Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[Br:8]Br>>[Br:8][CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[Br:8][CH:2]([I:1])[CH2:3][C:4]([F:7])([F:6])[F:5]
Reactant: BrBr
Reactant: FC(F)(F)CCI
Product: FC(F)(F)CC(Br)I
Product: FC(F)(F)CCBr

Procedure:
Reaction of 3-iodo-1,1,1-trifluoropropane (CF3CH2CH2I) with bromine has been reported to produce 3-bromo-1,1,1-trifluoropropane, 3,3-dibrom-1,1,1-trifluoropropane and 3-bromo-1,1,1-trifluoro-3-iodopropane in yields of 13%, 26%, and 14%, respectively (J. Chem. Soc., 1951, 2495). Treatment of 3-iodo-1,1,1-trifluoropropane with bromine under ultraviolet irradiation also is known to produce 3-bromo-1,1,1-trifluoropropane (J. Chem. Soc., 1953, 1199).
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[NH2:5][C:6]1[CH:26]=[C:25]([Cl:27])[C:9]2[O:10][C:11]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:12]=3[S:13](=[O:16])(=[O:15])[CH2:14][C:8]=2[CH:7]=1.O>C(O)=O>[Cl:27][C:25]1[C:9]2[O:10][C:11]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:12]=3[S:13](=[O:15])(=[O:16])[CH2:14][C:8]=2[CH:7]=[C:6]([NH:5][CH:1]=[O:2])[CH:26]=1
Reactant: O=C[O-]
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(NC=O)cc1CS2(=O)=O

Procedure:
Sodium formate (0.308 g, 4.58 mmol) was added to a solution of compound of Example 2 (0.8 g, 2.26 mmol) in formic acid 85% (8 mL) and refluxed for 2 h. The reaction mixture was diluted using water (20 mL) and the solid obtained was filtered, washed with water and dried. The product was purified by crystallisation using DMF/methanol to obtain the title compound. Yield: 0.78 g, (91%); 1H NMR (DMSO-d6, 300 MHz): δ 2.64 (s, 3H, CH3), 5.31 (s, 2H, CH2), 7.70 (s, 1H, Ar), 7.87 (s, 1H, Ar), 7.93 (s, 1H, Ar), 8.08 (s, 1H, Ar), 8.31 (s, 1H, CHO), 10.57 (s, 1H, NH); MS: m/e (ES−) 380 (M−1);
Reaction SMILES: [ClH:1].[CH:2]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH3:29])[CH:22]=1>>[ClH:1].[CH:2]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][C:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH3:29])[CH:22]=3)([OH:15])[CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOc1cccc(Br)c1
Reactant: CN(C)CC1CC(CCC2CCCC2)CCC1=O
Agent: Cl
Product: CCOc1cccc(C2(O)CCC(CCC3CCCC3)CC2CN(C)C)c1
Yield: 52 %

Procedure:
The base of compound (56) was reacted with 1-bromo-3-ethoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with diisopropyl ether via a silica gel column and was taken up in 2-butanone/ether. After adding trimethylchlorosilane/water, compound (58) was obtained in a yield of 52% theoretical.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:16](=[O:22])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:31]1([CH2:37][CH2:38][NH2:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:11][C:4]1[S:3][C:2]2[NH:1][C:16](=[O:22])[N:39]([CH2:38][CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:7](=[O:9])[C:6]=2[CH:5]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)c1cc(C)sc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(=O)n(CCc3ccccc3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution (200 mL) of methyl 2-amino-5-methylthiophene-3-carboxylate (3.8 g) in methylene chloride were added triphosgene (2.8 g) and triethylamine (4.8 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-phenylethanamine (8.3 mL), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (150 mL), sodium methoxide (10.6 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (5.04 g, 80%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>FC(F)(F)C1C=CC=CC=1.C(OCC)(=O)C.Cl>[Br:15][CH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)c(C(F)(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Solvent: FC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CBr)cc1C(F)(F)F
Temperature: 90 °C

