Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([C:8]([CH3:20])([CH3:19])[CH2:9][C:10]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:11]([OH:13])=O)[CH:7]=1.S(Cl)(Cl)=O.[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:34](=[O:35])[O:33][CH2:32]2.Cl>CC(N(C)C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([C:8]([CH3:19])([CH3:20])[CH2:9][C:10]([OH:18])([C:14]([F:15])([F:17])[F:16])[C:11]([NH:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[C:34](=[O:35])[O:33][CH2:32]3)=[O:13])[CH:7]=1
Reactant: CC(C)(CC(O)(C(=O)O)C(F)(F)F)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Nc1ccc2c(c1)COC2=O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(CC(O)(C(=O)Nc1ccc2c(c1)COC2=O)C(F)(F)F)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 22.6 %

Procedure:
255 mg of 4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleric acid in 3 ml of dimethyl acetamide is mixed at 0° C. with 0.105 ml of thionyl chloride, stirred for 30 minutes at 0° C. and 45 minutes at room temperature and combined with 300 mg of 5-aminophthalide. After 16 hours at room temperature, it is mixed with 2 M hydrochloric acid and ethyl acetate, the organic phase is washed neutral with water, dried (Na2SO4) and concentrated by evaporation. After chromatography on silica gel with hexane-ethyl acetate (3:2) and recrystallization from diisopropyl ether, 80 mg of 5-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]phthalide is obtained, flash point 200–201° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1C(F)(F)F)[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.[CH3:27][N:28]1[C:32]([C:33]2[CH:34]=[C:35]([C:38]([OH:40])=O)[S:36][CH:37]=2)=[CH:31][CH:30]=[N:29]1.Br[C:42]1C=C(C(O)=O)SC=1C1N(C)N=CC=1>>[NH2:5][CH2:4][CH:3]([N:2]([CH3:42])[C:38]([C:35]1[S:36][CH:37]=[C:33]([C:32]2[N:28]([CH3:27])[N:29]=[CH:30][CH:31]=2)[CH:34]=1)=[O:40])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cn1nccc1-c1csc(C(=O)O)c1
Reactant: Cn1nccc1-c1sc(C(=O)O)cc1Br
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Product: CN(C(=O)c1cc(-c2ccnn2C)cs1)C(CN)Cc1ccccc1

Procedure:
The title compound was prepared as a white solid according to the procedure of Example 6, except substituting 2-[2-(methylamino)-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.7 mmol)[prepared according to the procedure of Preparation 6] for 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl and substituting 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (150 mg, 0.72 mmol) for 4-bromo-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid. The reaction mixture was absorbed onto silica and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound, which was further purified by Gilson reverse phase chromatography 5-95% H2O (1% TFA)/MeCN (1% TFA) to afford the TFA salt: LC-MS (ES) m/z 355 (M+H)+, 1H NMR (400 MHz, MeOD) δ ppm 2.86 (s, 3H) 2.97 (dd, J=14.02, 8.72 Hz, 2H) 3.12-3.23 (m, 2H) 3.70 (m, 1H) 3.97 (s, 3H) 6.47 (d, J=2.02 Hz, 1H) 7.30-7.35 (m, 1H) 7.37-7.43 (m, 5H) 7.51 (d, J=2.02 Hz, 1H) 7.88 (d, J=1.52 Hz, 1H) 7.94 (d, J=1.52 Hz, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[C:12]([C:18]#[N:19])=[N:13][CH:14]=[C:15](F)[CH:16]=1.[NH2:20][C@H:21]1[C@@H:26]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:25][CH2:24][S:23](=[O:36])(=[O:35])[CH2:22]1>CN1C(=O)CCC1.O>[Br:10][C:11]1[CH:16]=[C:15]([NH:20][C@H:21]2[C@@H:26]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:33])[CH3:31])[CH2:25][CH2:24][S:23](=[O:36])(=[O:35])[CH2:22]2)[CH:14]=[N:13][C:12]=1[C:18]#[N:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS(=O)(=O)C[C@H]1N
Reactant: N#Cc1ncc(F)cc1Br
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCS(=O)(=O)C[C@H]1Nc1cnc(C#N)c(Br)c1
Temperature: 150 °C

Procedure:
A mixture of Hunig's base (2.69 ml, 15.4 mmol), 3-bromo-5-fluoropyridine-2-carbonitrile (1.55 g, 7.69 mmol), tert-butyl rel-[(3S,4S)-3-amino-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]carbamate (2.51 g, 9.50 mmol) in NMP (8 ml) was heated to 150° C. for 30 minutes. The reaction mixture was diluted with water (50 mL) and stirred. The reaction mixture was filtered, and the collected solids were washed with cold water. The solids were dried under reduced pressure to afford tert-butyl rel-{(3S,4S)-3-[(5-bromo-6-cyanopyridin-3-yl)amino]-1,1-dioxidotetrahydro-2H-thiopyran-4-yl}carbamate. MS ESI calc'd. for C16H22BrN4O4S [M+H]+ 445 and 447. found 445 and 447.
