Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH2:29][C:30]#[N:31])=[CH:10][CH:9]=1.C(I)C>O1CCCC1.[Cl-].[NH4+]>[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH:29]([CH2:1][CH3:2])[C:30]#[N:31])=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: N#CCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC(C#N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
Potassium t-butoxide (315 mg, 2.81 mmol) was added to a stirred solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]acetonitrile (500 mg, 1.28 mmol) and ethyl iodide (499 mg, 3.20 mmol) in tetrahydrofuran (13 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol/ethyl acetate to give the title compound as a colorless crystal (202 mg, 0.481 mmol, 38%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH3:6].[CH2:7]([C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:29]1([CH:36]=CC(O)=[CH:32][CH:31]=1)[OH:30]>CCOCC.CN(C)C=O.CN(C)P(=O)(N(C)C)N(C)C>[CH2:7]([CH:8]([O:30][C:29]1[CH:31]=[CH:32][C:3]([O:4][CH2:5][CH3:6])=[CH:2][CH:36]=1)[CH3:13])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: Oc1ccc(O)cc1
Reactant: CCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(OC(C)Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
28.2 g of 2-chloroethyl-ethyl ether is added dropwise in the course of one hour at a bath temperature of 105°-110° C, with stirring, to a mixture of 36.8 g of 4-benzylphenol, 40 g of finely pulverised anhydrous potassium carbonate, 0.5 g of potassium iodide, 0.1 g of hydroquinone, 90 ml of hexamethylphosphoric acid triamide and 90 ml of dimethylformamide; and the mixture is held for a further 20 hours at this temperature. In further processing, the cooled reaction mixture is poured into about 800 ml of ice water, and extraction is repeatedly performed with ether. The combined ether phases are washed neutral with 10% potassium hydroxide solution followed by saturated sodium chloride solution; they are then dried over sodium sulphate and treated with active charcoal. After the solvent has been distilled off, the crude product is chromatographed on silica gel (eluant: diethyl ether/hexane 1:4) to yield pure 1-benzyl-4-(2-ethoxy)-ethoxybenzene (nD20 : 1.5502).
Reaction SMILES: [H-].[Na+].C1COCC1.CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:19]([N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[S:23][CH2+:22]1SCC)[CH3:20].[C:33]1([CH:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41](=[O:48])[CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CO.O>[CH2:19]([N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[S:23][C:22]1=[C:40]1[CH:39]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]1=[O:48])[CH3:20]
Reactant: CCS[CH2+]1Sc2ccccc2N1CC
Reactant: O=C1CC(c2ccccc2)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCN1C(=C2C(=O)c3ccccc3C2c2ccccc2)Sc2ccccc21
Temperature: 25 °C
Yield: 22.2 %

Procedure:
A flask was charged with 1.2 g (30 mmol) of sodium hydride (60 wt %), and 100 ml of THF was added thereto in a stream of nitrogen and stirred to make a suspension. While ice-cooling, to this was added 5.9 g (15 mmol) of 3-ethyl-2-(ethylthio)-2(3H)-benzothiazolium 4-methylbenzenesulfonate powder in small portions. Next, to this was added dropwise 50 ml of THF solution containing 6.24 g (30 mmol) of 3-phenyl-1-indanone. The reaction solution was stirred under ice-cooling for 3 hours and at room temperature for 3 hours and then mixed with 20 ml of methanol. When the reaction solution was poured in small portions into a stirred mixed solution of 100 ml of water and 100 ml of methanol, yellow crude crystals were obtained. The crude crystals were suspended in 100 ml of methanol, refluxed, purified and then collected by filtration, thereby obtaining 1.23 g (3.33 mmol) of yellow crystals of D14. Yield was 22%. Its structure was identified by nuclear magnetic resonance spectrum, infrared absorption spectrum, mass spectrometry spectrum and elemental analysis (found; carbon 78.00%, hydrogen 5.15% calcd.; carbon 78.02%, hydrogen 5.18%).
Reaction SMILES: CC(O)(C)C.CC[Mg+].[Br-].[NH2:10][C:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:12][C:13]([O:15][CH3:16])=[O:14].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH:30]=[C:31]([C:36](=O)[CH2:37][CH2:38][C:39]1[S:40][CH:41]=[CH:42][N:43]=1)[C:32]([O:34][CH3:35])=[O:33].C(O)(=O)C>C1COCC1>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[CH:30]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:36]([CH2:37][CH2:38][C:39]2[S:40][CH:41]=[CH:42][N:43]=2)[NH:10][C:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:12]1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(=Cc1c(Cl)cccc1Cl)C(=O)CCc1nccs1
Reactant: COC(=O)C=C(N)CC(=O)OC
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2nccs2)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a stirred solution of 2-methyl-2-propanol (92.8 g, 1252 mmol; 2.1 eq.) in anhydrous THF (1100 ml) was added a 1.0 M solution of EtMgBr in THF (1192 ml, 1192 mmol; 2.0 eq.) dropwise slowly at 0° C. under nitrogen atmosphere for 2 hours period. The resulting solution was stirred at room temperature for 1 hour. Then to the mixture was added a solution of dimethyl 3-amino-2-pentenedioate (113.5 g, 655 mmol; 1.1 eq.) in anhydrous THF (550 ml) dropwise slowly at 0° C. for 20 minutes. The resulting pale yellow solution was stirred at the same temperature for 1 h, then a solution of methyl 3-(2,6-dichlorophenyl)-2-[(1,3-thiazol-2-yl)propanoyl]-2-propenoate (219.9 g, 594 mmol; 1.0 eq.) in anhydrous THF (550 ml) was added at 0° C. for 30 minutes. The reaction mixture was stirred at room temperature for 16 hours under nitrogen atmosphere, then acetic acid (170 ml; 5.0 eq.) was added at 0° C. The resulting mixture was stirred at room temperature for 6 hours. The mixture was poured into 2 NNaOHaq. (1000 ml), the organic phase was separated and the aqueous phase was extracted with EtOAc (2000 ml). The combined organic phase was washed with H2O (1000 ml) and brine (1000 ml), dried (Na2SO4) and concentrated to give a crude mixture. Purification on silica gel column chromatography (3 times 1700 g) eluted with hexane/EtOAc (2/1 to 1/2) to afford 246.0 g (85% ) of dimethyl 4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydropyridine-3,5-dicarboxylate as a brown oil
Reaction SMILES: BrC[CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[S-:18][C:19]#[N:20].[K+]>CN(C)C=O>[CH3:15][C:13]1[CH:14]=[C:5]2[CH2:4][CH:3]([S:18][C:19]#[N:20])[O:17][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:16])[CH:9]=[CH:8]2
Reactant: N#C[S-]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(SC#N)C2
Temperature: 100 °C
Reaction time: 5 h
Yield: 88.2 %

