Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1.S(=O)(=O)(O)[OH:13].[N+]([O-])([O-])=O.[Na+]>O>[O:13]=[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[NH:3]1
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1[nH]c(=O)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 97 %

Procedure:
To a suspension of 2-amino-5-nitro-6-methylpyridine (40.24 g, 260 mmol) was added concentrated sulfuric acid (48 mL). The homogeneous solution was cooled to 0° C., and sodium nitrate (26.97 g, 390 mmol) dissolved in 120 mL of water was added. The reaction mixture was warmed to room temperature over 4 hours, then cooled to 0° C. The resulting ivory precipitate was collected, washed with cold water, and dried at 40° C. in vacuo overnight to provide 39.05 g (97%) of the title compound. EA calculated for C6H6N2O3: C, 46.76; H, 3.92; N, 18.18. Found: C, 46.49; H, 3.94; N, 17.99.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:10]=[O:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:3]([CH2:10][OH:11])=[N:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: COc1cnc(C=O)c(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cnc(CO)c(Cl)n1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of 3-chloro-5-methoxy-pyrazine-2-carbaldehyde (560 mg, 3.24 mmol) in MeOH (15 mL) is added sodium borohydride (183 mg, 4.83 mmol) at 0° C. After the mixture is stirred at this temperature for 0.5 hour, the reaction is quenched with saturated NH4Cl (1 mL) and solvent removed in vacuo until dryness. DCM (50 mL) is added, and the solution is dried and solvent removed to give 550 mg of (3-chloro-5-methoxy-pyrazin-2-yl)-methanol as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: Oc1cncc(C(F)(F)F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(C(F)(F)F)c1

Procedure:
A 332.9. mg (1.56 mmol) sample of (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol and 224.9 mg (1.30 mmol) of 3-hydroxy-5-trifluoromethylpyridine were reacted with triphenylphosphine and DEAD (1.56 mmol each) in 5 mL of THF according to the procedure of Example 14a, to give 386 mg of the title compound. MS (DCI/NH3) m/e 347 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.50 (s, 1H), 8.48 (s, 1H), 7.46 (s, 1H), 4.28-3.90 (m, 3H), 3.48-3.84 (m, 2H), 2.12-1.87 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Cl[CH2:17][C@H:18]([N:20]1[C:29](=[O:30])[CH2:28][C:23]2([CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:22][C:21]1=[O:31])[CH3:19]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:19][C@H:18]([N:20]2[C:29](=[O:30])[CH2:28][C:23]3([CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:22][C:21]2=[O:31])[CH3:17])[CH2:14][CH2:15]1
Reactant: Fc1cc(F)c(N2CCNCC2)cc1F
Reactant: C[C@H](CCl)N1C(=O)CC2(CCCC2)CC1=O
Solvent: CO
Product: C[C@H](CN1CCN(c2cc(F)c(F)cc2F)CC1)N1C(=O)CC2(CCCC2)CC1=O
Temperature: 160 °C
Reaction time: 5 h
Yield: 46.5 %

