[CH3:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[CH:23]=[CH:22][C:14]([C:15]([OH:17])=[O:16])=[C:13]([NH:24][C:25]([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:32]=2)=[O:26])[CH:12]=1
Reactant: Cn1cccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cn1cccc1-c1ccc(C(=O)O)c(NC(=O)c2cncc(-c3ccccc3)c2)c1
Temperature: 52.5 °C
Reaction time: 2 h
Yield: 80.4 %

Procedure:
Methanol (1.5 mL), dioxane (1.5 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.24 mL) were added the obtained tert-butyl 4-(1-methyl-1H-pyrrol-2-yl)-2-(5-phenylpyridine-3-carboxamido)benzoate (71 mg), followed by stirring at 50 to 55° C. for 2 hours. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid was added thereto. The solid substance was collected by filtration to obtain 50 mg of 4-(1-methyl-1H-pyrrol-2-yl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a white solid.
Reaction SMILES: [C:1](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:3])[CH3:2].[C:14]1(=[O:21])[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1.C(N(CC)CC)C>CC(C)(O)C#N.C(#N)C>[C:1]([CH:15]1[C:16](=[O:20])[CH2:17][CH2:18][CH2:19][C:14]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCCC(=O)C1
Agent: CC(C)(O)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)C1C(=O)CCCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 518.9 %

Procedure:
A 200-mL 2-necked round bottom flask was fitted with thermometer, reflux condenser, magnetic stirrer, and nitrogen bypass. The flask was charged with 4.53 g (25 mmol) of 4-nitrophenyl acetate, 2.94 g (26.25 mmol) of 1,3-cyclohexanedione, 5.69 g (56.25 mmol) of triethylamine, 0.22 g (2.5 mmol) of acetone cyanohydrin, and 60 mL of acetonitrile. The mixture was heated to reflux with stirring for 3 hr. The mixture was allowed to cool to room temperature and volatiles were removed under reduced pressure to give 20.0 g of red oil. Chromatographic separation on silica gel afforded the title product. 1H NMR (CDCl3): δ 1.99 (m, 2), 2.52 (m, 2), 2.62 (s, 3), 2.68 (m, 2).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3OS(C(F)(F)F)(=O)=O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].[Cs+].Br[C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[C:44]([F:49])[C:43]=1[F:50]>C(#N)C.[Pd].C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Pd]>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[C:42]3[CH:47]=[C:46]([F:48])[CH:45]=[C:44]([F:49])[C:43]=3[F:50])=[O:16])=[CH:37][CH:38]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: Fc1cc(F)c(F)c(Br)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3cc(F)cc(F)c3F)ccc2c1

Procedure:
Dissolve trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-methoxynaphthalen-2-yl ester (2.60 g, 6.53 mmol) in 200 mL acetonitrile and add to this bis(pinacoloato)diboron (1.5 g, 7.96 mmol), bis(tricyclohexylphosphine)palladium (0) (0.72 g, 1.50 mmol) and cesium fluoride (7.33 g, 67.0 mmol). Heat the reaction to 100° C. until LC/MS indicates all starting material is consumed. Add to this mixture 1-bromo-2,3,5-trifluorobenzene (2.00 g, 13.06 mmol) and another 720 mg of palladium catalyst and heat at 80° C. for 24 hours. Filter the reaction, concentrate filtrate and purify on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient. The yield is 1.85 g (53%)