Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C(OCC)(=O)C.C(#N)C>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 80 °C
Yield: 26.4 %

Procedure:
To 1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (4.0 g, 13.19 mmol) in ethyl acetate/acetonitrile (30 mL15 mL) is added trifluoroacetic acid (2 mL) and anhydrous cupric chloride (3.56 g, 26.4 mmol). The mixture is heated to reflux at 80° C. for 1.5 h. The mixture is concentrated. The residue is dissolved in ethyl acetate (50 mL) and filtered to remove inorganic solids. The filtrates are washed with saturated potassium carbonate solution followed by water, dried over magnesium sulfate and concentrated. The residue is dissolved in DMF (15 mL) to which is added lithium bromide (2.4 g, 27.7 mmol) and lithium carbonate (2.04 g, 27.7 mmol). The mixture is heated at 120° C. for 4.5 h then partitioned between water and CH2C2 with the organic layer being washed twice with brine (30 mL). Column chromatography (200 g silica gel) using EtOAc/hexanes (20/80) as eluent gave 1.05 g (26%) of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol.
Reaction SMILES: N(C(OC(C)(C)C)=O)CC(N1CCC[C@H]1C(O)=O)=[O:4].C1C([N+]([O-])=O)=CC=C(O)C=1.[CH2:30]1[CH2:35][CH2:34][CH:33]([N:36]=[C:37]=[N:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:32][CH2:31]1>C(Cl)Cl>[C:37]([NH:36][CH:33]1[CH2:32][CH2:31][CH2:30][CH2:35][CH2:34]1)([NH:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
Boc-Gly-Pro-OH (2.8 g, 0.01 mol.) and p-nitrophenol (1.7 g, 0.012 mol.) were dissolved in DCM (100 ml) and DCC (2.1 g, 0.01 mol.) was added to the solution by portions while stirring the solution. A precipitate (dicyclohexylurea, DCU) soon formed. After stirring the solution at room temperature for 3.5 hours, TLC analysis (developing solvents:ethyl acetate/hexane, 3:1) showed that all the starting material Boc-Gly-Pro-OH was consumed. The Rf for the product Boc-Gly-Pro-ONp is 0.45 in this solvent system. DCU was removed by filtration and DCM was removed under reduced pressure. Ethyl acetate was added to the remaining oil and the resulting solution was chilled to 0° C. More precipitate formed and was removed by filtration. The above procedures were repeated and a brownish oil was obtained. The product was directly used in the synthesis of Boc-Gly-Pro-Hyp(OBz)--OH without further purification and characterization.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)(O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:25].C1(C)C=CC=CC=1.S(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]=[C:10]([C:16]2[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
1.37 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 2.74 g of toluene and 0.89 g of thionyl chloride were fed, and the mixture was heated to 80° C. 0.48 g of pyridine was slowly added in dropwise, and the mixture was stirred for 90 minutes at 80° C. The mixture was cooled to room temperature, and separated by adding iced water. The organic phase was washed with a diluted aqueous solution of sodium hydroxide, and the solvent was distilled off under reduced pressure. 1.31 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([O:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])(=[O:13])[CH3:12]
Reactant: O=C(O)c1ccccc1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 90 °C

Procedure:
0.0072 moles of salicylic acid and 0.029 moles acetic anhydride (molar ratio=1:4) were taken in a 20 ml reaction vessel of reaction station. Nano-crystalline sulfated zirconia catalyst (SZ-1), activated at 450° C. in static air with salicylic acid to catalyst weight ratio 10:1, was added and the mixture was heated at 90° C. for 30 minutes. The reaction mixture was filtered to separate the catalyst. The acetyl salicylic acid was crystallized from the reaction mixture. The crude yield of acetyl salicylic acid obtained was 75%. It was further re-crystallized with ethanol-water to obtain pure crystals of acetyl salicylic acid and was characterized by melting point, FT-IR, and NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH:19](I)([CH3:21])[CH3:20].O>C(#N)C>[Cl:1][C:2]1[C:3]([O:12][CH:19]([CH3:21])[CH3:20])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 20 °C
Yield: 57.9 %

Procedure:
To a solution of 2-chloro-4-fluoro-5-nitrophenol (19.1 g) in acetonitrile (100 ml), there was added anhydrous potassium carbonate (8 g). After stirring at room temperature (ca. 20° C.) for several minutes, isopropyl iodide (25 g) was added thereto, and the resultant mixture was heated under reflux for 3 hours. After being allowed to cool to room temperature (ca. 20° C.), water was added thereto, and the reaction mixture was extracted with ether. The ether extract was washed with a 5% aqueous sodium hydroxide solution and water in order, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give 13.5 g of 4-chloro-2-fluoro-5-isopropoxynitrobenzene. M.P., 61.3°-62.4° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][OH:13]>>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([O:13][CH3:12])[CH:10]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Product: COc1cc(Cl)ccc1C(=O)O
Temperature: 80 °C
Yield: 86.3 %

