Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reaction time: 15 h

Procedure:
To a solution of 4-bromophenol (5.1 g; 29 mmol) and imidazole (2 g; 29 mmol) in CH2Cl2 (50 ml) at 0° C. is added t-butyldimethylsilyl chloride (4.4 g; 29 mmol) and the reaction is stirred for 15 hours. This is then diluted with CH2Cl2, washed with H2O, ammonium chloride solution, NaHCO3, dried (MgSO4) and concentrated in vacuo to yield 4-bromo-t-butyldimethylsilyloxybenzene as an oil which is used directly in Step B without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]=[O:10])[CH:2]=1
Reactant: OCCCc1cccnc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCCc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.5 %

Procedure:
3-Pyridinepropanol (300 mg, 2.2 mmol) was dissolved in dichloromethane (5 mL). To this, the Dess-Martin reagent (1.0 g) was added with cooling in an ice bath and the mixture was stirred at the same temperature for 2 hours and successively at room temperature for 3 hours. The solvent in the reaction mixture was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=1/0 to 10/1) to give 3-(pyridin-3-yl)propanal (180 mg, yield: 61%).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][NH2:5].[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7]1>CO>[SH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:13])[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C1CCCC(=O)O1
Reactant: NCCCS
Solvent: CO
Product: O=C(O)CCCC(=O)NCCCS
Temperature: 25 °C
Yield: 126.7 %

Procedure:
To a solution of 6.84 g (0.075 mole) of 3-mercapto propyl amine (homocysteamine) in 20 cm3 of methanol, maintained under an inert atmosphere and stirred at ambient temperature, there are added, by portions, 8.56 g (0.075 mole) of glutaric anhydride while maintaining the temperature of the reaction mixture lower than 40° C. After stirring for 6 hours 30 minutes the reaction is complete. The solution is evaporated to dryness under reduced pressure. The product is then dried under a vacuum at a temperature lower than 60° C. and 19.5 g of N-(3-mercapto propyl) glutaramic acid are obtained in the form of a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:28][CH:29]([F:31])[F:30])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])[C:10]([CH2:17][CH3:18])=[N:11]2.CO.O.[OH-].[Li+]>C(O)(=O)C>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[CH2:19][C:9]1[C:10]([CH2:17][CH3:18])=[N:11][C:12]2[C:7]([C:8]=1[O:28][CH:29]([F:30])[F:31])=[C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(F)cc1F

Procedure:
A solution of [3-(2,4-difluorobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.54 g), methanol (20 mL), water (1.0 mL) and 5.0 M aqueous lithium hydroxide solution (0.5 mL) was stirred at room temperature for 2 hours. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water and the solid collected by filtration, washed with water and dried to afford title compound as a cream solid, 0.089 g.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:31])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:9][CH2:10][CH2:11][C:12](OC)=[O:13].O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][C:8]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:31])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: COC(=O)CCC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=CCCCO)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
Under a nitrogen atmosphere, 9.6 g (0.25 mol) of lithium aluminum hydride was added little by little at 0° C. to a solution of 150 g (0.425 mol) of methyl 5,9,13,17-tetramethyloctadec-4-enoate in dry tetrahydrofuran (850 mL). After being stirred at 50° C. for 2 hours, the reaction mixture was cooled on ice, followed by careful addition of water until the resulting gray suspension turned white. Sodium sulfate was added to the solution at room temperature for drying. After filtration, the filtrate was concentrated to obtain 133.8 g of the title compound (97% yield) as a colorless transparent liquid. The results of NMR analysis of the resulting compound are as shown below.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1.CI.[C:19]([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:19][S:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CCc2ccc(S)cc2O1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)C1CCc2ccc(SC)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of ethyl 7-mercaptochromane-2-carboxylate (3.4 g, 14.3 mmol), Methyliodide (3.03 g, 21.4 mmol) and K2CO3 (7.88 g, 57 mmol) in ACN (100 ml) was stirred for 2 h at RT. Filtration and evaporation of solvents gave the title compound (3.28 g). MS m/z (rel. intensity, 70 eV) 252 (M+, bp), 179 (94), 177 (40), 132 (55), 131 (63).
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4](=[O:24])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:20]3[O:19][CH:18]=[CH:17][C:16]=3[CH:15]=[C:14]([N+:21]([O-])=O)[CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].NC1C=C(N2CCN(C(OC(C)(C)C)=O)CC2)C2OC=CC=2C=1>>[NH2:21][C:14]1[CH:13]=[C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][C:4]([N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])=[O:24])[CH2:7][CH2:8]2)[C:20]2[O:19][CH:18]=[CH:17][C:16]=2[CH:15]=1
Reactant: CCN(CC)C(=O)CN1CCN(c2cc([N+](=O)[O-])cc3ccoc23)CC1
Agent: CC(C)(C)OC(=O)N1CCN(c2cc(N)cc3ccoc23)CC1
Product: CCN(CC)C(=O)CN1CCN(c2cc(N)cc3ccoc23)CC1

