Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S[CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=4)=[C:23]([Cl:38])[CH:22]=3)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=[CH:12]1)(C)(C)C.CO.[C:41](OO)([CH3:44])([CH3:43])[CH3:42].[S:47]([O-:51])([O-])(=[O:49])=S.[Na+].[Na+]>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:41]([S:47]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=4)=[C:23]([Cl:38])[CH:22]=3)=[N:17][CH:16]=[N:15][C:14]=2[CH:13]=[CH:12]1)(=[O:51])=[O:49])([CH3:44])([CH3:43])[CH3:42]
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)(C)OO
Reactant: CC(C)(C)SCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)CCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-{2-[2-(tert-Butylthio)ethoxy]ethyl}-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (140 mg) was dissolved in dichloromethane (5.0 mL), titanium tetraisopropoxide (0.90 mL), methanol (0.20 mL) and 70% aqueous tert-butyl hydroperoxide solution (7.0 mL) were added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium thiosulfate solution was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hr and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=90:10). Crystallization from diethyl ether/ethyl acetate/hexane gave the title compound (10.6 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:9]([CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:8]([CH:43]([CH3:45])[CH3:44])[N:7]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(OCC)(=O)C>[OH:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:9]([CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:8]([CH:43]([CH3:44])[CH3:45])[N:7]=1
Reactant: CCCCCc1c(COC(C)=O)nc(C(C)C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCc1c(CO)nc(C(C)C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1-c1ccc(F)cc1
Yield: 107 %

Procedure:
A mixture of the intermediate obtained in Step A (60 mg, 0.096 mmol) and potassium carbonate (5 equiv) in methanol (8 mL) and water (2 mL) was refluxed for 1.5 h. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. Concentration of the organic phase provided a colorless solid (60 mg, 100%) that was used in the next step without purification. 1H NMR (300 MHz, CDCl3): δ 7.4-7.2 (m, 10H), 7.11 (m, 4H), 4.90 (s, 2H), 4.39 (s, 2H), 3.34 (sept, 7.0 Hz, 1H), 2.34 (m, 2H), 1.25 (d, 7.0 Hz, 6H), 1.2 (m, 2H), 1.04 (m, 4H), 0.90 (s, 9H), 0.68 (t, 7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[CH:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[C:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1
Reactant: C#CCOCCn1c(CCOC)nc2cnc3ccccc3c21
Reactant: Ic1ccccc1
Product: COCCc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 0.75 h
Yield: 346.4 %

Procedure:
Using the general method of Example 12 Part A, 2-(methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (2.72 g, 1.79 mmol) was reacted with iodobenzene (1.1 mL, 9.67 mmol) at ambient temperature. After 45 minutes the reaction was judged complete. The volatiles were removed under reduced pressure and the resulting oil partitioned between dichioromethane and 5% aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The organic fractions were combined, washed with brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to leave a brown solid. The solid was purified by chromatography over silica gel (95/5 (dichloromethane/methanol) and trituration with hexane to provide 2.39 g of 2-(methoxyethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as a yellow solid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O-].[Na+].[CH2:13](Br)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([CH2:14][CH2:13][CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)C(C)=O
Reaction time: 20 h
Yield: 91.3 %

Procedure:
Ethyl acetoacetate (53.8 g., 0.29 mole) was dissolved in 110 ml. of anhydrous ethanol. Sodium methoxide (17.3 g., 0.36 mole) was added portionwise to the stirred solution, allowing the temperature to rise to 40°-50°. The mixture was then heated to reflux (80°-82°) and phenethyl bromide (53.8 g., 0.32 mole) added dropwise over 1 hour. Reflux was continued for 20 hours. The reaction mixture was cooled to 30°-35° and filtered over diatomaceous earth with ethanol wash. The combined filtrate and wash were concentrated in vacuo to a pot temperature of 50°, cooled to 25°, diluted with 150 ml. of hexane and 40 ml. of water, acidified to pH 6.5-7.0 with 6N HCl. The hexane layer was separated and washed with 25 ml. of fresh water. The aqueous layer were combined and back-washed with 40 ml. of fresh hexane. The hexane layers were combined, washed with 60 ml. of water, dried over 15 g. MgSO4, filtered and evaporated to yield title product as an oil (62 g., 91%).
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C2C(=CC=C3CCCC3=2)[C:14](=[O:24])[C:13]1=[O:25]>>[CH:7]1[CH:6]=[C:5]2[CH:4]=[CH:3][C:2]3[C:13](=[O:25])[C:14](=[O:24])[NH:11][C:1]=3[C:10]2=[CH:9][CH:8]=1
Reactant: O=C1Nc2c(ccc3c2CCC3)C1=O
Reactant: Nc1cccc2c1CCCC2
Product: O=C1Nc2c(ccc3ccccc23)C1=O
Yield: 54 %