Reaction SMILES: Cl[C:2]([F:7])([F:6])[C:3]([O-])=O.[Na+].[CH:9]1([CH:14]([C:35]2[CH:40]=[CH:39][C:38](C=O)=[CH:37][CH:36]=2)[C:15]([NH:17][C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[CH2:21][C:22]2([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(OCC)(=O)C>[CH:9]1([CH:14]([C:35]2[CH:40]=[CH:39][C:38]([CH:3]=[C:2]([F:7])[F:6])=[CH:37][CH:36]=2)[C:15]([NH:17][C:18]2[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=2)[CH2:21][C:22]2([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:23][CH2:24]2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(C=O)cc3)C3CCCC3)c2)CC1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(C=C(F)F)cc3)C3CCCC3)c2)CC1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
At 60° C., 475.6 mg (3.12 mmol) of sodium chloro(difluoro)acetate were added to a mixture of 800.0 mg (1.73 mmol) of (+/−)-tert-butyl 1-(3-{[cyclopentyl(4-formylphenyl)acetyl]-amino}benzyl)cyclopropanecarboxylate and 681.9 mg (2.60 mmol) of triphenylphosphine. The mixture was heated to 110° C. and stirred at this temperature for 30 min. After cooling, the mixture was poured into water. Ethyl acetate was added, and the organic phase was separated off, washed with saturated sodium chloride solution, dried with magnesium sulphate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 319.2 mg (37.2% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:26])[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:16][CH2:17][OH:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:18][CH2:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:26])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CN(CCCO)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
(S)-6-Benzyloxycarbonylamino-4-(tert-butoxycarbonyl)-4-azaheptan-1-ol (380 g, 1.04 mol) and triethylamine (147 g, 1.45 mol) were dissolved in methylene chloride (5.0 L). The resulting solution was cooled to 0° C., to which a solution of methanesulfonyl chloride (143 g, 1.25 mol) in methylene chloride (0.1 L) was added at an internal temperature of 5° C. or below. Subsequently, the reaction mixture was stirred at room temperature for 16 hours. After confirming the disappearance of the starting materials by TLC, purified water was added to the reaction mixture for extraction. The resulting organic layer was washed with 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The resulting mixture was filtered and concentrated under reduced pressure to give the target product as a yellow oil (425 g, yield 92.0%). Despite the fact that the compound thus obtained was refrigerated, the degradation reaction proceeded, revealing that this compound was unstable.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([S:15](Cl)(=[O:17])=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>N1C=CC=CC=1>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][S:15]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:17])=[O:16]
Reactant: Nc1nccs1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)c2ccccc12
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nccs2)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.1 %

Procedure:
To a solution of 4-acetamidonaphthalene-1-sulfonyl chloride (3.69 g, 2.42 mmol) and pyridine (2 ml) was added 2-aminothiazole (0.24 g, 2.42 mmol). This mixture was stirred at RT for 72 h. Purification via silica gel chromatography (first using 2% MeOH in CH2Cl2 to wash out remaining amine, then using 8% MeOH in CH2Cl2) gave N-[4-(thiazol-2-ylsulfamoyl)-naphthalen-1-yl]-acetamide (0.48 g, 57%). LC/MS (10-99% CH3CN), M/Z: M+1 obs=348.10; tR=1.78 min.