Procedure:
A suspension of 4-methyl-2-trifluoromethyl-benzoic acid (commercially available) (20.242 g), N-bromosuccinimide (“NBS”) (19.52 g) and 2,2′-azobis-(2-methylpropanenitrile) (“AIBN”) (0.859 g) in α,α,α-trifluorotoluene (160 ml) was heated to 90° C. for 1.5 hours. The reaction mixture was allowed to cool to ambient temperature and then diluted with ethyl acetate (200 ml) and aqueous hydrochloric acid (1M) (100 ml). The phases were separated and the organic phase was washed with aqueous hydrochloric acid (1M) (100 ml) and brine (150 ml), dried over sodium sulfate and concentrated. The residue was triturated with dichloromethane (40 ml). The solids were isolated by filtration and dried to give 4-bromomethyl-2-trifluoromethyl-benzoic acid (5.01 g) as a white powder. The filtrate was concentrated, re-dissolved in heptane/dichloromethane (1:1) (40 ml) and the dichloromethane slowly evaporated to initiate crystallization. The solids were isolated by filtration, rinsed with pentane and dried to give a second fraction of 4-bromomethyl-2-trifluoromethyl-benzoic acid (7.00 g) as a white powder. 1H-NMR (CDCl3, 400 MHz): 11.5 (br s, 1H), 8.03-7.20 (m, 3H), 4.52 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]=2)([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:36]([O:38][C:39]([CH3:41])=[CH2:40])=[O:37]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]([NH:20][C:36](=[O:37])[O:38][C:39]([CH3:41])=[CH2:40])([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: COc1ccc(C(N)(Cc2ccccc2)c2cc(F)cc(C(F)(F)F)c2)nc1
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(OC)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a solution of 1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(5-methoxy pyridin-2-yl)-2-phenylethanamine (200 mg, 0.512 mmol) in THF (2 mL) was added 2N K2CO3 (0.5 mL, 1.0 mmol) and isopropenyl chloroformate (100 μl, 1.02 mmol). The resulting mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was dried in vacuo to yield prop-1-en-2-yl 1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(5-methoxypyridin-2-yl)-2-phenylethylcarbamate as white powder (120 mg, 50%). LCMS: RT=3.56 min [M+H] 475.2 (LCMS Method 1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH3:24])(=[O:23])=[O:22].C(OCC)(=O)C>CN(C)C=O>[ClH:20].[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:14]([CH:19]=1)[CH2:13][N:10]1[CH:9]=[C:8]([CH3:11])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2]1=[NH:1]
Reactant: Cc1cnc(N)c(C(N)=O)c1
Reactant: CS(=O)(=O)c1ccc(Cl)cc1CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(N)=O)c(=N)n(Cc2cc(Cl)ccc2S(C)(=O)=O)c1
Product: Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 29.7 %

Procedure:
To a solution (3 ml) of 2-amino-5-methylnicotinamide (100 mg) in N,N-dimethylformamide was added 2-(bromomethyl)-4-chloro-1-(methylsulfonyl)benzene (220 mg), and the mixture was stirred at 100° C. for 4 hr. The mixture was allowed to cool to room temperature, ethyl acetate was added, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in 1N sodium hydroxide solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=5:1→ethyl acetate:methanol=10:1). The obtained yellow solid was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (1 ml) was added, and the mixture was crystallized from methanol-ethyl acetate to give the title compound (45 mg).
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:28]([C:32]1[CH:33]=[C:34]([CH:61]=[C:62]([C:64]([CH3:67])([CH3:66])[CH3:65])[CH:63]=1)[CH:35]=[CH:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([CH:45]=[CH:46][C:47]2[CH:52]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:50]=[C:49]([C:57]([CH3:60])([CH3:59])[CH3:58])[CH:48]=2)[CH:44]=1)[CH:40]=O)([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[C:28]([C:32]1[CH:33]=[C:34]([CH:61]=[C:62]([C:64]([CH3:67])([CH3:66])[CH3:65])[CH:63]=1)[CH:35]=[CH:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([CH:45]=[CH:46][C:47]2[CH:52]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[CH:50]=[C:49]([C:57]([CH3:60])([CH3:59])[CH3:58])[CH:48]=2)[CH:44]=1)[CH:40]=[CH2:2])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1cc(C=Cc2cc(C=O)cc(C=Cc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cc(C=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)cc(C=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.3 %

