Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][CH2:38][CH2:39][OH:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34](=[O:35])(=[O:36])[NH:37][CH2:38][CH2:39][OH:40])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)NCCO)cc2)c1C
Temperature: 25 °C
Yield: 42.1 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.200 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.082 g, 0.071 mmol), 4-bromo-N-(2-hydroxyethyl)-benzenesulfonamide (0.2 g, 0.71 mmol) and 2.0 M aqueous sodium carbonate (1.0 mL, 2.0 mmol) were added simultaneously to the reaction mixture under argon. The reaction was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography to afford {6-chloro-4-[4-(2-hydroxy-ethylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.100 g, 42%) as a solid. MS calcd. for C22H21ClNO5S [(M−H)−] 446, obsd. 446.4.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:10]([CH3:13])=[CH:11][CH:12]=1)[NH:6][C:7]([CH3:9])=[O:8].[C:14]([O-:17])(=O)[CH3:15].[K+].C(OC(=O)C)(=O)C.C(O[N:32]=O)CC(C)C.C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:7]([N:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH2:2][O:1][C:14](=[O:17])[CH3:15])[CH:4]=2)[CH:13]=[N:32]1)(=[O:8])[CH3:9]
Reactant: CC(C)CCON=O
Reactant: CC(=O)[O-]
Reactant: CC(=O)Nc1cc(CO)ccc1C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1ccc2cnn(C(C)=O)c2c1
Yield: 95.8 %

Procedure:
To a suspension of 3-(hydroxymethyl)-6-methyl-N-(methylcarbonyl)aniline (10.0 g, 45 mmol) (97) and potassium acetate (8.6 g, 88 mmol) in chloroform (300 mL), was added acetic anhydride (8.3 mL, 88 mmol), isoamylnitrite (35 mL, 300 mmol) and 18-crown-6 (1.5 g, 0.6 mmol) at room temperature. The reaction mixture was heated at its reflux temperature for 28 hours. The reaction mixture was diluted with methylene chloride (600 mL) and washed with saturated NaHCO3 aqueous solution (300 mL), water (300 mL) and brine (50 mL). After drying (Na2SO4), the organic solvent was removed under vacuum to give a yellow oil which was purified by a flash chromatography on silica gel (85:15 hexane-ethyl acetate) to yield the title compound (98) (10.01 g, 95%). TLC Rf 0.47 (70:30 of hexane-ethyl acetate); MS (electrospray) 233 (M+1); 1H N MR (CDCl3) δ2.10 (s, 3H), 2.78 (s, 3H), 5.27 (s, 2H), 7.36 (d, 1H, J=8.0 Hz), 7.73 (d, 1H, J=8.0 Hz), 8.12 (s, 1H), 8.47 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([CH2:41][C:42]([O:44]CC)=[O:43])[CH:38]=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([CH2:41][C:42]([OH:44])=[O:43])[CH:38]=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(CC)n4)cc3OC)c(C)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(CC(=O)O)c4)oc3C)c(OC)c2)cs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a mixture of ethyl {3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.36 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give {3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (0.29 g, 85%). Recrystallization from acetone-hexane gave pale-yellow prism crystals. melting point: 154-155° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-])=O>CC(O)=O.CCOC(C)=O.C([O-])(O)=O.[Na+].[Fe]>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[NH2:12]
Reactant: O=[N+]([O-])c1cc(F)c(Br)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1cc([N+](=O)[O-])cc(F)c1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.6 %

Procedure:
A mixture of 2-bromo-1,5-dinitro-3-fluorobenzene (100 mg, 0.38 mmol, 1 equiv) and iron powder (64 mg, 1.14 mmol, 3 equiv) in 3 mL of HOAc was stirred at room temperature for 90 minutes. The reaction mixture was diluted with EtOAc (20 mL) and saturated NaHCO3 (to ca. pH 7-8). The organic layer was separated and evaporated under vacuum. The crude residue was purified by column chromatography on silica gel using EtOAc/hexanes (1:4) as eluent to give 47 mg of 2-bromo-3-fluoro-5-nitroaniline (52%).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15][O:16][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(CO)cn2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(Oc2ccc([N+](=O)[O-])cc2)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
[6-(4-nitrophenoxy)pyridin-3-yl]methanol (6.1 g, 24.8 mmol) was dissolved in dichloromethane (150 mL), and to the resulting solution was added triethylamine (4.15 mL, 29.8 mmol) under ice cooling. To the resulting solution was added dropwise methanesulfonic acid chloride (2.11 mL, 27.3 mmol), and then stirred under a nitrogen atmosphere for 30 minutes at 0° C. The reaction solution was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. To the residue was added a mixed solvent (50 mL) of n-hexane:ethyl acetate=1:1. The precipitated crystals were removed by suction filtration, to thereby yield 7.9 g of the title compound.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O.O>[O:17]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][CH2:8][CH:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)C1CNc2ccccc2O1
Yield: 23.6 %