Procedure:
The benz[g]isatin was prepared in two steps from 5,6,7,8-tetrahydro-1-naphthylamine using the methods described for 1,6,7,8-tetrahydrocyclopenta[g]indole-2,3-dione (G. W. Rewcastle et. al., J. Med. Chem., 1991, 34, 217). The product (54% yield from N-[1-(5,6,7,8-tetrahydronaphthalenyl)]-2-(hydroximino)acetamnide) was obtained as an orange solid: mp. 234-235° C. (lit. [U.S. Pat. No. 1,856,210, 1929] 232° C.); NMR δH (400 MHz; DMSO-d6) 1.73 (4H, m), 2.49 (2H, m), 2.73 (2H, m), 6.78 (1H, d, J 7.7 Hz), 7.21 (1H, d, J 7.7 Hz) and 10.92 (1H, s).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Cl[C:8]1[CH:12]=[CH:11][O:10][C:9]=1[C:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]([C:25]([O:27]C)=[O:26])(O)[O:15][N:14]=1.[ClH:29]>O.CO>[Cl:29][C:11]1[O:10][C:9]([C:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:16]([C:25]([OH:27])=[O:26])[O:15][N:14]=2)=[CH:8][CH:12]=1
Reactant: COC(=O)C1(O)ON=C(c2occc2Cl)C1c1ccccc1
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1onc(-c2ccc(Cl)o2)c1-c1ccccc1