Procedure:
Dry tetrahydrofuran (300 ml) was added to a mixture of methyltriphenylphosphonium iodide (17.00 g, 42.0 mmoles) and potassium t-butoxide (4.72 g, 42.0 mmoles) and stirred at room temperature for 10 minutes. 3,5-bis(3′,5′-di-t-butylstyryl)benzaldehyde (17.00 g, 42.0 mmoles) was then added and the reaction mixture was stirred at room temperature for 75 minutes. The solvent was then evaporated and the remaining sludge was triturated with dichloromethane-pet.ether (40-60) (1:9) and filtered through silica, rinsing thoroughly with the same solvent mixture. The solvent was evaporated to give 3,5-bis(3′,5′-di-t-butylstyryl)styrene (14.83 g, 99%), mp 150° C. (Found: C, 90.03; H, 9.98. C40H52 requires C, 90.16; H, 9.84%); λmax(CHCl3)/nm 318 (ε/dm3 mol-1 cm-1 68500); δH(500 MHz; CDCl3) 1.39 (36H, s, tBu), 5.34 (1H, d, J 11, 8-H), 5.88 (1H, d, J 18, 8-H), 6.79 (1H, dd, J 11 and 18, 7-H), 7.15 (2H, d, J 16, 7′-H), 7.25 (2H, d, J 16, 8′-H), 7.38 (2H, t, J 1.75, 1′-H), 7.42 (4H, d, J 1.75, 3′, 5′-H), 7.49 (2H, d, J 1.3, 3,5-H), 7.63 (1H, m, 1-H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=O)[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.[CH3:11][CH:12]([CH3:15])[CH2:13][NH2:14].[S-:16][C:17]#[N:18].[K+].II>>[CH2:13]([N:14]1[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]=2[S:16][C:17]1=[NH:18])[CH:12]([CH3:15])[CH3:11]
Reactant: N#C[S-]
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: CC(C)CN
Agent: II
Agent: [K+]
Product: CC(C)Cn1c2c(sc1=N)C(C)(C)OC2(C)C

Procedure:
Commercially available 2,2,5,5-tetramethyldihydrofuran-3(2H)-one (Aldrich), 2-methylpropan-1-amine (Aldrich), potassium thiocyanate (Aldrich) and iodine (EMD chemicals) were processed using the method described in Example 17A to afford the title compound. MS (ESI+) m/z 255 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O.O.Cl>C(O)C.CC(C)=O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(O)CNc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: Nc1ccc(NCC(=O)O)cc1
Reaction time: 0.5 h
Yield: 114.3 %

Procedure:
1 g (5 mmol) of (4-nitrophenyl)glycine is dissolved in 20 ml of ethanol, 5 ml of water and 2.5 ml (2.5 eq) of 5N hydrochloric acid in a 250 ml glass reactor (Paar apparatus). 1 g of palladium-on-charcoal (50% moisture and 10% active) is then introduced. The mixture is hydrogenated under a pressure of approximately 2.76×105 Pa for 1 hour 30 minutes at a temperature of 20° C. After filtering through celite, the filtrate is evaporated to dryness. A white solid is obtained which is taken up in 50 ml of acetone, filtered and dried under vacuum at 40° C. 0.95 g of a white powder is obtained.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][CH:12]1[S:16](=[O:18])(=[O:17])[O:15][CH2:14][CH2:13]1>O1CCOCC1.O>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][CH2:13][CH:12]([S:16]([OH:18])(=[O:17])=[O:15])[CH3:11]
Reactant: CC1CCOS1(=O)=O
Reactant: Sc1nc2ccccc2[nH]1
Solvent: C1COCCO1
Solvent: O
Product: CC(CCSc1nc2ccccc2[nH]1)S(=O)(=O)O
Yield: 86 %