Procedure:
A mixture of 1-(2,4,5-trifluorophenyl)piperazine (105 mg, 0.49 mmol) and (R)-8-(2-chloro-1-methylethyl)-8-azaspiro[4.5]decane-7,9-dione (105 mg, 0.43 mmol) was heated with stirring at 160° C. for 5 hours. The residue was dissolved in methanol, transferred to a preparative thin layer chromatographic plate (silica gel), and eluted with ethyl acetate/hexane (1:1). A band at Rf=0.8 was removed and rinsed with chloroform/methanol (4:1). The solvent was removed, giving the title compound as a pale yellow oil (86.2 mg, 0.20 mmol, 47%). 1H NMR (300 MHz, CDCl3) δ6.89 (ddd, 1H, J=11.7, 10.2, 7.5 Hz), 6.71 (dt, 1H, J=12.0, 8.1 Hz), 5.08-4.96 (m, 1H), 3.14 (dd, 1H, J=12.6, 10.5 Hz), 2.92 (t, 4H, J=4.7 Hz), 2.73-2.66 (m, 2H), 2.58 (s, 4H), 2.51-2.44 (m, 2H), 2.36 (dd, 1H, J=12.6, 5.4 Hz), 1.75-1.68 (m, 4H), 1.57-1.50 (m, 4H), 1.34 (d, 3H, J=6.9 Hz); ESI-MS m/z 424 (MH+). The title compound was dissolved in ether and precipitated by addition of 1N HCl in ether, giving a white solid: mp 231-235° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[N:26][CH:27]=1>>[F:17][C:16]1([F:18])[CH2:15][O:14][C:13]([NH2:19])=[N:12][C@@:11]21[C:4]1[C:5](=[CH:6][CH:7]=[C:2]([C:24]3[CH:25]=[N:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH:3]=1)[O:8][CH2:9][CH2:10]2
Reactant: NC1=N[C@@]2(CCOc3ccc(Br)cc32)C(F)(F)CO1
Reactant: COc1cncc(B(O)O)c1
Product: COc1cncc(-c2ccc3c(c2)[C@@]2(CCO3)N=C(N)OCC2(F)F)c1
Yield: 60 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (R)-6-bromo-5′,5′-difluoro-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.1) with 5-methoxypyridin-3-ylboronic acid yielded the title compound (60% yield) as a pale yellow solid. MS (ISP): m/z=362.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[Br-].[CH3:4][PH+](C)C.[CH3:8][C:9]1[CH:10]=[C:11]([N:16]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=2)[CH:12]=[CH:13][C:14]=1[CH3:15]>COCCOC>[CH3:8][C:9]1[CH:10]=[C:11]([N:16]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[CH2:4])=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=2)[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1ccc(N(c2ccc(C=O)cc2)c2ccc(C)c(C)c2)cc1C
Reactant: C[PH+](C)C
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=Cc1ccc(N(c2ccc(C)c(C)c2)c2ccc(C)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Into a three-necked flask, 12.1 g of sodium hydride and 580 ml of 1,2-dimethoxyethane were placed, and 108.5 g of trimethylphosphonium bromide was added thereto with stirring at room temperature. Next, after a drop of absolute alcohol was added, the reaction was allowed to proceed at 70° C. for 4 hours. Then, 100.0 g of 4-[N,N-bis(3,4-dimethylphenyl)amino]benzaldehyde was added to the reaction mixture, to carry out reaction at 700° C. for 5 hours, followed by filtration to collect a cake. The cake was extracted with ether and the extract was put together with the filtrate and washed with water. Then, the ether solution was dehydrated with calcium chloride, and thereafter the ether was removed to obtain a crude product. After twice recrystallized from ethanol, acicular 4-[N,N-bis(3,4-dimethylphenyl)amino]styrene was obtained in an amount of 84.5 g (yield: 85.0%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]1([NH:26][CH2:27][C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33]([C:35]2[C:36]([CH3:43])=[C:37]([CH:41]=O)[NH:38][C:39]=2[CH3:40])=[O:34])[CH2:25][CH2:24]1>N1CCCCC1.C(O)C>[CH:23]1([NH:26][CH2:27][C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2[C:33]([C:35]2[C:36]([CH3:43])=[C:37](/[CH:41]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:38][C:39]=2[CH3:40])=[O:34])[CH2:24][CH2:25]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(F)cccc3F)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(F)cccc4F)cc32)c(C)c1C(=O)N1CCC[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 5-(2,6-difluoro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (280 mg, 0.87 mmol), 4-((S)-2-cyclopropylaminomethyl-pyrrolidine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (250 mg, 0.86 mmol) and piperidine (2 drops) in ethanol (2 mL) was stirred at rt for 4 days. The reaction was concentrated and purified on a silica gel column to give the titled compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:38][CH3:39])=[CH:33][C:32]=1[N+:40]([O-:42])=[O:41])[C:16]1[N:21]=[CH:20][N:19]=[C:18]([N:22](C)[C:23](=O)OC(C)(C)C)[CH:17]=1)=O)(C)(C)C>C(Cl)Cl>[CH3:39][O:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([NH:15][C:16]2[CH:17]=[C:18]([NH:22][CH3:23])[N:19]=[CH:20][N:21]=2)=[C:32]([N+:40]([O-:42])=[O:41])[CH:33]=1
Reactant: COCc1ccc(N(C(=O)OC(C)(C)C)c2cc(N(C)C(=O)OC(C)(C)C)ncn2)c([N+](=O)[O-])c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc(Nc2ccc(COC)cc2[N+](=O)[O-])ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 139.4 %