Procedure:
Reduction of the nitro group in N,N-diethyl-2-[4-(5-nitro-1-benzofuran-7-yl)piperazin-1-yl]acetamide (0.3 g, 0.83 mmol; Intermediate 22) was performed according to the procedure of Intermediate 10. Yield: 0.19 g (70%). This material was used in the next step without further purification. MS (ESI+) m/z 331.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][S:11](=[O:20])(=[O:19])[C:10]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:9]1=2)=[O:6].[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH2:12][S:11](=[O:20])(=[O:19])[C:10]4[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:9]3=4)=[O:6])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: Cc1ccc2c(c1)C(NC(=O)CCCCl)c1ccccc1CS2(=O)=O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(NC(=O)CCCN1CCN(c3ccc(F)cc3)CC1)c1ccccc1CS2(=O)=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
A mixture of 2.0 g of 11-(4-chlorobutyrylamino)-2-methyl-6,11-dihydrodibenzo[b,e]thiepin-5,5-dioxide, 2.0 g of 1-(4-fluorophenyl)piperazine, 2.0 g of sodium iodide and 20 ml of dimethylformamide is stirred at 100° C. for one hour. After the reaction mixture is cooled to room temperature, 100 ml of 10% aqueous potassium carbonate solution is added and the solution is extracted with three 300-ml portions of chloroform. The combined extracts are washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate, and the chloroform is distilled off. The residue is recrystallized from chloroform-diethyl ether to give 2.1 g of the title compound, m.p. 163°-165° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[O:14][C:13]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:12][CH:11]=2)[S:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[C:19]([O:18][C:16]([NH:15][C:13]1[O:14][C:10]([C:8]2[S:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:9]=2)=[CH:11][N:12]=1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1csc(-c2cnc(NC(=O)OC(C)(C)C)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ncc(-c2cc(C(=O)O)cs2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
5-(2-tert-Butoxycarbonylamino-oxazol-5-yl)-thiophene-3-carboxylic acid methyl ester (0.152 g, 0.47 mmol) was suspended in methanol (2 mL), sodium hydroxide (1 M, 1.17 mL, 1.18 mmol) was added and the mixture stirred overnight at room temperature. The mixture was evaporated then HCl (1 N, 1.2 mL) and water (1 mL) were added. The resultant white precipitate was collected by filtration then dried under vacuum to afford 5-(2-tert-butoxycarbonylamino-oxazol-5-yl)-thiophene-3-carboxylic acid (0.077 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[Br:27][Br-]Br>CC(O)=O.O>[Br:27][C:9]1[S:10][C:11]2[NH:12][C:13](=[O:20])[C:14]([C:18]#[N:19])=[C:15]([OH:17])[C:16]=2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: N#Cc1c(O)c2c(-c3ccc(Cl)cc3)csc2[nH]c1=O
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(O)c2c(-c3ccc(Cl)cc3)c(Br)sc2[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(4-chlorophenyl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.17 g, 0.55 mmol) in AcOH (6 mL) was added pyridine hydrobromide perbromide (0.18 g, 0.6 mmol) in a single portion at room temperature. The reaction was stirred at room temperature for 1 h, diluted with water (25 mL). The resultant solid was filtered and dried to give the title compound. MS (ESI) m/e 380.79 (M−H)+; 1H NMR (300 MHz, DMSO-d6): ppm 7.45 (d, 2H), 7.33 (d, 2H).
Reaction SMILES: [S:1]([CH:5]([N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[C:6](O)=[O:7])([OH:4])(=[O:3])=[O:2].S(Cl)([Cl:16])=O.CN(C)C=O.CCCCCC>CCOCC>[S:1]([CH:5]([N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[C:6]([Cl:16])=[O:7])([OH:4])(=[O:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(n1cccc1)S(=O)(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Cl)C(n1cccc1)S(=O)(=O)O
Temperature: 40 °C

Procedure:
2-Sulfo-2-(1-pyrryl)acetic acid is treated with thionyl chloride in ether at room temperature according to the general procedure in J. Med. Chem., 15, 1105 (1972) until the evolution of gas stops. Dimethylformamide is added, the solution is warmed to about 40° C. for 1 hour. Then ether is added, followed by hexane and the solution cooled to about -25° C. 2-Sulfo-2-(1-pyrryl)acetyl chloride is isolated from the solvent by decantation.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]#[N:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Yield: 92 %