Procedure:
Ethyl 2,3-dibromopropionate (24 g, 92 mmol) was added dropwise to a refluxing solution of o-aminophenol (10 g, 92 mmol) and potassium carbonate (15 g, 110 mmol) in acetone (100 ml). After 18 h the mixture was cooled and reduced. Ethyl acetate and water were added and the mixture separated. The organic phase was washed with brine, filtered and reduced. Chromatography (30% EtOAc/70% 60-80 petroleum ether) afforded ethyl benzomorpholine-2-carboxylate (4.5 g, 24%) as a red oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[C:20]([OH:24])(=[O:23])[CH2:21][CH3:22].C[CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=O>>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:27]3[CH:28]([CH2:22][CH2:21][C:20]([OH:24])=[O:23])[CH2:29][CH2:30][CH2:31][C:26]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CC1CCCCC1=O
Reactant: CCC(=O)O
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Product: COc1ccc2c(c1)c1c(n2Cc2ccc(Cl)cc2)C(CCC(=O)O)CCC1

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methoxyphenyl)hydrazine hydrochloride and methyl-2-cyclohexanone propionate as starting materials, the title compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>CCO>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[CH:13][NH:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cn1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)OCC
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A solution of 5-amino-2-methoxypyridine (Aldrich, 100 g, 0.806 mole) and diethyl ethoxymethylenemalonate (Aldrich, 163 mL, 0.806 mole) in EtOH (1 L) was heated at reflux for 4 h, then was cooled to RT. Concentration to dryness gave the title compound (238 g, quantitative).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[O:3].[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)(=[O:10])[CH3:9]>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:1](=[O:4])[CH:2]([OH:3])[CH2:9][C:8](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:7]
Reactant: CC(=O)c1ccccn1
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)CC(=O)c1ccccn1
Temperature: 135 °C
Yield: 44 %

Procedure:
A mixture of ethyl glyoxalate (3.060 g, 30.000 mmol) (6.2 mL of a 50% solution in toluene) and 2-acetylpyridine (3.630 g, 30.000 mmol) was heated in an oil bath at 135° C. for 16 hours. The crude residue after removal of toluene was purified by column chromatography. The pure 2-hydroxy-4-oxo-4-pyridin-2-ylbutyric acid ethyl ester was isolated in 44% yield (2.910 g, 13.000 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[N:29]=[C:28]([C:30](O)=[O:31])[O:27][N:26]=2)[CH:20]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:28]3[O:27][N:26]=[C:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[N:29]=3)=[O:31])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1nc(-c2cccnc2)no1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1nc(-c2cccnc2)no1
Yield: 11.9 %