Reaction SMILES: OCC[C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8].[CH3:15][C:16](C(OC1[C@@]2(C)C(C)(C)[C@H](CC2)C1)=O)=C.C1(C)C(S(O)(=O)=O)=CC=CC=1.COC1C=CC(O)=CC=1.[OH:51][CH2:52][NH:53][C:54](=[O:57])[CH:55]=[CH2:56]>C(#N)C=C>[C:7]1(=[O:8])[N:9]([CH2:15][CH2:16][O:51][CH2:52][NH:53][C:54](=[O:57])[CH:55]=[CH2:56])[C:10](=[O:11])[C:5]2=[CH:4][CH:14]=[CH:13][CH:12]=[C:6]12
Reactant: O=C1NC(=O)c2c(CCO)cccc21
Reactant: C=CC(=O)NCO
Reactant: C=C(C)C(=O)OC1C[C@H]2CC[C@]1(C)C2(C)C
Agent: COc1ccc(O)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: C=CC#N
Product: C=CC(=O)NCOCCN1C(=O)c2ccccc2C1=O
Temperature: 120 °C

Procedure:
Approximately equimolar amounts of N-(2-hydroxyethyl phthalimide (about 5 molar percent excess) and dried IBMA were mixed together in a reaction flask with 0.5 weight percent toluene sulfonic acid, based on the weight of IBMA, and 200 ppm MEHQ added. The nearly dry blend was stirred and heated using an external oil bath. When the temperature reached 65° C., a rapid reaction ensued and the reaction mixture partially liquified. After a short period of time, the reaction rate (as evidenced by the isobutyl alcohol removal) almost stopped, and the reaction mixture solidified. The reaction mixture was then rapidly heated to about 120° C., and the reaction again proceeded vigorously, going to near quantitative yields in a few more minutes. The product was a clear, low viscosity liquid at 120° C. which solidified at about 65° C. to a waxy, opaque white solid which was found to be readily soluble in acrylonitrile. The product was the 2-hydroxyethyl phthalimide ether of N-(hydroxymethyl) acrylamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH2:11][CH:12](O)[CH3:13])=[CH:9][N:8]([C@@H:15]3[O:30][C@H:29]([CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=4[Cl:41])[C@@H:18]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@:16]3([CH3:42])[OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:62]1(=[O:72])[NH:66][C:65](=[O:67])[C:64]2=[CH:68][CH:69]=[CH:70][CH:71]=[C:63]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([CH2:11][CH:12]([N:66]3[C:62](=[O:72])[C:63]4=[CH:71][CH:70]=[CH:69][CH:68]=[C:64]4[C:65]3=[O:67])[CH3:13])=[CH:9][N:8]([C@@H:15]3[O:30][C@H:29]([CH2:31][O:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=4[Cl:41])[C@@H:18]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@:16]3([CH3:42])[OH:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1cn([C@@H]2O[C@H](COCc3ccc(Cl)cc3Cl)[C@@H](OCc3ccc(Cl)cc3Cl)[C@@]2(C)O)c2ncnc(Cl)c12)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of compound 4.3 (1.28 g, 1.89 mmol) in THF (70 mL) were added triphenylphosphine (648 mg, 2.47 mmol) and phthalimide (364.0 mg, 2.47 mmol) followed by DEAD (440 μL, 2.53 mmol), and the solution was stirred for overnight at room temperature. The reaction mixture was diluted by adding 100 mL of CH2Cl2 and water (100 mL) and the aqueous layers extracted three times with CH2Cl2, dried over Na2SO4, filtered and evaporated. The residue obtained was purified by flash column chromatography using 20-30% EtOAc in hexanes as eluent to give the desired compound 4.4 (1.5 g, 100%) as a white solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[O:22]C(=O)C)[C:8]([N:10]1[CH2:14][CH2:13][N:12]([C:15]([NH2:17])=[O:16])[C:11]1=[O:18])=[O:9])(=O)C.N>C(O)C.O>[OH:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[OH:22])[C:8]([N:10]1[CH2:14][CH2:13][N:12]([C:15]([NH2:17])=[O:16])[C:11]1=[O:18])=[O:9]
Reactant: CC(=O)Oc1ccc(C(=O)N2CCN(C(N)=O)C2=O)cc1OC(C)=O
Agent: N
Solvent: O
Solvent: CCO
Product: NC(=O)N1CCN(C(=O)c2ccc(O)c(O)c2)C1=O
Reaction time: 0.17 h

Procedure:
To a suspension of 6.2 g (0.017 mol) of 3-[3,4-bis(acetyloxy)benzoyl]-2-oxo-1-imidazolidinecarboxamide in 50 ml of a 1:1 mixture of ethanol/water was added dropwise 2.1 ml of ammonia. After stirring for 10 minutes, a clear solution formed from which 3-(3,4-dihydroxybenzoyl)-2-oxo-1-imidazolidinecarboxamide began to crystallize after 15 minutes, yielding 3.8 g.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([C:18]1([S:24]([N:27]2[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35][OH:36])[CH2:29][CH2:28]2)(=[O:26])=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:11]([O:15][C:16]([C:18]1([S:24]([N:27]2[CH2:28][CH2:29][CH:30]([CH2:33][CH2:34][CH:35]=[O:36])[CH2:31][CH2:32]2)(=[O:26])=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)C1(S(=O)(=O)N2CCC(CCCO)CC2)CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(S(=O)(=O)N2CCC(CCC=O)CC2)CCOCC1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