Procedure:
Except for using 2.8 g of 2,4-dichlorobenzoic acid (14.6 mM), 0.75 g of cuprous chloride (7.5 mM) and 100 ml of methanol containing 20% dimethylamine (77 g), the same apparatus, reagents and procedures were employed for reaction as in Example 1. The reaction was followed by reversed-phase HPLC as in Example 1, and as a result, completion of the methanol reaction within two hours was confirmed. After the methanol was removed, 50 ml of water was added and heated in a bath temperature of 80° C., to turn the solution into a uniform mixture solution of green. The green solution was cooled in ice-water to a room temperature. Then, 1.2 ml of conc. HCl was added to consequently deposit needle-liuke crystal. Effecting separation, washing and drying processes in the same manner as in Example 1, about 2.3 g of 4-chloro-2-methoxybenzoic acid was obtained in crystal at a yield of 86.3%. Concerning 1H-NMR, IR(KBr), GC-MSE1 and melting point, the product was confirmed to show the data agreeable with the reference standard data.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.[NH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[C:26]1([CH:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:18][C:6]([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[O:8])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)c1c[nH]cn1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC(c1ccccc1)c1ccccc1)c1c[nH]cn1
Temperature: 35 °C
Reaction time: 48 h

Procedure:
A mixture of 11.7 g of 4-imidazolecarboxylic acid, 18.7 g of 1,1'-carbonyldiidmidazole, 20 ml of diisopropylethylamine and 600 ml of DMF was heated at 35° C. for approximately 18 hours. Twenty milliters of aminodiphenylmethane were added and the solution stirred at 35° C. for approximately 21/2 days. The mixture was concentrated in vacuo and the residue added to 400 ml of water. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. Two crystallizations from hot ethyl acetate/hexane provided 11 grams of the desired titled intermediate, m.p. 201°-202° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:15])=O>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
A mixture of p-nitrobenzoic acid (500 g, 3.0 moles, 1 equiv) and thionyl chloride (600 mL, 8.2 moles, 2.73 equiv) is heated to reflux for approximately 6-7 hours until a clear solution is obtained. Excess of thionyl chloride is removed by distillation followed by co-distillation with toluene (300 mL). The reaction mass is cooled to room temperature, and hexane (1.5 L) is added, forming; a precipitate, which is then filtered and dried under vacuum, yielding 4-nitrobenzoyl chloride as a yellow solid (530 g, approximately 100% yield), which is used without any further purification.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[O:28][C:27]([C:29]([OH:31])=O)=[CH:26][CH:25]=1.Cl.[CH3:33][NH:34][CH3:35].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:33][N:34]([CH3:35])[C:29]([C:27]1[O:28][C:24]([CH2:23][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:22]4[C:13](=[CH:14][C:15]5[O:20][CH2:19][CH2:18][O:17][C:16]=5[CH:21]=4)[O:12][CH2:11]3)[C:2]2=[O:1])=[CH:25][CH:26]=1)=[O:31]
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Yield: 76.2 %