Procedure:
A solution of Na2CO3 (237 mg, 2.24 mmoles) in water (10 ml) was added to the methyl [3-(chlorofuran-2-yl)-4-phenyl-5-hydroxy-2-isoxazolin-5-yl]carboxylate (360 mg, 1.12 mmoles) in MeOH (10 ml). The reaction mixture was heated under reflux conditions for 2 h. It was then acidified with HCl and then the MeOH was distilled at a reduced pressure and CHCl3 was added. The two phases were separated and the aqueous phase was extracted three times with CHCl3. The combined organic phases were dried over anhydrous Na2SO4 and the solvent evaporated at a reduced pressure to give the crude [3-(5chlorofuran-2-yl)-4-phenylisoxazol-5-yl]carboxylic acid which is purified by crystallisation from CHCl3/hexane (300 mg, 93% yield). M.p. 168-170° C. FT-IR (KBr): 3500-2850, 1709, 1614, 1592, 1521, 1454, 1416, 1392, 1305, 1249, 1208, 1153, 1122, 1022, 1006, 981, 941, 899, 779, 696 cm−1. 1H NMR (300 MHz, CDCl3, δ): 7.48-7.42 (m, 3H, aromatic protons); 7.39-7.32 (m, 2H, aromatic protons); 7.00-6.50 (bs, 1H, OH: exchange with D2O); 6.14 (d, J=3.6 Hz, 1H, furyl proton); 6.12 (d, J=3.6Hz, 1H, furyl proton). 13C NMR (75 MHz, CDCl3, δ): 159.9, 154.8, 153.6, 141.6, 139.2, 129.4, 129.1, 128.3, 126.8, 123.9, 114.8, 107.9. LC-MS (ESI−): 288[(M−1)−, 69], 117 (100). Anal. Calc. for C14H8ClNO4: C, 58.05; H, 2.78; N, 4.83. Found: C, 58.07; H, 2.75; N, 4.80.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[C:6]([F:8])[CH:7]=1.CCN(S(F)(F)[F:17])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][F:17])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OCc1cc(F)cc(Br)c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-bromo-5-fluorophenyl)methanol (4 g, 19.51 mmol) in DCM (39.0 mL) at 0° C., DAST (3.35 mL, 25.4 mmol) was added. The reaction mixture was allowed to return to room temperature and stirred at room temperature overnight. Sat. NaHCO3 was added, the reaction mixture was then extracted by DCM. The organic was dried and concentrated. The crude material was purified by flash chromatography (0-10% EtOAc/heptanes) to yield the final product as colorless oil. LCMS (m/z): no mass (MH+), 0.86 min. 1H NMR (400 MHz, CDCl3) δ ppm 7.30 (s, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 5.41 (s, 1H), 5.29 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N1C=CC=C[CH:15]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].O>C(Cl)Cl>[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([O:7][CH3:15])=[O:6])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(NC(C)=O)cc([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
3-Amino-5-nitrobenzoic acid ([23218-93-1], 0.99 g, 5.05 mmol) was stirred in DCM (20 mL) and pyridine (2 mL) at 0° C. Acetic anhydride (1 mL, 10 mmol) was added. The reaction was stirred overnight. Water (30 mL) was added. A precipitate formed and was collected by filtration. [M+H] calc'd for C10H10N2O5 239; found, 239.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:11])=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2].[N:12]#[C:13]Br.[NH4+].[OH-]>CO.O>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=2[N:11]=[C:13]1[NH2:12])[CH3:2]
Reactant: N#CBr
Reactant: CCNc1ccc(F)cc1N
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1c(N)nc2cc(F)ccc21
Temperature: 25 °C

