Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>O1CCCC1.O>[NH2:1][C:2]1[C:7]([NH:8][S:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)(=[O:18])=[O:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1cccnc1N
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncccc1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
1.97 g (18 mmol) of 2,3-diaminopyridine was dissolved in a mixed solution of tetrahydrofuran and water, and a tetrahydrofuran solution containing 1.90 g (9.0 mmol) of 3-chlorobenzenesulfonyl chloride was added thereto. After stirring at room temperature overnight, the mixture was concentrated, and water and dichloromethane were added to the residue. The organic layer was separated, and the wall of the reactor was rubbed. The resulting crystals were collected by filtration, to give 1.41 g of N-(2-amino-3-pyridiny)-3-chlorobenzenesulfonamide. 530 mg (1.87 mmol) of the crystals was dissolved in methanol and 367 mg (1.87 mmol) of an aqueous 40% chloroacetoaldehyde solution was added thereto. After heating under reflux for 4 hours, the mixture was concentrated to dryness. A small amount of methanol was added to the residue and the crystals were collected by filtration, to give 373 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH2:9].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CCOCC>[C:24]1([CH3:34])[CH:25]=[CH:26][C:27]([S:30]([OH:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1.[CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Yield: 47 %

Procedure:
This titled amide was prepared by general procedure B from trans-2-(dimethylamino)cyclohexylamine and 3-trifluoromethylbenzoyl chloride. The crude oil was converted to the salt with 1 mole of p-toluenesulfonic acid in ether, and was crystallized from MeOH-ether, 47% yield, colorless plates, m.p. 208°-209°.uv λmax 222 nm (ε22,150); sh 227 (17,900); sh 259 (1,550); sh 266 (1,100); sh 274 (566). ir NH/NH+ 3280, 3040; C=O 1660; C=C/amide II 1615, 1595, 1550, 1495; CF3 /SO3- /CN 1335, 1320, 1275, 1200, 1180, 1160, 1120, 1075, 1035, 1010; aromatic/SO3- 705, 690, 680. NMR in CDCl3 (100 MHz) was in accord. Mass spectrum M+ 3l4.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[CH:7]=[C:6]([CH3:12])[N:5]=2.C(N(CC)C(C)C)(C)C.[Cl:31][CH2:32][C:33](Cl)=[O:34].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[CH3:1][C:2]1[N:3]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[C:4]2[C:9]([N:10]=1)=[C:8]([NH:11][C:33](=[O:34])[CH2:32][Cl:31])[CH:7]=[C:6]([CH3:12])[N:5]=2
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C)c(-n2c(C)nc3c(N)cc(C)nc32)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(-n2c(C)nc3c(NC(=O)CCl)cc(C)nc32)c(C)c1
Temperature: 25 °C

Procedure:
Treat a solution of 2,5-dimethyl-3-(2,4,6-trimethylphenyl)imidazolo[5,4-b]pyridine-7-ylamine (0.8 g, 2.85 mmol), and N,N-diisopropylethylamine, (0.54 mL, 3.13 mmol) in 1,2-dichloroethane (10 mL) with chloroacetyl chloride (0.25 mL, 3.13 mmol). Heat the solution to reflux for 5 h, cool to ambient temperature, and pour into an aqueous potassium carbonate solution. Extract the resulting mixture with CH2Cl2 and wash with saturated aq NaCl. Separate the organic layer, dry over Na2SO4, filter and concentrate. Purify by preparative TLC (5% MeOH in CH2Cl2) to obtain the title compound as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:50][C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][C:58]=1[NH2:59])[C:54]#[N:55]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:59][C:58]2[CH:57]=[CH:56][C:53]([C:54]#[N:55])=[CH:52][C:51]=2[NH2:50])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(C#N)cc2N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (14.1 g, 0.061 mol) in DMF (282 mL) was added HBTU (27.76 g, 0.073 mol), DMAP (10.2 g, 0.084 mol) and diisopropylethyl amine (24.2 mL). The reaction mixture was stirred for 30 minutes at rt before 3,4-diaminobenzonitrile (8 g, 0.059 mol) was added. The mixture was stirred overnight at rt before the reaction was quenched by pouring into water (2 L). The mixture was extracted with CH2Cl2 and the organic phase washed successively with 1M aq. HCl solution and 10% aq. Na2CO3 solution, dried (Na2SO4) and concentrated in vacuo. Purification by chromatography on silica gel afforded the title compound.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[C:24]([N:27]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:28])(=[O:26])[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[C:24]([N:27]([C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:31][CH:30]=1)[CH3:28])(=[O:26])[CH3:25]
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-(N-acetyl-N-methyl-amino)-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>>[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:27]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Cc1cccc(C(=O)Cl)c1
Product: Cc1cccc(C(=O)N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)c1