Procedure:
TFA (5 mL) was slowly added to a stirred solution of tert-butyl (6-((tert-butoxycarbonyl)(4-(methoxymethyl)-2-nitrophenyl)amino)pyrimidin-4-yl)(methyl)carbamate (0.85 g) in dry DCM (10 mL) under argon atmosphere at 0° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 1 h. After completion of the reaction, excess solvents were removed under reduced pressure and washed with ether to afford the title compound (0.7 g crude) as a solid. MS (ESI): 290.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[N:17][C:18]([N+:21]([O-])=O)=[CH:19][CH:20]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1>C(OCC)(=O)C.[C].[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[N:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])nc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 108.2 %

Procedure:
To a solution of tert-butyl{3-[(6-nitropyridin-3-yl)oxy]phenyl}carbamate (6.00 g, 18.1 mmol) in ethyl acetate (500 mL)/tetrahydrofuran (150 mL) was added 10% palladium-carbon (600 mg), and the mixture was stirred at room temperature for 16 hr under a hydrogen atmosphere (1.0 atm). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (5.9 g, quantitative) as a brown oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@:25]([CH3:47])([C:43](OC)=[O:44])[C:24]1=[O:48])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](CC)CC)C.[Li+]>C1COCC1>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@:25]([CH2:43][OH:44])([CH3:47])[C:24]1=[O:48])[CH2:21][CH3:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@@](C)(CO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (3S,5R,6S)-methyl 1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidine-3-carboxylate (450 mg, 0.640 mmol; Example 248, Step A) at 0° C. in THF (4 mL) under a nitrogen atmosphere was added dropwise lithium triethylborohydride (1.60 mL, 1.60 mmol, 1M solution in THF). The reaction was stirred at 0° C. for 1 hour and then it was quenched with methanol (0.2 mL) and treated with Oxone® (2 KHSO5.KHSO4.K2SO4, DuPont, Wilmington, Del.) (1.18 g, 1.92 mmol) in water (50 mL). The mixture was stirred for 1 hour and then extracted with ethyl acetate (100 mL). The separated organic layer was washed with Na2S2O3 (50 mL, saturated aqueous solution) and then dried over MgSO4, filtered and evaporated in vacuo. Column chromatography (SiO2, hexanes:EtOAc, 1:0 to 7:3) gave the title compound. Mass Spectrum (ESI) m/z=674.2 (M+1).
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:26])[CH2:4]2)[CH3:2].Cl.Cl[CH2:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1>>[CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:29][C:30]4[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([OH:18])[C@@H:5]([OH:26])[CH2:4]2)[CH3:2]
Reactant: CC[C@@]12C[C@H](O)[C@](O)(c3ccc(F)cc3)C[C@H]1CCc1cc(O)ccc12
Reactant: Cc1ncccc1CCl
Agent: Cl
Product: CC[C@@]12C[C@H](O)[C@](O)(c3ccc(F)cc3)C[C@H]1CCc1cc(OCc3cccnc3C)ccc12