A 50 mL round-bottom flask was charged with oxalyl chloride (0.4 mL, 3.82 mmol) and methylene chloride (9 mL). The flask was then immersed into a dry ice/acetone bath. Afterward, dimethylsulfoxide (0.54 mL, 7.7 mmol) was added dropwise, maintaining the temperature at less than −65° C. After complete addition, the mixture was stirred for 15 min. A solution of the alcohol from Example A7 (1.50 g, 3.82 mmol) in methylene chloride (9 mL) was then added dropwise while maintaining the temperature at less than-65° C. The resulting mixture was stirred for 45 min after complete addition. Diisopropylethylamine (3.3 mL, 19 mmol) was then added dropwise. Subsequently, the mixture was stirred for 30 min with cooling. The dry ice/acetone bath was then removed. After 1 hr, the reaction mixture was diluted with methylene chloride (50 mL) and extracted with water (50 mL). The aqueous layer was re-extracted with methylene chloride (25 mL). The combined organic layers were then dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography using a gradient of 10–30% ethyl acetate/hexane afforded a white crystalline solid (1.24 g, 83% yield). 1H NMR (CDCl3) δ 1.20–1.42 (m, 5H), 1.51 (s, 9H), 1.53–1.59 (m, 2H), 1.68 (d, J=11.2 Hz, 2H), 2.10 (td, J=4.5, 12.8 Hz, 2H), 2.31 (d, J=11.2 Hz, 2H), 2.92 (t, J=12.6 Hz, 2H), 3.30 (t, J=12.4 Hz, 2H), 3.62 (t, J=6.6 Hz, 2H), 3.76 (d, J=12 Hz), 3.95 (dd, J=4, 11.6 Hz, 2H); Electrospray mass spectrometry showed m/z=390 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:44]=[CH:45][C:46]=1[CH3:47])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH:41]3[CH3:43])=[O:39])[N:36]=2)[N:33]=1>CN(C)C(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([NH:23][C:24]2[CH:25]=[C:26]([O:27][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]5[CH2:42][CH:41]5[CH3:43])=[O:39])[N:36]=4)[N:33]=3)[CH:44]=[CH:45][C:46]=2[CH3:47])=[O:10])[N:5]([CH3:11])[N:4]=1
Reactant: COc1cc(C(=O)O)n(C)n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4C)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5C)cn4n3)ccc2C)n(C)n1
Yield: 68.8 %

Procedure:
Using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (194 mg, 1.24 mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (109 μL, 1.22 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]-2-methylcyclopropanecarboxamide (300 mg, 0.89 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 249, the title compound (291 mg, 69%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2](Br)([F:4])[F:3].[CH3:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10](Cl)=[O:11].CCCCCC>C(Cl)Cl>[CH3:6][C:7]1[CH:8]=[C:9]([C:10](=[O:11])[C:2]([F:4])([F:3])[F:1])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: FC(F)(F)Br
Reactant: Cc1ccc(C(=O)Cl)cc1C
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1ccc(C(=O)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
Under protective gas, 41 g (0.27 mol) of trifluoromethyl bromide are condensed into a solution of 42 g (0.25 mol) of 3,4-dimethylbenzoyl chloride in 150 ml of CH2Cl2 in a round-bottomed flask at about -70° C. A solution of 66.7 g (0.27 mol) of phosphorous acid trisdiethylamide in 50 ml of CH2Cl2 are then metered in at about -70° C., the first 90% of the solution being added rapidly and the last 10% of the solution being metered in slowly (during the course of about 2 hours). The mixture is subsequently stirred for one hour more at this temperature and then warmed to room temperature. After addition of the same volume of hexane, 2 phases are formed. After phase separation, the lower phase is carefully extracted using hexane; the combined hexane phases are concentrated and distilled under reduced pressure. 20.8 g (41% yield) of 1-(3,4-dimethylphenyl)- 2,2,2-trifluoroethan-1-one of b.p. 98°-99° C./22 mbar are obtained.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][C@H:8]([C:10]([OH:12])=O)[C@H:7]([CH2:13][CH3:14])[CH2:6]1)(=[O:3])[CH3:2].[NH:15]([C:17]1[N:18]=[C:19]2[CH:25]=[CH:24][N:23]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:20]2=[N:21][CH:22]=1)[NH2:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH2:13]([C@H:7]1[C@@H:8]([C:10]([NH:16][NH:15][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=2)=[O:12])[CH2:9][C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6]1)[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Reactant: CC[C@@H]1C[C@H](NC(C)=O)C[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC[C@@H]1C[C@H](NC(C)=O)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
