Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]([CH:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)=[O:16].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:39])(=O)=O)=CC=1>C1COCC1>[CH3:13][O:14][C:15]([C:17]1([F:39])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)=[O:16]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(F)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
n-Butyl lithium (2.5M/Hexanes, 3.83 ml; 9.575 mmol) added dropwise to solution of diisopropylamine (1.36 ml; 9.62 mmol) at −78° C. Solution was allowed warm to room temperature and stirred for 30 minutes, then cooled to −78° C. A solution of Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2 g, 8.72 mmol) in THF (10 ml) was added dropwise, warmed to −40° C. for 1 hour, then cooled to −70° C.A solution of N-fluorobenzene-sulfonimide (3.02 g, 9.57 mmol) in THF (15 ml) was added dropwise, stirred at −78° C. for 1 hour, then stirred at room temperature overnight. Precipitated solid was filtered, washed with EtOAc (2×150 ml). Organic layer was washed with 1N HCl (30 ml), brine (100 ml), dried (MgSO4), filtered and solvent evaporated. The residue was chromatographed on silica gel eluting with 10% v/v EtOAc/hexanes yielding product as colorless oil (1.38 g: 64% yield). MS (ESMS, MH 249).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].CO.Cl.[CH2:14](N=C=NCCCN(C)C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([O:7][CH3:14])=[O:6]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccnc(Br)c1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To an ice cooled solution of 2-bromoisonicotinic acid (73 g, 0.361 mol) in dichloromethane (500 mL) and methanol (35 g, 1.08 mol) was added 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (67 g, 0.434 mol) by portions. The mixture was stirred at ambient temperature overnight. Then 120 g silica gel was added and the solvent evaporated. The residue was purified by flash chromatography, eluting with 5% ethyl acetate in petroleum ether to afford 58 g (75%) of methyl 2-bromoisonicotinate as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[NH:14][CH2:13]3)=[O:5])[CH3:2].[H-].[Na+].CI.[C:32](OCC)(=O)C>CN(C=O)C>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[N:14]([CH3:32])[CH2:13]3)=[O:5])[CH3:27]
Reactant: CCOC(C)=O
Reactant: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CNC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CN(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
To a solution of 17β-N,N-diethylcarbamoyl-6-azaandrost-4-en-3-one (24 mg, 0.065 mmol) in DMF (2 mL) at room temperature is added NaH (16 mg, 80% oil dispersion, 0.5 mmol) and, after 30 min, methyl iodide (50 μL, excess). After stirring for 30 min ethyl acetate (30 mL) is added, the solution washed with H2O and saturated aqueous NACl, dried over MgSO4, concentrated and flash chromatographed on silica gel (100% ethyl acetate to 5% methanol/chloroform) to give 17β-N,N-diethylcarbamoyl-6-methyl-6-azaandrost-4-ene-3-one as a white solid; yield 19 mg (76%). This material is then recrystallized from hexanes/methylene chloride to give 14 mg pure white solid; m.p. 158°-159° C. Anal. Calcd. for C24H38N2O2 ; C, 74.57; H, 9.91; N, 7.25. Found: C, 74.38; H, 9.84; N, 7.18.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])[CH3:2].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCOC(=O)CS(C)(=O)=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccccc1)S(C)(=O)=O
Reaction time: 0.5 h

Procedure:
6.648 g of methylsulphonyl-acetic acid ethyl ester in 20 ml of DMF are added dropwise at -25°, within 25 minutes, to 1.745 g of sodium hydride dispersion (55% in oil) in 40 ml of DMF. The solution is subsequently stirred for 30 minutes at -25°, then 6.84 g of benzyl bromide in 40 ml of DMF are added dropwise. The reaction mixture is then stirred for 1 hour at room temperature, left to stand overnight and concentrated by evaporation. The residue is taken up in ethyl acetate, washed with water, dried, concentrated by evaporation and purified by flash chromatography on 700 g of silica gel 60 (eluant E). 1H-NMR (DMSO-d6): 1.1 ppm (t, 3H); 3.05 (s, 3H), 3.1-3.6 (m, 2H); 3.9-4.3 (m, 3H); 7.25 (m, 5H).
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:2]([C@H:3]2[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]2)[CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CN[C@H]1CC[C@H](O)CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: CN([C@H]1CC[C@H](O)CC1)S(=O)(=O)c1ccc(Br)cc1