Procedure:
The title compound was prepared starting from the title product of Example 28 and 3-chloromethyl-2-methylpyridine hydrochloride using the same procedure outlined for Example 2. Product was isolated by flash chromatography eluting with 35% ethyl acetate in hexane. Mass spectrum: m/e 462 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:16])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].[NH2:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:41])[CH2:39]Br)=[C:33]([Cl:42])[CH:32]=1)(=[O:30])=[O:29]>CN(C)C=O.C(OCC)(=O)C>[NH2:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:41])[CH2:39][N:8]2[CH:9]=[CH:10][C:11]([C:12]([F:15])([F:13])[F:14])=[C:6]([O:5][C:4]3[CH:17]=[C:18]([Cl:20])[CH:19]=[C:2]([Br:1])[CH:3]=3)[C:7]2=[O:16])=[C:33]([Cl:42])[CH:32]=1)(=[O:30])=[O:29]
Reactant: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Br)c1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(NC(=O)Cn2ccc(C(F)(F)F)c(Oc3cc(Cl)cc(Br)c3)c2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-(3-bromo-5-chlorophenoxy)-4-(trifluoromethyl)pyridin-2(1H)-one (3B, 0.050 g, 0.136 mmol) and potassium carbonate (0.019 g, 0.136 mmol) suspended in dimethylformamide (1 mL) was added N-[4-(aminosulfonyl)-2-chlorophenyl]-2-bromoacetamide (0.046 g, 0.136 mmol) as a solution in dimethylformamide (1 mL). The reaction mixture was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (3×10 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on a pre-packed silica gel Redi Sep 12 gram column, eluting with 0-5% methanol in CH2Cl2 to yield the title compound. 1H NMR (DMSO-d6) δ 10.23 (s, 1H), 8.0 (d, J=8.6 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.75 (dd, J=8.6 Hz, J=2.1 Hz, 1H), 7.48-7.44 (m, 2H), 7.44-7.42 (m, 1H), 7.19-7.17 (m, 1H), 7.12-7.10 (m, 1H), 6.66 (d, J=7.2 Hz, 1H), 5.02 (s, 2H). HRMS (M+1)=613.913.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:11][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Reactant: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1Cl)C(Cn1ccnc1)c1ccccc1

Procedure:
A solution of 1-(2,4-dichlorophenyl)-2-phenylpropen-1-one (4g), imidazol (1.36 g) and tetramethylquanidine (0.5 ml) in tetrahydrofuran (100 ml) was heated at reflux for 12 hours. The reaction mixture was cooled and concentrated under reduced pressure to yield a gum. The gum was dissolved in ethyl acetate, washed with distilled water, and acidified with 4N hydrochloric acid. The aqueous phase was basified with sodium carbonate and extracted with ethyl acetate. The organic phase was separated, washed with distilled water, dried over anhydrous magnesium sulphate and concentrated under reduced pressure to yield an oil which was chromatographed on silica gel using a mixture of methanol/dichloromethane (1:9) as an eluent to yield 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-phenylpropan-1-one (600 mg), which was treated with ethereal hydrogen chloride to yield the hydrochloride salt of 1-(2,4-dichlorophenyl)-3-(imidazol-1-yl)-2-phenylpropan-1-one, m.p. 110° C., (Found: C, 55.38; H, 4.37; N, 7.40%; C18H15Cl3N2O.1/2H2O requires C, 55.34; H, 4.13; N, 7.17%) having the formula: ##STR28##
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][N:16]=[C:15]([C:18]4[CH:19]=[C:20]([CH3:26])[C:21]([O:24]C)=[CH:22][CH:23]=4)[C:14]=3[CH:27]=2)[C:8](=[O:28])[CH:7]=[C:6]([C:29]([F:32])([F:31])[F:30])[N:5]=1)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]3[S:17][N:16]=[C:15]([C:18]4[CH:19]=[C:20]([CH3:26])[C:21]([OH:24])=[CH:22][CH:23]=4)[C:14]=3[CH:27]=2)[C:8](=[O:28])[CH:7]=[C:6]([C:29]([F:32])([F:30])[F:31])[N:5]=1)[CH3:2]
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1ccc2snc(-c3ccc(OC)c(C)c3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOc1nc(C(F)(F)F)cc(=O)n1-c1ccc2snc(-c3ccc(O)c(C)c3)c2c1
Reaction time: 6 h