Procedure:
Compound 60 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-methylbenzoyl chloride and conditions outlined in procedure N. M.p.=188-190° C.; 300 MHz 1H NMR (CDCl3) δ 8.08 (d, J=7.8 Hz, 1H), 7.77 (d, J=6.9 Hz, 1H), 7.68 (m, 1H), 7.51 (m, 1H), 7.25 (m, 4H), 4.60 (m, 1H), 3.80 (m, 1H), 3.42 (m 2H), 2.98 (s, 2H), 2.38 (s, 3H), 2.24 (brm, 2H), 1.90 (brm, 2H); LCMS: 420 [M+H].
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]([CH3:16])[C:6]=1[C:17]([O:19]C)=O)#[N:2].C(N(CC)CC)C.[H][H].C[O-].[Na+]>O1CCCC1.[Co]>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:16])[C:6]3[C:17](=[O:19])[NH:2][CH2:1][CH2:3][O:4][C:5]=3[C:13]=2[CH:12]=1
Reactant: [H][H]
Reactant: COC(=O)c1c(OCC#N)c2cc(OC)ccc2n1C
Agent: [Co]
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)c1c(n2C)C(=O)NCCO1
Temperature: 80 °C
Yield: 33.2 %

Procedure:
A mixture of methyl 3-(cyanomethoxy)-5-methoxy-1-methyl-1H-indole-2-carboxylate (0.60 g, 2.2 mmol) and triethylamine (0.40 mL, 0.29 g, 2.9 mmol) in 35 mL of tetrahydrofuran in a pressure reaction vessel is treated with Raney cobalt catalyst (0.40 g). The reactor is pressurized with hydrogen (590 psi) and heated at 80° C. for 10 hours. The cooled reaction mixture is filtered and the filtrate evaporated. The oil residue is dissolved in 50 mL of methanol, and sodium methoxide (0.80 g, 15 mmol) is added to the solution. The mixture is heated at reflux for 3 hours, then cooled and evaporated. The residue is distributed between 75 mL of ethyl acetate and 150 mL of brine. The aqueous layer is extracted several times with fresh ethyl acetate. The combined organic layers are washed with brine, dried (anhydrous sodium sulfate) and evaporated. The crude product residue is purified by flash chromatography (silica gel, 5% methanol in dichloromethane elution) to yield 0.18 g (33%) of product. A sample recrystallized from ethyl acetatehexane has mp 184°-186° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@@H:7]([CH3:18])[CH2:6][NH:5]2.N1C=CC=CC=1.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=1[F:25]
Reactant: O=C(Cl)c1ccccc1F
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)c2ccccc2F)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A 50-mL round bottomed flask equipped with a magnetic stir bar was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.500 g, 1.547 mmol), dichloromethane (10 mL), and pyridine (0.188 mL, 2.321 mmol). The resulting solution was cooled to 0° C. and slowly treated with 2-fluorobenzoyl chloride (0.194 mL, 1.625 mmol). The solution was stirred at 0° C. for 1 h and then allowed to warm to rt. After stirring overnight at rt, the reaction mixture was diluted with dichloromethane and washed with 1 M aqueous HCl solution (10 mL) followed by 5% aqueous sodium chloride solution (10 mL). The dichloromethane extract was concentrated to afford crude (S)-1-(6-bromo-4-(2-fluorobenzoyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.686 g, 100%). MS (ESI, pos. ion) m/z 445, 447 [M+1].
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([N:18]=[C:19]=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[N+:8]([C:7]1[C:2]([NH:1][C:19]([NH:18][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:20])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CCCCCCCN=C=O
Reactant: Nc1ncccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)Nc1ncccc1[N+](=O)[O-]
Yield: 36.8 %