Procedure:
In analogy to example 11.9D. trans-4-Methylamino-cyclohexanol and 4-bromobenzenesulfonylchloride were reacted to yield trans-4-Bromo-N-(4-hydroxy-cyclohexyl)-N-methyl-benzenesulfonamide as off-white solid, MS: 348 (MH+, 1Br).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[OH:15])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>>[NH2:26]/[C:4](/[C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[CH3:1])=[C:6]1\[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[S:10]\1
Reactant: N
Reactant: Cc1ccccc1C(=O)c1sc2ccccc2c1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1ccccc1/C(N)=C1\Sc2ccccc2C1=O
Yield: 50 %

Procedure:
Prepared as in Example 1 from 2-(2-methylbenzoyl)-benzo-[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated aqueous ammonia with a yield of 50% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8](CCCCCCCCCCCCCCC)[C:4]=1[C:5](Cl)=[O:6].[NH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1.C(N(CC)CC)C>ClCCl>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([NH:27][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:29][C:30]=1[C:36]([F:37])([F:38])[F:39])#[N:33]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Methoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methoxy-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: N[C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:10][CH3:11])=[CH:4][N:3]=1.S(=O)(=O)(O)[OH:13].N([O-])=O.[Na+].NC(N)=O>O>[OH:13][C:2]1[C:7]([O:8][CH3:9])=[N:6][C:5]([O:10][CH3:11])=[CH:4][N:3]=1
Reactant: COc1cnc(N)c(OC)n1
Reactant: O=S(=O)(O)O
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cnc(O)c(OC)n1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-amino-3,5-dimethoxypyrazine (0.02 mole) in 300 ml. of 6 M sulfuric acid at 0°-5° C. is treated with 0.022 mole sodium nitrite in 25 ml. of water at such a rate to insure that the temperature of the reaction mixture does not rise above 5° C. After standing 45 minutes at 0°-5° C., a little urea is added to destroy excess nitrous acid and the mixture then is treated with sodium hydroxide solution until strongly basic. The reaction mixture is warmed to 60° C. for one hour and then brought to pH 8.5. The mixture is concentrated to a third of the original volume and cooled in the refrigerator overnight. The product is separated by filtration and dried in vacuo, recrystallized from a suitable solvent to give 2-hydroxy-3,5-dimethoxypyrazine.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].[CH3:29]C(C)([O-])C.[K+].CI>CS(C)=O>[F:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:29])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])[N:8]=1)=[O:5]
Reactant: O=C(Nc1ccn(Cc2ccc(O)cc2C(F)(F)F)n1)c1c(F)cccc1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: COc1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[4-hydroxy-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Example 36)(72 mg, 0.181 mmol) in DMSO (0.5 ml) was added potassium t-butoxide (20 mg, 0.178 mmol). The reaction mixture was stirred for 5 min before adding methyl iodide (0.011 ml, 0.181 mmol, Aldrich). The reaction was stirred at ambient temperature, overnight and under nitrogen. The reaction mixture was filtered through a hydrophobic frit and the filtrate diluted with methanol (0.5 ml) and the sample purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a white solid (20.3 mg);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:36])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([N:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)=[O:36])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Reactant: CC1(C)O[C@H](CCN)C[C@H](CC(=O)N2CCCCC2)O1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)N2CCCCC2)OC(C)(C)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl)-1-(piperidin-1-yl)ethanone.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH:11]1[CH:12]=[CH:13][C:8]([NH:14][C:15]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[O:16])=[CH:9][CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: OCCNCCO
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N(CCO)CCO
Reaction time: 1 h
Yield: 119.7 %

Procedure:
A mixture of 15.62 ml (0.136 mol) of diethanolamine and 163 ml of methylene chloride is poured, at a temperature of 10° C., into a three-necked flask containing 18.25 ml (0.168 mol) of phenyl isocyanate dissolved in 37 ml of CH2Cl2. The mixture is left at that temperature for one hour, and then at room temperature overnight, and concentrated in vacuo to obtain 36.5 g of the expected product. (Yield=100%).
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:44]=[CH:43][C:33]([NH:34][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[N:32][C:30]3=[O:31])[C@@H:26]([F:45])[C@@H:25]2[OH:46])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Si:49](O[C@@H]1[C@@H](CO)O[C@@H](N2C=CC(NC(=O)C3C=CC=CC=3)=NC2=O)C1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>>[Si:49]([O:46][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:44]=[CH:43][C:33]([NH:34][C:35](=[O:42])[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[N:32][C:30]2=[O:31])[C@H:26]1[F:45])([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)[C@@H](F)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: CC(C)(C)[Si](C)(C)O[C@H]1[C@H](F)[C@H](n2ccc(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO

Procedure:
This compound is prepared from 1-[2-deoxy-5-O-(4,4'-dimethoxytrityl)-2-fluoro-β-D-arabinofuranosyl]-N4 -benzoylcytosine by the same procedure used for the preparation of 3'-O-t-butyldimethylsilyl-N4 -benzoyl-2'-deoxycytidine.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:14][Si:13]([C:11]#[C:12][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1)([CH3:16])[CH3:15]
Reactant: Brc1cnc2cnccn12
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1cnc2cnccn12
Temperature: 50 °C
Yield: 91.7 %

Procedure:
A mixture of 3-bromoimidazo[1,2-a]pyrazine (0.15 g, 0.76 mmol; prepared according to J. Bradac, et al. J. Org. Chem. (1977), 42, 4197-4201), 0.09 g (0.91 mmol) of ethynyltrimethylsilane, 0.044 g (0.038 mmol) of Pd(PPh3)4, 0.014 g (0.076 mmol) of CuI, and 0.26 mL (1.52 mmol) of diisopropylethylamine in 3.8 mL of DMF was heated at 50° C. overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes) to provide 0.15 g of product: 216 m/z (M+H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14](C(Cl)(Cl)Cl)[O:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31].O>CS(C)=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH:33][CH:30]([CH3:32])[CH3:31])[O:13][N:12]=3)[CH:9]=2)[N:4]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(C(Cl)(Cl)Cl)n4)ccc32)cc1
Reactant: CC(C)N
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(NC(C)C)n4)ccc32)cc1
Temperature: 90 °C
Yield: 83.3 %

Procedure:
To a solution of 3-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(trichloromethyl)-1,2,4-oxadiazole (600 mg, 1.03 mmol) in DMSO (6 mL) was added isopropyl amine (1.2 mL). The reaction was heated to 90° C. in a sealed tube for 12 h then cooled to RT. The mixture was treated with water and extracted with EtOAc (2×20 mL). The organic layer was dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified with basic alumina column chromatography (eluent: 35% EtOAc in petroleum ether) to give 3-(3-iodo-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,2,4-oxadiazol-5-amine (450 mg, 83.3%) as an off brown solid. MS (ESI, pos. ion) m/z: 523.0 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 9.44 (d, J=7.6 Hz, 1H), 8.18 (s, 1H), 8.09-8.07 (m, 1H), 7.96-7.93 (m, 3H), 7.83 (d, J=1.2 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 3.88-3.83 (m, 1H), 2.32 (s, 3H), 1.22 (d, J=6.4 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:19]=1[CH2:20]Br>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:19]=1[CH2:20][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: Clc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1cccc(Cl)c1COc1ccc2[nH]ccc2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of 5-hydroxyindole (5.0 g, 37.6 mmol) in dimethylformamide (200 mL) at room temperature was added cesium carbonate (18.4 g, 56.3 mmol). The reaction mixture was stirred at 60° C. for 30 min followed by the addition of 2,6-dichlorobenzyl bromide (9.0 g, 37.6 mmol). After stirring at 60° C. for 16 h, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried (Na2SO4). Purification by flash column chromatography (silica gel, hexane/ethyl acetate) yielded a clear oil (8.05 g, 73%). MS(ES) m/e 292.0 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=O.[NH2:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[F:28])[C:18]([NH2:20])=[O:19].Cl>O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:17]2[C:18](=[O:19])[NH:20][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:16]=2)=[C:22]([F:28])[CH:23]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: NC(=O)C(N)c1ccc(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 35.5 g of sodium carbonate and 120 ml of water was added dropwise 22.7 g of 1,1-dibromo-3,3,3-trifluoroacetone at such a rate that the temperature of the reaction mixture became not higher than 55° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, followed by adding 150 ml of water and then 12.8 g of 2-amino-2-(4-chloro-2-fluorophenyl)acetamide, and the reaction was allowed to proceed at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. or lower, made acidic by adding 20 ml of concentrated hydrochloric acid at the same temperature, and extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=4:1), which afforded 5.83 g (yield, 32%) of the desired compound, 3-(4-chloro-2-fluorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1005; m.p., 83.2° C.). The continued elution with the above solvent system gave 4.32 g of the configurational isomer, 3-(4-chloro-2-fluorophenyl)-5-trifluoromethyl-2-oxo-1,2-dihydropyrazine.
Reaction SMILES: O[C:2](=[C:4]1[C:9](=O)[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH2:6][C:5]1=[O:18])[CH3:3].O.[NH2:20][NH2:21]>C(O)C>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:7]1[CH2:8][C:9]2[NH:21][N:20]=[C:2]([CH3:3])[C:4]=2[C:5](=[O:18])[CH2:6]1
Reactant: CC(O)=C1C(=O)CC(c2ccccc2Cl)CC1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Yield: 85.2 %