Procedure:
To a solution of N1-ethyl-4-fluoro-benzene-1,2-diamine (1.54 g, 10.0 mmol) in MeOH (20 mL) and H2O (20 mL) was added cyanogen bromide (2.1 mL, 10.5 mmol, 5.0 M in acetonitrile). The resulting mixture was stirred at room temperature over night. The resulting mixture was then adjusted to pH>9 with coned NH4OH and the resulting solid was collected by filtration, washed with H2O and hexanes to yield 1-ethyl-5-fluoro-1H-benzimidazol-2-ylamine MS 180 (M+1)+
Reaction SMILES: [F:1][C:2]([F:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:11]([OH:13])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[F:51][C:52]1[CH:59]=[CH:58][C:55]([CH2:56][NH2:57])=[CH:54][CH:53]=1>CN(C=O)C>[F:21][C:2]([F:1])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:11]([NH:57][CH2:56][C:55]1[CH:58]=[CH:59][C:52]([F:51])=[CH:53][CH:54]=1)=[O:13]
Reactant: O=C(O)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Reactant: NCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1ccc(F)cc1)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
To a solution of 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-thiazole-5-carboxylic acid (0.15 g, 0.45 mmol) in DMF (3 ml) are added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (216 mg, 0.68 mmol) and N-methylmorpholine (0.01 ml, 0.9 mmol) at 0° C. followed by the addition of 4-fluorobenzyl amine (67 mg, 0.54 mmol). The reaction mixture is stirred at RT for 3 h. After completion of the reaction, the mixture is poured onto ice-water, extracted with EtOAc (3×50 ml). The combined organic layers are washed with brine (50 ml), dried over sodium sulfate and evaporated to dryness to yield the crude product, which is purified by column chromatography (silica gel, 15% acetone/hexane) affording 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-thiazole-5-carboxylic acid amide (example 14) (93 mg, 0.21 mmol, 47%). [M+H]+ 441.1.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[C:14]([CH:15]=O)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[CH:11]=2)[N:6]=1>O.C(O)C>[Cl:4][C:5]1[C:14]([CH:15]=[N:2][OH:3])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[CH:11]=2)[N:6]=1
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc2nc(Cl)c(C=NO)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
A solution of 6.5 g hydroxylamine hydrochloride in 25 ml water was added to a suspension of 18.7 g 2-chloro-6-methoxy-3-quinolinecarboxaldehyde in 500 ml 95% ethanol. The mixture was stirred at room temperature for two hours and then heated at reflux for three hours. The reaction mixture was cooled to 0° C., filtered, and the filtrate concentrated to a volume of 200 ml. The product separated from solution to give 16.3 g 2-chloro-6-methoxy-3-quinolinecarboxaldehyde oxime, m.p. 195° C. (decompn.).
Reaction SMILES: [CH:1]1[CH:2]=[C:3](C(O)=O)[S:4][CH:5]=1.[Br:9]Br.C[C:12]([OH:14])=[O:13]>>[Br:9][C:3]1[S:4][CH:5]=[C:1]([C:12]([OH:14])=[O:13])[CH:2]=1
Reactant: O=C(O)c1cccs1
Reactant: BrBr
Reactant: CC(=O)O
Product: O=C(O)c1csc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Prepare a solution of thiophene carboxylic acid (500 mg, 3.90 mmol) in HOAc (5 mL). Add Br2 (0.17 mL, 0.85 mmol), in HOAc (3 mL), dropwise. Then stir the mixture for 15 minutes at room temperature under nitrogen. Quench the reaction with ice cold water and stir for an additional 10 minutes. Cool the solution −10° C. when the product will precipitate out. Filter the solution, rinse the filter cake with ice cold water, and dry the product to afford 473 mg of 5-bromothiophene-3-carboxylic acid as a white solid. 1H NMR (dimethylsulfoxide-d6) δ 12.90 (br s, 1H), 8.18 (d, J=1.5 Hz, 1H), 7.46 (d, J=1.5 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19].[C:22]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:22][C:2]1[N:1]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: O=C([O-])O
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the solution of imidazole (2.20 g, 26.8 mmol) in 20 mL DMF at 0° C. under argon atmosphere is added with sodium hydride (60% dispersion in mineral oil, 1.43 g, 35.7 mmol) potion wise. After 15 min, 1-Fluoro-4-nitro-2-trifluoromethyl-benzene (5.0 g, 23.9 mmol) is added. The resulting reaction mixture is allowed to warm to room temperature and kept stirring for 2 hr. Then the reaction mixture is poured into 100 mL saturated NaHCO3 solution, extracted three times with 150 mL ethyl acetate. The organic extracts are washed with brine, and dried over MgSO4. Filtration and concentration under reduced pressure, afforded the title compound as white powder, which is directly used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH:20]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[S:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:15][N:14]=1)=[O:12])(C)(C)C.ClC(OC)=O.C(N(CC)CC)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH3:1][O:5][C:6](=[O:39])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([CH:20]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[F:38])[S:21]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])=[CH:15][N:14]=1)=[O:12]
Reactant: Cc1cc(C(=O)NCCNC(=O)OC(C)(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COC(=O)NCCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of tert-butyl[2-[[[5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]meth yl]-4-methylpyridin-2-yl]carbonyl]amino]ethyl]carbamate (90 mg, 0.160 mmol) obtained in Example 82 in methylene chloride (5 ml), trifluoroacetic acid (2 ml) was added, and the mixture was stirred for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure, and methylene chloride and a 0.5 N aqueous sodium hydroxide were added thereto. The organic layer was separated, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was dissolved in methylene chloride (5 ml), and methyl chloroformate (19 μl, 0.240 mmol) and triethylamine (26 μl, 0.240 mmol) were added thereto. The reaction solution was stirred for 20 hours at room temperature, and was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with 60% ethylacetate/hexane was concentrated under reduced pressure. Ethyl acetate-hexane was added to the resulting concentration residue, and the solid thus precipitated was collected by filtration, to obtain the title compound (71 mg, 0.136 mmol, 85%) as a white powder.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH:13]1([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:13]1([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:2][C:3]3[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=3[C:5]([O:7][CH3:8])=[O:6])=[CH:26][CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: Oc1ccc(C2CCc3ccccc32)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1COc1ccc(C2CCc3ccccc32)cc1
Yield: 94.5 %