Procedure:
To a hot solution of 2-mercaptobenzimidazole (2.0 g, 13.3 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was added via syringe pump (1 hour addition) a solution of 2,4-butane sultone (1.80 g, 12.7 mmol in 1,4-dioxane (total of 3 mL)). The solution was stirred at reflux for an additional 3 hours. The solid was collected by filtration. It was washed with acetone (2×20 mL) and dried in vacuo. Yield: 86%. 1H NMR (DMSO, 500 MHz) δ ppm 7.64(m, 2H), 7.44 (m, 2H), 3.63 (t, 2H, J=7.3 Hz), 2.68 (m, 1H), 2.10 (m, 1H), 1.90 (m, 1H), 1.15 (d, 3H, J=6.8 Hz). 13C (DMSO, 125 MHz) δ ppm 152.64, 133.32, 125.66, 113.67, 53, 10, 39.72, 33.48, 30.14, 16.85. ES-MS 287 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:18][CH:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]1[C:34]([S:35][C:36]2[CH:41]=[C:40]3[O:42][CH2:43][O:44][C:39]3=[CH:38][C:37]=2I)=[N:33][C:27]2[C:28]([NH2:32])=[N:29][CH:30]=[N:31][C:26]1=2)[CH3:20].C([O-])(O)=O.[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:37]2[C:36]([S:35][C:34]3[N:25]([CH2:24][CH2:23][CH2:22][NH:21][CH:19]([CH3:20])[CH3:18])[C:26]4[C:27]([N:33]=3)=[C:28]([NH2:32])[N:29]=[CH:30][N:31]=4)=[CH:41][C:40]3[O:42][CH2:43][O:44][C:39]=3[CH:38]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C

Procedure:
3,5-Bis(trifluoromethyl)phenylboronic acid (22.6 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (0.5 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 3 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 4:5:2:1) to give 24.4 mg (70%) of DZ2-391. 1H NMR (500 MHz, CDCl3) δ 8.22 (s, 1H), 7.79 (s, 3H), 7.12 (s, 1H), 6.86 (s, 1H), 6.09 (s, 2H), 5.71 (br s, 2H), 4.07 (t, J=6.6 Hz, 2H), 2.82 (septet, J=6.2 Hz, 1H), 2.49 (t, J=6.5 Hz, 2H), 1.95 (m, 2H), 1.12 (d, J=6.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 154.1, 152.3, 151.5, 149.6, 148.6, 147.5, 142.1, 137.2, 131.2 (q, J=33 Hz), 129.6, 123.1 (q, J=270 Hz), 121.3, 119.6, 119.4, 114.9, 110.8, 102.4, 49.5, 42.8, 40.6, 28.8, 21.7; HRMS (ESI) m/z [M+H]+ calcd. for C26H25F6N6O2S, 599.1664; found. 599.1653; HPLC: method A Rt=7.45, method B Rt=9.38.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH3:20])=[C:15]([CH:17]4[CH2:19][CH2:18]4)[N:16]=3)[CH:13]=2)[C:4](=[O:21])[CH:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:25][CH:26]=[C:27]([CH2:29][OH:30])[N:28]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[CH:17]1([C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:30][CH2:29][C:27]5[N:28]=[C:24]([C:23]([F:32])([F:31])[F:22])[S:25][CH:26]=5)=[CH:3][C:4]4=[O:21])=[CH:13][N:12]3[C:14]=2[CH3:20])[CH2:19][CH2:18]1
Reactant: OCc1csc(C(F)(F)F)n1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)n4)cc3=O)cn12
Temperature: 100 °C
Yield: 15.6 %