Procedure:
A mixture of 2-amino-3-nitropyridine (1.39 g), heptyl isocyanate (1.41 g) and 4-dimethylaminopyridine (0.37 g) was stirred in toluene (5 ml) at 100°-110° C. for 5 hrs. The solvent was distilled off and the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1-(3-nitro-2-pyridyl)-3-heptylurea (1.03 g, 37%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C[N:23]([CH3:26])C=O>NC1C2C(=CC=CC=2)CC1.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:23][CH:26]4[C:20]5[C:5](=[CH:4][CH:3]=[CH:2][CH:21]=5)[CH2:6][CH2:9]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: NC1CCc2ccccc21
Solvent: CCO
Product: O[C@H](CNC1CCc2ccccc21)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-aminoindan in ethanol, essentially as described above in Example 70. Purity by LC/MS=94%, [M+H]+=419.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:9]([C:4]1[C:3]([N+:12]([O-:14])=[O:13])=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[CH3:8])([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1ccc(F)c([N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Fuming sulfuric acid (180 mL) is added dropwise to 4-fluoro-2-nitrotoluene (50.21 g) under an argon atmosphere. The internal temperature of the mixture is maintained at 0°-5° C. using an ice/sodium chloride bath. A preformed (ice bath) mixture of fuming nitric acid (30 mL) and fuming sulfuric acid (90 mL) is added dropwise to the previous solution over three hours. The reaction is then allowed to warm to room temperature. After stirring at room temperature for two hours, the mixture is poured slowly into ice and the products are extracted with methylene chloride (4×500 mL). The combined extracts are dried over magnesium sulfate, filtered and rotary evaporated. The crude product is purified by flash chromatography on silica gel, eluting with 5% ethyl acetate/hexane to afford 2,3-dinitro-4-fluorotoluene as a pale yellow solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.C1(CN2CCC3(CCCC3)C2=O)C=CC=CC=1>C1COCC1>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:10]1[CH2:11][CH2:12][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]1=[O:13]
Reactant: BrCCCCBr
Reactant: O=C1CCCN1Cc1ccccc1
Agent: O=C1N(Cc2ccccc2)CCC12CCCC2
Solvent: C1CCOC1
Product: O=C1C(CCCCBr)CCN1Cc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 1-(phenylmethyl)-2-pyrrolidinone (0.47 g, 2.7 mmol) in THF (10 ml) at −78° C. was added lithium hexamethyldisilylazine (2.8 ml, 2.7 mmol, 1M solution) over 5 min. After 15 min 1,4-dibromobutane (0.32 ml, 2.7 mmol) was added and the solution allowed to attain ambient temperature over 2 h then stirred for a further 18 h. The solution was separated between ethyl acetate and water and the organics isolated, dried and concentrated. Chromatography over silica (20 g SPE) eluting with cyclohexane then DCM and finally ether provided a clear oil which was a 1:1 mixture of the title compound and 2-(phenylmethyl)-2-azaspiro[4.4]nonan-1-one (0.17 g). This was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3B3OC(C)(C)C(C)(C)O3)[S:8][C:7]=2[CH:6]=1)=[O:4].Cl[C:29]1[O:30][C:31]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][C:33](=[O:35])[CH:34]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:10]3[C:9](=[CH:14][CH:13]=[CH:12][C:11]=3[C:29]3[O:30][C:31]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:32][C:33](=[O:35])[CH:34]=3)[S:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)Sc1cccc(B3OC(C)(C)C(C)(C)O3)c1S2
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)Sc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 90 °C

Procedure:
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-thianthrene-2-carboxylic acid methyl ester (1.1 g, 2.83 mmol), 2-chloro-6-morpholin-4-yl-pyran-4-one (0.73 g, 3.4 mmol) and K2CO3 (0.8 g, 5.66 mmol) were dissolved in dry 1,4-dioxane (7 ml). The mixture was degassed for 15 mins and Pd(PPh3)4 (0.16 g, 5 mol %) was then added The dark brown mixture was heated to 90° C. under an atmosphere of N2 for 24 hour. The reaction mixture was concentrated in vacuo and water (100 ml) was added. The brown solid was filtered and washed with water (1.23 g, 96%). m/z (LC-MS, ESP), RT=4.49 min, (M++1)=454.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-:29])=[O:28])=[CH:25][CH:24]=1)[CH2:7][CH2:8][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].[Na+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:6]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:1][CH:3]2[O:5][CH2:4]2)=[O:28])=[CH:30][CH:31]=1)[CH2:7][CH2:8][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]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Reactant: ClCC1CO1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC2CO2)cc1
Temperature: 105 °C
Reaction time: 5 h

Procedure:
A mixture of 89.0 g of epichlorohydrin, 92.0 g of sodium 4-(n-hexadecylamino)benzoate, and 350 ml of hexamethylphosphoramide is stirred at 105° C. for 5 hours, allowed to cool, and poured into 1.0 liter of water. The white solid is collected by filtration, recrystallized from acetonitrile and then from hexane-methylene chloride to yield 2,3-epoxypropyl 4-(n-hexadecylamino)benzoate, mp 86°-89° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:21][C:20]=2[NH2:32])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:32][C:20]1[CH:21]=[C:22]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH:23]=[CH:24][C:19]=1[O:18][CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:33])=[O:5])[S:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2N)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cc2N)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
2-[(4-{2-[(3-Amino-4′-fluorobiphenyl-4-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (230 mg) obtained in Example 98-1 was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (the objective compound was extracted in the ethyl acetate layer). The ethyl acetate layer was washed with aqueous 10% citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1 to 1:1) to give the title compound (148 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][NH:10][CH2:9][CH:8]2[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][N:10]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:9][CH:8]2[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CC1CNCC(=O)N1Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC1CN(C(=O)OCc2ccccc2)CC(=O)N1Cc1ccc(F)cc1