Procedure:
A solution of 5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid (0.42 g, 1.00 mmol), dimethylamine hydrochloride (0.17 g, 2.04 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g, 1.35 mmol), 1-hydroxybenzotriazole hydrate (0.21 g, 1.54 mmol) and 4-methylmorpholine (0.30 mL, 2.7 mmol) in N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure, the residue was taken up into ethyl acetate (75 mL) and washed sequentially with 1 M hydrochloric acid (2×50 mL), water (50 mL) and brine (50 mL). The organic phase was further diluted with dichloromethane until all the material was in solution, then was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/methanol (29:1) afforded N,N-dimethyl-5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide (0.34 g, 77%) as a colorless solid: mp 224-226° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ7.32 (dd, J=7.5, 7.5 Hz, 1H), 7.22-7.14 (m, 2H), 7.05 (dd, J=7.8, 7.5 Hz, 1H), 6.96 (m, 1H), 6.62 (m, 1H), 6.51 (s, 1H), 6.06 (s, 1H), 5.06 (d, J=16.4 Hz, 1H), 4.97 (d, J=16.4 Hz, 1H), 4.76 (d, J=9.3 Hz, 1H), 4.66 (d, J=9.3 Hz, 1H), 4.22-4.14 (m, 2H), 4.14-4.06 (m, 2H), 3.05 (br s, 3H), 2.94 (br s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.4, 158.9, 154.6, 150.8, 147.2, 144.2, 141.8, 137.8, 131.6, 128.8, 123.6, 123.3, 121.2, 116.5, 111.0, 109.9, 109.4, 98.8, 79.3, 64.2, 63.6, 57.2, 37.7, 36.7, 35.8; MS (ES+) m/z 446.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11](NCC(OC)=O)=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC([O:30][CH2:31][CH:32](C)[CH3:33])=O.[BH4-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11](/[CH:33]=[CH:32]/[CH2:31][OH:30])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COC(=O)CNc1ccn(-c2ccc(OC)cc2)n1
Reactant: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-n2ccc(/C=C/CO)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.5 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-[E-2-(carboxy)ethenyl]-1H-pyrazole-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carboxyamide (1.0 g, 1.93 mmol) in 20 mL of tetrahydrofuran at −20° C. was added triethylamine (0.27 mL, 1.93 mmol) and iso-butyl chloroformate (0.25 mL, 1.93 mmol). This mixture was stirred for 30 min and then there was added sodium borohydride (0.22 g, 5.78 mmol) in a minimal amount of water. The reaction mixture was stirred with slow warming to room temperature for 1 h and then was quenched with 10% aq HCl. After diluting with ethyl acetate, the organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 0.5 g (52%) of the title compound as a white powder. LRMS (ES+): 504.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:11][Si](C=[N+]=[N-])(C)C>O1CCCC1CO>[NH2:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NC1(C(=O)O)CCCCC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: OCC1CCCO1
Product: COC(=O)C1(N)CCCCC1
Yield: 52 %

Procedure:
To a solution of 1-aminocyclohexanecarboxylic acid (600 mg) in tetrahydrofuran-methanol was added dropwise trimethylsilyl diazomethane (4.2 mL) under ice-cooling and stirring, and the mixture was stirred overnight. The reaction mixture was concentrated in vacuo, and to the residue were added successively diethylether-hexane (1/1) and a solution of 4N hydrochloric acid in ethyl acetate (1.05 mL). The precipitates were collected by filtration and dried to give methyl 1-amino-cyclohexanecarboxylate (423 mg, yield: 52%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:33])([F:32])[S:28](Cl)(=[O:30])=[O:29]>CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][S:28]([C:27]([F:33])([F:32])[F:26])(=[O:30])=[O:29]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
A mixture of (+)-6,7-dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (25.05 g, 0.0837 mole) and potassium carbonate (35.4 g. 0.256 mole) in dimethylformamide (100 ml.) is stirred at 25° C. for 1 hour, cooled to 0° C. then treated with trifluoromethanesulfonyl chloride (10.5 ml., 0.984 mole) over a 3 minute period. The reaction mixture is stirred at 25° C. for 1 hour, poured into ice water (700 ml.) extracted with ether, washed with water and brine and dried over MgSO4. The ether is evaporated at reduced pressure to give 34.2 g of (+) (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)trifluoromethanesulfonate which melts at 104°-6° C. and is used in Step B without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:11]([C:18]1[S:22][C:21]([CH2:23][NH2:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:21]1[S:22][C:18]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:19][CH:20]=1)=[O:6]
Reactant: Nc1ncccc1C(=O)O
Reactant: NCc1ccc(Oc2ccccc2)s1
Product: Nc1ncccc1C(=O)NCc1ccc(Oc2ccccc2)s1

Procedure:
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (250 mg, 0.768 mmol) obtained from 2-aminonicotinic acid and C-(5-phenoxy-thiophen-2-yl)methylamine described in Preparation Example 24 according to an analogous method to Preparation Example A+-5, and N-iodosuccinimide (190 mg, 0.845 mmol) were dissolved in tetrahydrofuran (5 mL), and the solution was stirred for 16 hours at room temperature. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1), and title compound (45 mg, 0.10 mmol, 13%) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].Cl>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:15](=[O:16])[CH2:14][CH2:13][Cl:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(NC(=O)CCCl)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 139.2 %