Procedure:
The title compound (1.58 g, 92%) was prepared using 4-[4-(3-thiomorpholin-4-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile and lithium aluminium hydride similarly to the procedure used for intermediate 51. LRMS APCI+ m/z 351 [MH]+.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5]C(C)(C)C.C1CCC(N=C=NC2CCCCC2)CC1.N[C@H](C(OCC1C=CC=CC=1)=O)CC1C2C(=CC=CC=2)NC=1.Cl>C(Cl)Cl>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:5])[OH:10]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 189.2 %

Procedure:
41 mg of Fmoc-Asp(Ot-Bu)-OH was dissolved in 1 ml of methylene chloride. The solution was cooled to 0° C., and then 12 mg of HONSu and 21 mg of DCC were added thereto. The mixture was stirred at 0° C. for 30 minutes. To the mixture were added 1 ml of a methylene chloride containing 33 mg of H-Trp-OBzl.HCl and 14 μl of TEA, followed by stirring at 0° C. for 3 hours. The insoluble matters were filtered off and the filtrate was washed with cold methylene chloride. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Wakogel C-200, manufactured by Wako Junyaku Kogyo, 50 g, elution with chloroform/methanol=25/1), to obtain 67 mg of Fmoc-Asp(Ot-Bu-Trp-OBzl as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)NCC2

Procedure:
A suspension of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (21.9 g, 0.1 mol) and 10% palladium/charcoal (1.5 g) in glacial acetic acid (200 ml) is hydrogenated at 50° C. under a hydrogen pressure of 5 bar. After the catalyst has been filtered off the solvent is evaporated in vacuo and the residue is taken up in methylene chloride. After extraction with sodium bicarbonate solution and washing with water, the product is dried over magnesium sulphate, concentrated by evaporation and purified over silica gel with methylene chloride and then with increasing amounts of methanol (up to 10%).
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]>CO.COC(COC)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]([O:19][CH3:1])=[O:18])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(CCC(=O)O)cc1OC
Reactant: CC(=O)Cl
Solvent: CO
Solvent: COCC(C)OC
Product: COC(=O)CCc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (20 cc) was added dropwise over 10 minutes with stirring to methanol (400 cc); the resulting solution was added all at once to a magnetically stirred suspension of 3-(3,4-dimethoxyphenyl)propionic acid (500 g, 2.378 moles) in methanol (1.6 1) and 2,3-dimethoxypropane (250 cc). The reaction mixture was stirred overnight at room temperature and then at reflux for 1 hour. After cooling, the solution was evaporated in vacuo to a light yellow syrup; yield: 533 g (100%).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[CH2:23][CH2:24][CH3:25].[N+:26]([O-])([OH:28])=[O:27]>>[OH:6][C:7]1[C:8]([CH2:23][CH2:24][CH3:25])=[CH:9][C:10]([C:13]([OH:22])([C:14]([F:15])([F:16])[F:17])[C:18]([F:19])([F:20])[F:21])=[CH:11][C:12]=1[N+:26]([O-:28])=[O:27]
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc([N+](=O)[O-])c1O
Temperature: 40 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
Concentrated sulfuric acid (1.2 mL) was added to 2-(4-hydroxy-3-propylphenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (500 mg, 1.65 mmol) under ice-cooling. Then, a mixed solution of nitric acid (109 μL) and concentrated sulfuric acid (219 μL) was added dropwise at 30 to 35° C., followed by stirring at 40° C. for three hours. The reaction solution was cooled and then added dropwise to ice water. After neutralization to pH 7 with a sodium hydroxide solution (1 mol/L), the neutralized solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 94.3 mg of the title compound (yield: 16%) as a red orange oil.
Reaction SMILES: ON[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([CH3:14])=[N:12][N:11]=[N:10]1.N([O-])=O.[Na+].S(=O)=O.[S:22](Cl)([Cl:25])(=[O:24])=[O:23]>Cl.C(O)(=O)C.O>[Cl:25][S:22]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([CH3:14])=[N:12][N:11]=[N:10]1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1nnnn1-c1ccccc1NO
Agent: Cl
Agent: O=N[O-]
Agent: O=S=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1nnnn1-c1ccccc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5 g of 1-(2-hydroxylaminophenyl)-5-methyl-1H-tetrazole in 12 mL of 37% hydrochloric acid and 5 mL of acetic acid at 0°-5° C. was added 2.3 g of sodium nitrite in 10 mL of water. The resultant solution was stirred at -5° to +5° C. for one hour and then added portionwise, with stirring, to a mixture of 25 mL of acetic acid, 0.5 g of cupric chloride and 5 mL of liquified sulfur dioxide at below 5° C. After stirring for two hours, during which time the mixture was allowed to warm to room temperature, it was poured into 150 mL of ice and water and extracted twice with 150 mL of methylene chloride. The methylene chloride solution was washed three times with 100 mL portions of water, two times with 100 mL of saturated aqueous sodium bicarbonate followed by single washes with 100 mL of saturated aqueous sodium chloride and 100 mL of water. The methylene chloride solution was then dried over magnesium sulfate and filtered to yield a solution containing the desired sulfonylchloride. This solution was used without further work-up to prepare the sulfonamide of Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.ClCCl.O.N1C=CC=CC=1>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:13](=[O:15])[NH:1][C:2]=2[CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Temperature: 50 °C
Yield: 79411 %