Procedure:
A solution of 2-(1-hydroxyethylidene)-5-(2-chlorophenyl)cyclohexane-1,3-dione (0.31 g) and hydrazine hydrate (0.065 g) in ethanol (10 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give colorless crystals of 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.26 g).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].O.O.[C:9]([O-:14])(=[O:13])[CH:10]([CH3:12])[OH:11].C[N+](C)(C)C>CN(C)C=O>[C:9]([O:14][CH2:2][C:3]([O:5][CH3:6])=[O:4])(=[O:13])[CH:10]([CH3:12])[OH:11]
Reactant: COC(=O)CBr
Reactant: CC(O)C(=O)[O-]
Agent: C[N+](C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COC(=O)C(C)O

Procedure:
Methyl bromoacetate (4.73 mL, 50 mmol) was added to a stirring solution of tetramethylammonium lactate dihydrate (11.0 g, 55 mmol) in 20 mL dimethylformamide at room temperature. Tetramethylammonium bromide separated from the reaction mixture as a white solid and the title compound was formed quantitatively within 60 min as determined by CG (Method A). The reaction mixture was filtered, the solids were washed with ethyl ether, and the combinated filtrate and ether solution was washed with 5% NaCl/5% NaHCO3. Sufficient ethyl ether was added to effect rapid separation of the phases, the aqueous phase was extracted with CH2Cl2, and the organic phases were combined and dried with MgSO4. The solvent was removed and the resulting residue was distilled under reduced pressure to give the title compound: b.p. 79° C./0.15 mm Hg.
Reaction SMILES: [OH:1][CH2:2][C:3]1([OH:6])[CH2:5][CH2:4]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9]>C(Cl)Cl>[CH3:7][S:8]([O:1][CH2:2][C:3]1([O:6][S:8]([CH3:7])(=[O:10])=[O:9])[CH2:5][CH2:4]1)(=[O:10])=[O:9]
Reactant: OCC1(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(OS(C)(=O)=O)CC1
Temperature: -10 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a mixture of 1-(hydroxymethyl)cyclopropanol (100 mg, 1.14 mmol) and TEA (202 mg, 1.82 mmol, Shantou Xilong chemical factory) in 20 mL of dry CH2Cl2 under N2, was added MsCl (156 mg, 1.32 mmol, Shanghai Haiqu chemical Ltd.) dropwise via a syringe at −10° C. After stirring for 4 hrs at −10° C., the mixture was washed with ice-water and extracted with CH2Cl2 (30 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give the desired compound as pale yellow oil (139 mg, 50%).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+:7]([CH3:9])C.C(N(CC)C(C)C)(C)C.[C:19]([C:21]1[N:26]=[CH:25][C:24]([CH:27]([C:42]2C(=O)[CH2:46][CH2:45][CH2:44][C:43]=2[OH:49])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]>ClCCl>[C:19]([C:21]1[N:26]=[CH:25][C:24]([CH:27]([C:42]2[C:43](=[O:49])[CH2:44][CH2:45][CH2:46][C:6]=2[O:7][CH3:9])[NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)=[O:30])=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CCCC2=O)cn1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)nc2)C(=O)CCC1
Temperature: 25 °C

Procedure:
Trimethyloxonium tetrafluoroborate (121 mg, 0.82 mmol) is added to a solution of N,N-diisopropylethylamine (276 μL, 1.58 mmol) and 1-((6-cyanopyridin-3-yl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 30, 346 mg, 0.804 mmol) in dichloromethane (10 mL). The mixture is stirred at room temperature over night, and another portion of trimethyloxonium tetrafluoroborate (121 mg, 0.82 mmol) is added. After 1 h the mixture is diluted with dichloromethane, and washed with water and saturated aqueous sodium chloride solution. The organic layer is dried over Na2SO4 and concentrated under reduced pressure. Yield: 300 mg; ESI mass spectrum [M+H]+=445, Retention time HPLC: 1.09 min (V011_S01).