Procedure:
A mixture of methyl 2-(bromomethyl)benzoate (10.00 g, 43.7 mmol), 4-(1-indanyl)phenol (11.47 g, 54.5 mmol), and potassium carbonate (13.27 g, 96.0 mmol) in DMF was heated at 60° C. for 4h, then was allowed to stir at room temperature for 3d. The resulting reaction mixture was partitioned between ether and water, then the organic phase was dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with 4% ethyl acetate in hexanes to afford 14.8 g of methyl 2-[4-(1-indanyl)phenoxymethyl]benzoate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].Cl[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].CC(C)([O-])C.[K+].Cl>O1CCCC1>[N+:10]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[C:5]([Cl:9])[C:4]=1[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([O-:12])=[O:11]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1c(Cl)c(Cl)cc(Cl)c1[N+](=O)[O-]
Temperature: -40 °C
Yield: 58.6 %

Procedure:
A solution of 2,4,5-trichloronitrobenzene (Jpn. Kokai Tokyo Koho JP 81,169,651 (1980), Chem. Abstr. 1981,96, 162307 q)(103 g, 0.46 mol) and t-butyl chloroacetate (79 ml, 0.55 mol) in dry tetrahydrofuran (400 ml) was added dropwise over 30 minutes to a solution of potassium t-butoxide (128 g, 1.14 mol) in dry tetrahydrofuran (800 ml) with stirring, under nitrogen keeping the temperature at -40° C. After the addition was complete, the resulting dark blue solution was stirred for a further 30 minutes. The mixture was poured into 0.5M hydrochloric acid (2 L) and the product was extracted into ethyl acetate (2.5L and 1 L). The combined organic solutions were dried (MgSO4) and evaporated onto silica gel (70-200 m, 200 g). The silica gel was applied to the top of a silica gel chromatography column (800 g), and the product was eluted using a hexane/ethyl acetate gradient. Product-containing fractions were combined and evaporated to give a yellow solid, which was triturated with hexane to give t-butyl 2-nitro-3,5,6-trichlorophenylacetate (91.8 g, 59%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[NH2:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CCC(N)CC
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)Nc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 97.4 %

Procedure:
To a solution of 5.38 g of 4-fluoro-3-nitro-benzoic acid methyl ester in 25 ml of abs. DMF was added 5.60 g of potassium carbonate, followed by 2.67 g of 3-aminopentane. After 3 h at rt, the mixture was poured into water, and extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over sodium sulphate and concentrated to yield 7.01 g (97%) of 4-(1-Ethyl-propylamino)-3-nitro-benzoic acid methyl ester as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[CH:3]=1.Cl.[NH2:18][NH:19][C:20]([NH2:22])=[O:21].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[N:18][NH:19][C:20]([NH2:22])=[O:21])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: NNC(N)=O
Reactant: O=Cc1ccc(Oc2cc(Cl)ccn2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)NN=Cc1ccc(Oc2cc(Cl)ccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 4-(4-chloro-2-pyridinoxy)benzaldehyde (330 mg, 1.41 mmol) in ethanol (10 mL) was added a solution of semicarbazide hydrochloride (213 mg, 1.84 mmol) and sodium acetate trihydrate (224 mg, 1.65 mmol) in water (5 mL). The mixture was stirred at room temperature for 30 min., and the resulting solid was collected by filtration, washed with water and dried in vacuo to yield the title compound as a white solid (400 mg, 1.36 mmol, 96%), mp: 231-233° C. 1H NMR (DMSO-d6): δ 10.22 (s, 1H), 8.22 (d, J=2.5, 1H), 7.97 (dd, J=2.5, 8.7, 1H), 7.85 (s, 1H), 7.77 (d, J=8.7, 2H), 7.15 (d, J=8.7, 2H) 7.12 (d, J=8.7, 1H), 6.47 (s, 2H).