Procedure:
Following the method of Example 34(d), the title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.27 g, 1.05 mmol), 3-(pyridin-3-yl)-1,2,4-oxadiazole-5-carboxylic acid (0.2 g, 1.05 mmol), HOBt (0.21 g, 1.57 mmol), DIPEA (0.55 mL, 3.14 mmol) and EDCI (0.3 g, 1.57 mmol) using DMF as solvent to afford 54 mg of the title product. 1H NMR (400 MHz; d6-DMSO): δ 1.23 (d, 3H), 4.37 (m, 2H), 4.50 (m, 1H), 6.96 (d, 1H), 7.65 (m, 1H), 7.88 (d, 1H), 7.92 (m, 2H), 8.04 (m, 1H), 8.38 (m, 1H), 8.83 (dd, 1H), 9.19 (dd, 1H), 9.50 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[N:4]=1)#N.[OH2:23].C(OCC)(=O)C.[OH2:30]>Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[N:4]=[C:3]([C:1]([OH:30])=[O:23])[CH:8]=1
Reactant: O
Reactant: COc1cc(C#N)nc(Oc2cccc(OC(F)(F)F)c2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(OC(F)(F)F)c2)nc(C(=O)O)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2-cyano-4-methoxy-6-[3-(trifluoromethoxy)phenoxy] pyridine (1.72 g, 0.0055 mol) was suspended in about 15 ml of concentrated hydrochloric acid. The obtained suspension was stirred at about 100° C. for about 4 hours. After being allowed to stand for cooling, the obtained reaction solution was mixed with water, and then distributed in ethyl acetate-water. The organic phase separated from the solution was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated, thereby obtaining an aimed product.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].Cl[CH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1>CN(C)C=O>[S:32]1[CH:33]=[CH:34][N:35]=[C:31]1[CH2:30][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:15]2[CH:14]=[C:13]([C:12]3[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=3)[O:17][N:16]=2)=[CH:20][CH:21]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: ClCc1nccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4nccs4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (50 mg, 0.18 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (35.4 μL, 0.18 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a suspension of this solid in N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-thiazole (28.4 mg, 0.21 mmol) described in manufacturing Example 88-1-2, which was stirred for 3 hours at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (43.0 mg, 64%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][CH2:9][C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:13])[CH2:4][CH3:5])[CH3:2].[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)#[N:26].Cl.[C:36]([C:39]1[O:40][CH:41]=[CH:42][CH:43]=1)(=[NH:38])[NH2:37].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]2[C:11]([C:12]([O:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:13])=[C:10]([CH2:9][O:8][CH2:7][CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[NH:38][C:36]([C:39]3[O:40][CH:41]=[CH:42][CH:43]=3)=[N:37]2)=[CH:29][CH:28]=1)#[N:26]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCN(CC)CCOCC(=O)CC(=O)OCCCc1ccccc1
Reactant: N=C(N)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOCC1=C(C(=O)OCCCc2ccccc2)C(c2ccc(C#N)cc2)N=C(c2ccco2)N1
Temperature: 60 °C
Yield: 21.2 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(N,N-diethylamino)ethoxy)acetoacetate (2.0 g, 5.96 mmol), 4-cyanobenzaldehyde (0.86 g, 6.56 mmol), 2-amidinofuran hydrochloride (0.962 g, 6.56 mmol) and sodium hydrogen carbonate (0.551 g, 6.56 mmol) was stirred in N,N-dimethylformamide (10 mL) for 24 h at room temperature and then heated to 60° C. for 5 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (683.7 mg) as an oil. Electrospray MS m/z 541 [M+H]+.
Reaction SMILES: N1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(OCC)(=O)C1C(=CC=CC=1)[C:13](OCC)=[O:14]>>[CH:7]1[CH:6]=[CH:5][C:4](/[CH:3]=[CH:2]/[CH2:13][OH:14])=[CH:9][CH:8]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)c1ccccc1C(=O)OCC
Product: OC/C=C/c1ccccc1

Procedure:
Indole--10% in Diethyl Phthalate: 2%
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17](O)=[O:18])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH:34][C:31]2[S:32][CH:33]=[C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:30]=2)=[O:18])(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCc3ccccc32)c1
Product: O=C(Nc1nc(-c2ccccn2)cs1)c1cccc(S(=O)(=O)N2CCCc3ccccc32)c1

Procedure:
3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (2) (100 mg, 0.32 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (47 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 75-100% EtOAc in hexanes. The resulting solid was triturated with diethyl ether to give 3-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an off white solid. Yield: 36 mg (29%). 1H-NMR: 8.65-8.61 (m, 1H), 8.50 (s, 1H), 8.42-8.35 (m, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.95-7.88 (m, 2H), 7.75-7.68 (m, 2H), 7.64 (d, J=8.5 Hz, 1H) 7.39-7.32 (m, 1H), 7.25-7.18 (m, 1H), 7.12-7.05 (m, 2H), 3.88-3.81 (m, 2H), 2.44 (t, J=7.0 Hz, 2H), 1.68-1.60 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]([C:20]2[O:30][C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[C:9]2[O:19][C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:3][CH:2]=1.[O:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[K]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[O:19]=[C:9]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[C:17]([O:31][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:18])[C:8](=[CH:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:20]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=1[C:28]([O:31][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])=[O:30]
Reactant: O=c1oc(C(=Cc2ccccc2)c2nc3ccccc3c(=O)o2)nc2ccccc12
Reactant: CC(C)(C)O[K]
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccccc1NC(=O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)OC(C)(C)C
Yield: 59 %