To a mixture of (1S,2R,4S)-4-acetamido-2-ethylcyclopentanecarboxylic acid (3.03 g, 15.2 mmol) in DCM (90 mL) was added 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (4.20 g, 13.8 mmol, Example #4, Step D), HATU (5.53 g, 14.5 mmol) and TEA (7.72 mL, 55.4 mmol). After stirring at ambient temperature for about 2 h, the reaction was diluted with water (60 mL). The layers were separated and the aqueous layer was extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentyl)acetamide (7.0 g, 90%, 87% purity) as a tan foam: LC/MS (Table 1, Method a) Rt=1.96 min; MS m/z: 485 (M+H)+. To a solution of impure N-((1S,3R,4S)-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)-cyclo-pentyl)acetamide (9.40 g, 19.4 mmol) in 1,4-dioxane (100 mL) was added TEA (8 mL, 58 mmol) and thionyl chloride (1.9 mL, 27.1 mmol). The reaction mixture was heated at about 80° C. for about 2 h, and then cooled to about 0° C. and saturated aqueous NaHCO3 and EtOAc (100 mL each) were added. The layers were separated and the aqueous layer was extracted with additional EtOAc (2×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 50-100% EtOAc/MeOH/Et2NH (90:9:1) in EtOAc to give N-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetamide (6.00 g, 66%): LC/MS (Table 1, Method a) Rt=2.03 min; MS m/z: 467 (M+H)+.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][OH:12])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:4]=1.[C:23](#N)C.O.O[O:28][S:29]([O-:31])=O.[K+]>C(OCC)(=O)C>[CH3:23][S:29]([C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][OH:12])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[N:4]=1)(=[O:31])=[O:28]
Reactant: CSc1nc(NCCO)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: CC#N
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1nc(NCCO)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a stirring suspension of 2-[2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl-amino]-ethanol (450 mg) in a 10:1 acetonitrile/water mixture (11 ml) was added oxone (1.93 g). The resulting suspension was stirred at room temperature for 4.5 hrs. After diluting with ethyl acetate (100 ml), washed with water (100 ml), brine (50 ml), dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow gum (493 mg).
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.[C:16]1(C)C=C[C:19](S(O)(=O)=O)=[CH:18][CH:17]=1.[OH2:27]>C1(C)C=CC=CC=1.CC(O)C(O)C>[CH3:16][CH:17]1[O:27][C:5]2([NH:4][C:3]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14](=[O:15])[C:2]=3[N:1]=[CH:6]2)[O:7][CH:18]1[CH3:19]
Reactant: O
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(O)C(C)O
Solvent: Cc1ccccc1
Product: CC1OC2(C=NC3=C(N2)c2ccccc2C3=O)OC1C
Yield: 78.5 %

Procedure:
A suspension of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione (2.0 g, 10.09 mmol) in toluene (50 ml), 2,3-butanediol (20 ml) and p-toluenesulfonic acid (40 mg) was refluxed with water separation for 20 hours. The reaction mixture was evaporated in vacuo to dryness and another portion of toluene, 2,3-butanediol and p-toluenesulfonic acid was added and the mixture was refluxed again for 20 hours. After evaporation to dryness, the residue was suspended in ethanol (10 ml) and the precipitate was filtered off and washed with ethanol and dried to give 2.14 g (78.5%) of the title compound as a mixture of isomers. 1H-NMR (DMSO-d6, δ): 1.24-1.4 (m, 6H), 4.03-4.87 (m, 2H), 7.42-7.91 (m, 5H), 12.6 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[CH:9]=[CH:10][C:11]([Br:13])=[CH:12][C:6]=2[CH:5]=1)(=O)[CH3:2].O.NN.[OH-].[K+].C1(C)C=CC=CC=1>C(O)CO.O>[Br:13][C:11]1[CH:10]=[CH:9][C:7]2[O:8][C:4]([CH2:1][CH3:2])=[CH:5][C:6]=2[CH:12]=1
Reactant: CC(=O)c1cc2cc(Br)ccc2o1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc2cc(Br)ccc2o1
Temperature: 150 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
2-Acetyl-5-bromobenzo[b]furan (10.00 g) and hydrazine monohydrate (8.00 g) were stirred in ethylene glycol (60 ml) at 150° C. for 2 hr. After cooling, potassium hydroxide (9.00 g) was added and the mixture was stirred at 150° C. for 2 hr. After cooling, toluene (200 ml) and water (100 ml) were added and the separated toluene layer was washed with 10% aqueous solution (100 ml) of ammonium chloride, dried over magnesium sulfate and concentrated to give the objective compound (8.30 g).