Procedure:
A solution of 2-ethoxy-[3-(6-methoxy-m-tolyl)-1,2-benzisothiazol-5-yl]-6-(trifluoromethyl)-4(3H)-pyrimidinone (0.490 g, 1.06 mmol) in methylene chloride is cooled to -5° C., treated with a 1 M solution of boron tribromide in methylene chloride (1.38 mL, 1.38 mmol), stirred for six hours, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as an off-white solid which is identified by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:13]Br>CO>[Br:13][CH2:11][C:10]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1)=[O:12]
Reactant: BrBr
Reactant: COc1ccc(C(C)=O)cc1Cl
Solvent: CO
Product: COc1ccc(C(=O)CBr)cc1Cl
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 1-(3-chloro-4-methoxyphenyl)ethanone (1.0 g, 5.42 mmol) in MeOH (29.5 mL) was added a solution of bromine (0.33 mL, 6.50 mmol) in MeOH (10 mL) at RT. The reaction mixture was then stirred for 2 h, quenched with ice and extracted with DCM (2×20 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to afford 2-bromo-1-(3-chloro-4-methoxyphenyl)ethanone (1.0 g, 70%) as solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][NH:14][CH:15]=2)=[O:8])=[CH:4][CH:3]=1.I[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]2=[O:29])=[CH:19][C:18]=1[F:30].OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]4=[O:29])=[CH:19][C:18]=3[F:30])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1c[nH]cn1)c1ccc(Cl)s1
Reactant: O=c1ccccn1-c1ccc(I)c(F)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2F)cn1)c1ccc(Cl)s1
Temperature: 130 °C

Procedure:
A mixture of 5-chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1 prepared above (0.940 g, 2.64 mmol), 1-iodo-2-fluoro-4-(2-oxopyridin-1(2H)-yl)benzene 3-2 prepared above (0.820 g, 2.60 mmol), 8-hydroxyquinoline (0.066 g, 0.45 mmol) and K2CO3 (0.630 g, 4.56 mmol) in DMSO (8 mL) was degassed with Ar before being charged with CuI (0.090 g, 0.47 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the title compound (0.480 g). MS 429.0 and 431.0 (M+H, Cl pattern).
Reaction SMILES: [C:1](=[O:4])(O)[O-].[Na+].[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](CBr)=[CH:9][CH:8]=1.O>CS(C)=O>[Br:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:1]=[O:4])=[CH:9][CH:8]=1
Reactant: O=C([O-])O
Reactant: BrCc1ccc(Br)c2ccccc12
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(Br)c2ccccc12
Temperature: 95 °C
Reaction time: 3 h

Procedure:
Sodium bicarbonate (1.4 g) is added to a solution of crude 1-bromo-4-bromomethyl-naphthalene (2.5 g) in DMSO (25 ml). The reaction is stirred for 3 h at 95° C. and cooled down to room temperature. Water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over MgSO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 4-bromo-naphthalene-1-carbaldehyde as colorless crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([N:9]1[CH2:14][CH2:13][S:12][CH2:11][CH2:10]1)=O.[P:15]([O:22]CC)([O:19]CC)[O:16]CC>C(Cl)Cl>[N:9]1([CH:7]([P:15](=[O:16])([OH:22])[OH:19])[P:15](=[O:22])([OH:19])[OH:16])[CH2:14][CH2:13][S:12][CH2:11][CH2:10]1
Reactant: O=CN1CCSCC1
Reactant: CCOP(OCC)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=P(O)(O)C(N1CCSCC1)P(=O)(O)O
Temperature: 25 °C

Procedure:
Oxalyl chloride (16.6 ml) was added dropwise at 0° C. to a stirred solution of N-formyl-thiomorpholine (26.2 g) in methylene chloride (200 ml). The mixture was stirred at room temperature until the gas evolution ceased (about 5 hours later). Triethyl phosphite (66 ml) was then added during 1.5 hours at room temperature. Unreacted triethyl phosphite was removed in vacuo, and the residue was refluxed with 20% hydrochloric acid (150 ml) for 3 hours. The mixture was evaporated to dryness in vacuo, and the residue was stirred with acetone. The crystalline product was filtered and recrystallized from water. M.p.: >250° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)(=[O:19])[CH3:18].Cl>CN(C)C=O>[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6])(=[O:19])[CH3:18]
Reactant: CC(=O)OCCCCBr
Reactant: O=Cc1cc(O)cc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCOc1cc(O)cc(C=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.5 %

Procedure:
3,5-Dihydroxybenzaldehyde (0.96 g) and potassium carbonate (1.44 g) were suspended in N,N-dimethylformamide (5 mL). To the mixture was added 4-bromobutyl acetate (1.49 g) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/5) to give the title compound (0.57 g).