Procedure:
To a solution of ethyl [1-(4-fluorobenzyl)-6-oxo-piperazin-2-yl]acetate (3.7 g, 12.5 mmol) in dichloromethane (100 mL) was added benzyl chloroformate (2.2 mL, 15.1 mmol) and triethylamine (3.5 mL, 25.1 mmol), stirred over night. The reaction mixture was diluted with dichloromethane, washed with 1N HCl, water and brine, dried over sodium sulfate, filtered and concentrated to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.23-7.38 (m, 7H), 7.01 (t, J=8.6 Hz, 2H), 5.12-5.22 (m, 3H), 4.40-4.56 (m, 1H), 3.90-4.24 (m, 5H), 3.72-3.86 (m, 1H), 3.04-3.18 (m, 1H), 2.49-2.62 (m, 2H), 1.12-1.28 (m, 3H). ES MS (M+1)=429.24.
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:10][C:11]=2[N:13]([CH3:22])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:28]([O:30]CC)=[O:29].Cl.O1CCCC1>C(O)C>[CH3:22][N:13]([S:14]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:16])[C:11]1[CH:10]=[C:9]([O:23][C:24]([F:26])([F:27])[F:25])[CH:8]=[C:7]2[C:12]=1[NH:4][C:5]([C:28]([OH:30])=[O:29])=[CH:6]2
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
A mixed solution of ethyl 1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylate (0.75 g), 6N hydrochloric acid (15 mL), tetrahydrofuran (4 mL) and ethanol (16 mL) was stirred at 80° C. for 18 hr. The reaction solution was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained colorless solid was dissolved in a mixed solution of tetrahydrofuran (10 mL) and methanol (10 mL). aqueous solution (5 mL) of 85% potassium hydroxide (0.35 g) was added, and the mixture was stirred at room temperature for 18 hr. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.65 g, yield 100%) as pale-pink crystals. The obtained crystals were washed with ethyl acetate-hexane to give colorless prism crystals. MS:421 (MH+). melting point 245-246° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15].[C:17]([Si:21]([CH3:36])([CH3:35])[O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([CH2:33]O)=[CH:28][CH:27]=[CH:26]2)([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH2:33][C:29]2[C:30]3[C:25](=[CH:24][C:23]([O:22][Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:36])[CH3:35])=[CH:32][CH:31]=3)[CH:26]=[CH:27][CH:28]=2)[C:7]1=[O:15]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(CO)cccc2c1
Reactant: COC(=O)CCn1c(=O)[nH]c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)CCn1c(=O)n(Cc2cccc3cc(O[Si](C)(C)C(C)(C)C)ccc23)c2ccccc21
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a stirred solution of 3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (180 mg, 0.82 mmol) in THF (12 ml) was added [6-(tert-butyl-dimethyl-silanyloxy)-naphthalen-1-yl]-methanol (283 mg, 0.98 mmol) and triphenylphosphine (257 mg, 0.98 mmol). The DIAD (0.20 ml, 0.98 mmol) was then introduced in a dropwise manner and the resulting mixture was stirred at ambient temperature over night. Silica gel was added and the reaction mixture was concentrated to dryness. The resulting solid was purified via column chromatography (silica gel, 40% ethyl acetate/hexanes) to give 240 mg (60%) of the desired product as an oil which solidified on standing.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[N+]([C:13]1[CH:14]=C(S([O-])(=O)=O)C=C[CH:18]=1)([O-])=O.[Na+].S(=O)(=O)(O)O>OCC(CO)O>[OH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]2[C:3]=1[CH:18]=[CH:13][CH:14]=[N:1]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: Cc1ccc(O)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: OCC(O)CO
Product: Cc1ccc(O)c2cccnc12
Yield: 5.8 %

Procedure:
Following the same procedure as in Example 23-(a), reaction and treatment were carried out using 3.9 g of 3-amino-4-methylphenol, 7 ml of glycerol, 8.7 g of sodium m-nitrobezene sulfonate and 29 ml of a 80% aqueous sulfuric acid solution in order to obtain 290 mg of 5-hydroxy-8-methylquinoline.