Procedure:
The compound 52 (1.0 g, 2.5 mmol) obtained in the same manner as in Example 21 (b) was dissolved in dry benzene (80 ml), treated with KOC(CH3)3 (684 mg, 6.1 mmol), and heated under reflux for 1 hour. After completion of the reaction, the solvent was evaporated and the residue was dried and suspended by adding a small amount of water under ice cooling. The aqueous layer was made neutral with 0.5N.HCl, and the residue was dissolved by adding chloroform. The mixed layer was removed to a separating funnel. After the solid was completely dissolved, water was added to wash the solution so as to make the chloroform layer neutral or weak acidic. The chloroform layer was separated, washed with saturated aqueous NaCl solution and dried over magnesium sulfate. The solvent was evaporated to give a white solid. The product was dissolved in chloroform and purified by silica gel column chromatography (developing solvent: benzene:ethyl acetate=4:1) to give the desired compound as white solid (801 mg, crude yield 58%). Recrystallization from the mixed solvent of methanol and water gave white crystals (654 mg, yield, 47%). m.p., 117°-118° C.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:3].[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.N1C2C(=CC=CC=2)CC=1.C([Al](Cl)Cl)C>ClCCCl>[CH3:1][C:2]1[CH2:3][CH:12]2[CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]2[C:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH2:9][CH:4]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: C=C(C)C1CCCCC1=O
Agent: C/C1=C\CCCCC(=O)N2c3ccccc3CC2C1
Agent: C1=Nc2ccccc2C1
Agent: CC[Al](Cl)Cl
Solvent: ClCCCl
Product: CC1=CCCCCC(=O)N2c3ccccc3CC2C1

Procedure:
Following the general procedure as described in Example 17, 2-(prop-1-en-2-yl)cyclohexanone (0.88 g, 6.38 mmol), 1H-indole (0.90 g, 7.65 mmol) which was in situ isomerized to 3H-indole, and EtAlCl2 (0.81 g, 6.38 mmol) in 1,2-dichloroethane (65 ml) were reacted to give the title product as a white solid (1.25 g, 77% yield).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1CC=C1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:18]C)([CH3:17])([CH3:16])C.CC([OH:24])(C)C.C[N+]1([O-])CCOCC1>O>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:16][CH:14]([OH:18])[CH:17]1[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)O
Reactant: C1=CC(COCc2ccccc2)C1
Reactant: COC(C)(C)C
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Product: OC1CC(COCc2ccccc2)C1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
In a 10 mL flask with 3-benzyloxymethyl-1-cyclobutene (0.1 g, 0.57 mmol) inside, 0.72 mL tBuOMe, 1.54 mL tBuOH and 0.54 mL H2O were added to give two layers. Then NMO (50% wt sol. in H2O, 0.36 mL, 1.71 mmol) and OSO4 (0.07 mL, 0.06 mmol) were added drop by drop successively to give a light brown solution. This was left stirring at room temperature. After 3 hr, the solution was diluted with H2O and extracted with EtOAc three times. The organic layer was washed with brine once, dried over MgSO4 and concentrated. The crude product was purified by silica gel flash chromatography (Hexane: EtOAc=3:1 to Hexane: EtOAc=1:1) to give 27.4 mg (23%) the desired product. 1H NMR (CDCl3, 300 MHz): δ 1.70-1.92 (m, 2H), 2.46-2.75 (m, 1H), 3.02-3.2 (m, 1H), 3.2-3.34 (m, 1H), 3.4-3.6 (m, 2H), 3.90-4.10 (m, 1H), 4.2-4.4 (m, 1H), 4.4-4.6 (s, 2H), 7.21-7.50 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ 28.08, 43.45, 68.32, 70.19, 71.41, 73.28, 127.83, 128.61, 138.56. IR (neat) νmax 3376, 2937, 2856, 1453, 1098, 738, 698.