Procedure:
To a stirred solution of 2-amino-4-chloro benzoic acid (10 g, 0.058 mmol) in acetonitrile (60 mL, 1 M), was added pyridine (9.4 mL, 0.117 mmol, 2 equiv), and triphosgene (17.3 g, 0.058 mmol, 1 equiv) in dichloromethane (85 mL, 0.7 M). The orange reaction solution was heated at 50° C. for two hours then cooled to room temperature. The solution was diluted with water (50 mL), and the organic and aqueous layers were separated. The aqueous layer was washed with dichloromethane (3×50 mL), and the combined organic layers were washed once with brine (50 mL), and dried over magnesium sulfate. The solvent was removed in vacuo leaving a yellow solid. The solid was titrated with hexanes to yield 7-chloro-1H-benzo[d][1,3]oxazine-2,4-dione (9.1 g, 74%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:20](I)([CH3:22])[CH3:21]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH:20]([O:15][C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:19])=[CH:18][CH:17]=1)([CH3:22])[CH3:21]
Reactant: CC(C)I
Reactant: O=C(O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Yield: 43.1 %

Procedure:
To a solution of 4-[2-(4-fluorophenyl)-2-oxoethyl]benzoic acid (Example 3, Step 1) (0.600 g, 2.32 mmol) in toluene(25 ml) was added silver carbonate (1.06 g) and isopropyl iodide (0.70 g).The reaction was refluxed for 2 hour. The reaction mixture was filtered on a pad of silica gel and washed with hexane/ethyl acetate 20%. to give (0.3 g) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:10][CH:9]2[NH:11][CH:6]([CH2:7][CH2:8]2)[CH2:5]1.C(N(CC)CC)C.[Cl:19][C:20]1[N:21]=[C:22](Cl)[C:23]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:27]([C:35]([O:37][CH3:38])=[O:36])[S:26][C:24]=2[N:25]=1>C(O)C.ClCCl.O>[CH3:38][O:37][C:35]([C:27]1[S:26][C:24]2[N:25]=[C:20]([Cl:19])[N:21]=[C:22]([N:11]3[CH:6]4[CH2:7][CH2:8][CH:9]3[CH2:10][CH:4]([CH2:3][O:2][CH3:1])[CH2:5]4)[C:23]=2[C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:36]
Reactant: COC(=O)c1sc2nc(Cl)nc(Cl)c2c1-c1ccccc1
Reactant: COCC1CC2CCC(C1)N2
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: COCC1CC2CCC(C1)N2c1nc(Cl)nc2sc(C(=O)OC)c(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 104 %

Procedure:
3-(Methoxymethyl)-8-azabicyclo[3.2.1]octane (0.106 g, 0.683 mmol) was dissolved in ethanol (2 mL) and dichloromethane (2 mL). Triethylamine (0.166 mL, 1.18 mmol) and methyl 2,4-dichloro-5-phenyl-thieno[2,3-d]pyrimidine-6-carboxylate (0.200 g, 0.590 mmol) were added and the mixture was stirred at room temperature for 5 hr. It was diluted with dichloromethane (2 mL) and water (2 mL). The layers were separated and the aqueous was extracted with dichloromethane (2×2 mL). The combined organic layers were evaporated to give a yellow oil (281 mg). This was purified by silica chromatography (10 g cartridge; eluent petroleum ether 40-60/ethyl acetate 0 to 20%; all output collected). Fractions corresponding to the main peak were combined and evaporated to give the target compound as a yellow solid (0.177 g). m/z [M+H]+458.0/460.0. Retention time 5.30 min (LCMS method+ve 6 min).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OCC)=O)=NC(OCC)=O>O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[O:18][C:11]([C:12]3[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=3)=[N:10][C:3]=2[CH:4]=1
Reactant: COc1ccc(O)c(NC(=O)c2ccncc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2oc(-c3ccncc3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.2 %

Procedure:
To a mixture of 1.17 g of N-(2-hydroxy-5-methoxyphenyl)isonicotinamide, 1.26 g of triphenylphosphine and 25 ml of tetrahydrofuran, a mixture of 0.85 g diethyl azodicarboxylate and 5 ml of tetrahydrofuran was added dropwise. The mixture was warmed to room temperature and stirred for four hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. Activated carbon was added thereto, which was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.11 g of 5-methoxy-2-(pyridin-4-yl)-benzoxazole (hereinafter, referred to as “active compound 11”).