Procedure:
A mixture of 4-bromo-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (80 mg), (2-(trifluoromethyl)-1,3-thiazol-4-yl)methanol (51.1 mg), potassium tert-butoxide (78 mg) and toluene (2 ml) was heated at 100° C. for 1 h. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (16.2 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.Br[C:16]1[N:17]=[C:18]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[S:19][CH:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[N:9]([C:16]1[N:17]=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[S:19][CH:20]=1)[CH:8]=[CH:7]2
Reactant: CS(=O)(=O)c1cc(F)c2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc(Br)cs2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc(-n3ccc4cc(S(C)(=O)=O)cc(F)c43)cs2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using 7-Fluoro-5-(methylsulfonyl)-1H-indole (intermediate 22) and tert-butyl 4-((4-bromothiazol-2-yl)oxy)piperidine-1-carboxylate (intermediate 46).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-])=O.[C:14](N1C=CN=C1)([N:16]1C=CN=C1)=O.C(=O)=O.[CH2:29]1COC[CH2:30]1>>[CH3:14][NH:16][C:11](=[O:13])[CH2:10][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:1][CH:30]=[CH:29]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: O=C=O
Product: CNC(=O)Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
4-Nitrobenzeneacetic acid (16.6 g, 0.0916 mol) was dissolved in THF (200 mL) and carbonyldiimidazole (CDI, 15.6 g, 0.0963 mol) was added. Carbon dioxide evolution rapidly ensued and the reaction mixture was stirred at RT for 30 min. Gaseous methylamine was then bubbled through the mixture until it was distinctly basic to litmus paper. The THF was removed in vacuo and water (70 mL) was added. The solid material was collected by filtration and placed in a Parr bottle were palladium on carbon (10%, 3 g). A solution of EtOH (200 mL) and 1N HCl (50 mL) was added and the mixture was hydrogenated at 60 psi for 4 h. The reaction was filtered, concentrated in vacuo and the residue made basic with saturated aqueous Na2CO3. The aqueous mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the product (6) (10.0 g, 66.6%) which was pure by NMR analysis.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[S:6][CH:7]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH:23]([OH:30])[CH2:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>C(#N)C>[ClH:1].[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([CH2:2][O:30][CH:23]([C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[Cl:15])[CH2:24][N:25]3[CH:29]=[CH:28][N:27]=[CH:26]3)[N:4]=2)=[CH:9][CH:10]=1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Solvent: CC#N
Product: Cl
Product: Clc1ccc(-c2nc(COC(Cn3ccnc3)c3ccc(Cl)cc3Cl)cs2)cc1

Procedure:
Following the procedure of Example 1b, 4-chloromethyl-2-(4-chlorophenyl)thiazole (m.p. 66°) is reacted with 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol to yield the title compound, m.p. 108°-110° C. (acetonitrile).
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6][N:5]=1)=O.[OH-].[Na+].CN(C)C(=[O:32])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[OH:32][C:4]1[N:9]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(S(C)=O)nc1NCc1ccc(OC)c(Cl)c1
Reactant: CC(=O)N(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cnc(O)nc1NCc1ccc(OC)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of a whole amount of 2-methylsulfinyl-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 68-(1)) in tetrahydrofuran 6 ml is dropped 2N aqueous sodium hydroxide solution 1.32 ml under ice cooling over a 2 minite period and the reaction mixture is stirred at the same temperature for 30 minutes. Further tetrahydrofuran 8 ml and N,N-dimethylacetamide 6 ml are added thereto and the mixture is stirred under ice cooling for 30 minites. Thereto are added water 5 ml and N,N-dimethylacetamide 2 ml and the mixture is stirred under ice cooling for one hour. The reaction mixture is acidified with an aqueous 10% citric acid solution and diluted with water, extracted twice with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is separated by silica gel chromatography (silica gel 20 g, solvent; chloroform:ethyl acetate=5:1→chloroform:isopropanol=30:1) to give 2-hydroxy-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine as a slightly yellowish crystalline powder, 618 mg. mp 195–197° C.