Procedure:
p-Anisidine (12.3 g) was dissolved in CH2Cl2 (30 ml) and the solution was cooled to 5° C. Aqueous NaOH (6.6 g in 13 ml water) and 3-chloro-propionyl-chloride (19.05 g) were simultaneous added to the above solution over 40 minutes. The two phase mixture was stirred at 5° C. for another 30 min. Water (250 ml) and concentrated HCl (3 ml) were then added. The product was isolated by filtration, washed with water and dried to a constant weight to give N-(4-methoxyphenyl)-3-chloropropionamide (29.7 g, 94.6%) in 99.3% purity by HPLC analysis.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)=[O:18])=[CH:14][C:15]=1[OH:16].C(N(CC)CC)C.CO>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[O:18])=[CH:14][C:15]=1[OH:16].[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: COc1ccc(C(=O)c2cc(OC)c(OC)c(OC)c2)cc1O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)[O-]
Reaction time: 0.5 h

Procedure:
Acetic anhydride (74 μL, 0.79 mmol) was added to a solution of phenstatin (3b, 0.2 g, 0.63 mmol), DMAP (7.8 mg, 0.063 mmol) and triethylamine (0.13 mL, 0.94 mmol) in dry methylene chloride (1.5 mL, under argon at room temperature). The yellow solution was stirred for 30 min (reaction was complete by TLC). Methanol (5 Ml) was added and the reaction mixture concentrated to a solid that was washed with diethyl ether (3 ×10 mL) and partitioned between ethyl acetate and cold Ln hydrochloric acid. The organic layer was washed with 10% aqueous sodium bicarbonate and dried. Solvent removed, in vacuo, gave an off-white solid that was recrystallized from ethyl acetate-hexane to give colorless snowflakes of analytical purity: EIMS m/z (peak height) 360 M+, 60%), 318 (100%), 303 (10%), 195 (20%), 151 (30%), 91 (32%), 44 (25%). 1H-NMR (CDCl3)δ H 7.740 (1H, dd, J6/2 2.1 Hz, J6/5 8.1 Hz, H-6). 7.556 (1H, d, J2/6 2.1 Hz, H-2), 7.026 (1H, d, J5/6 8.0 Hz, H-5), 7.013 (2H, s, H-2′, 6′), 3.914 (3H, s, 4-OCH3), 3.907 (3H, s, 4′-OCH3), 3.863 (6H, s, 3′, 5′-OCH3), 2.315 (3H, s, —OCOCH3).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl.[CH3:13]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 60 °C
Yield: 62 %

Procedure:
To a stirring solution of 4-bromo-2-methylbenzoic acid (3 g) in methanol (70 mL) was added concentrated hydrochloric acid (5 mL) and the reaction mixture was heated to 60° C. for 16 h. The reaction mixture was concentrated under reduced pressure, the residue was basified with sodium bicarbonate solution and extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford Methyl 4-bromo-2-methylbenzoate as a solid (2 g, 62%).
Reaction SMILES: [OH-].[K+].C[O:4][C:5]([C:7]1[C:16]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=2)=[CH:9][CH:8]=1)=[O:6]>C(O)C.O>[C:5]([C:7]1[C:16]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=2)=[CH:9][CH:8]=1)([OH:6])=[O:4]
Reactant: COC(=O)c1ccc2cccc(C(C)C)cc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1cccc2ccc(C(=O)O)c-2c1
Temperature: 25 °C

Procedure:
Potassium hydroxide (10.5 g) was dissolved in a mixture of ethanol (80 ml) and water (15 ml). The compound (17) (12.43 g) was added thereto and the mixture was heated under reflux for 50 minutes in an oil bath. The reaction solution was cooled to room temperature, and then poured into water (400 ml). The solution was made acidic (pH 3) with conc. HC1. The precipitate was filtered, washed with water and dried to obtain 1-carboxy-7-isopropylazulene (18), at a yield of 2.1 g (92.3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.O.C(Cl)CCl.Cl.[CH3:33][NH:34][CH3:35]>C1COCC1>[CH3:33][N:34]([CH3:35])[C:10]([C@@H:9]1[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:11]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O
Product: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 25.1 g of (4R)-1-(tert-butoxy carbonyl)-4-hydroxy-L-proline in THF (250 ml) was added 24.9 g of HOBt/H2O and 24.9 g of EDC/HCl under ice cooling, and the reaction mixture was stirred for 15 minutes. To the reaction mixture was added dropwise 10.7 g of an aqueous solution of 50% dimethylamine over 10 minutes, then, the reaction mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure, then, an aqueous solution of saturated NaHCO3 was added to the solution, and the resulting mixture was extracted with CHCl3. After drying with Na2SO4, the drying agent was separated by filtration, and the solution was concentrated under reduced pressure. The residue was purified by column chromatography (silicagel 60N; mobile phase: CHCl3/MeOH=20/1 to 9/1; v/v) to obtain 26.2 g of the title compound (colorless solid).