Procedure:
A mixture of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (0.882 g), potassium thiocyanate (2.915 g) and dimethylformamide (40 ml) was stirred in a hot bath at 100° C. for 5 hours. The solvent was distilled off under reduced pressure. The residue was combined with water and extracted with chloroform. The chloroform extract liquid was washed with water, dried and condensed. The residue was crystallized from chloroform--n-hexane to obtain 0.683 g of the title compound as white powder (mp.: 227°-229° C. (dec.)).
Reaction SMILES: [CH:1]12[CH:7]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([NH2:20])=[N:17][O:18][N:19]=4)=[CH:11][CH:10]=3)[CH:4]([CH2:5][CH2:6]1)[CH2:3][NH:2]2.[CH3:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>>[CH3:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:2]2[CH2:3][CH:4]3[CH:7]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([C:15]5[C:16]([NH2:20])=[N:17][O:18][N:19]=5)=[CH:11][CH:10]=4)[CH:1]2[CH2:6][CH2:5]3)=[CH:24][CH:23]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Nc1nonc1-c1ccc(NC2C3CCC2NC3)cc1
Product: Cc1ccc(CN2CC3CCC2C3Nc2ccc(-c3nonc3N)cc2)cc1

Procedure:
Reaction of Intermediate 40 with 4-methylbenzaldehyde affords the title compound.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:27][C:26]3[CH:28]=[CH:29][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CCOCC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidine-1-yl]-oxo-acetic acid (Example 1b) and 4-nitro-aniline (Aldrich) according to the method described in Example 1c. Melting Point: 157-159° C. (diethylether)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(C(=O)O)cc1Cl
Yield: 83.1 %

Procedure:
Methyl 3-chloro-4-isopropoxybenzoate (5.5 g, 24.1 mmol) was hydrolysed using 1M NaOH (36 ml) in methanol (80 ml). Extraction and work-up with ethyl acetate gave the title compound (4.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:26][CH3:27])[C:15]2[C:16]([CH3:25])=[C:17]([CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:70][CH2:71][C:72]1[C:73](=[O:80])[NH:74][C:75]([CH3:79])=[CH:76][C:77]=1[CH3:78]>CN(C=O)C.CCOC(C)=O>[Cl:24][C:22]1[CH:21]=[C:17]([C:18](=[O:19])[NH:70][CH2:71][C:72]2[C:73](=[O:80])[NH:74][C:75]([CH3:79])=[CH:76][C:77]=2[CH3:78])[C:16]([CH3:25])=[C:15]([N:14]([CH2:26][CH3:27])[CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]2)[CH:23]=1
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 89.1 %

Procedure:
To a solution of 3-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}(ethyl)amino)-5-chloro-2-methylbenzoic acid (60 mg, 0.15 mmol) in DMF (2 ml) at room temperature under nitrogen was added PyBOP (94 mg, 0.18 mmol) followed by N-ethyl-N-(propan-2-yl)propan-2-amine (40 μl, 0.23 mmol) and 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 28 mg, 0.17 mmol). After stirring for 1 hour at room temperature EtOAc (30 ml) was added to the reaction mixture and this was then washed with deionized water (5 ml) followed by saturated NaHCO3(aq) (3×5 ml). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (2 g silica, Isolute cartridge, gradient of eluents; 100% EtOAc to 96:4 EtOAc:MeOH) to give 71 mg (88%) of the title compound as a pale yellow solid. LC-MS 97%, m/z=531.1/533.1, 1H NMR (250 MHz, Chloroform-d) δ ppm 11.17 (1H, br. s.), 7.11-7.18 (1H, m), 7.06 (2H, dd, J=7.46, 2.28 Hz), 5.96 (1H, s), 4.53 (2H, d, J=5.94 Hz), 3.93-4.14 (2H, m), 2.97-3.08 (2H, m), 2.78-2.88 (1H, m), 2.68 (2H, t, J=11.57 Hz), 2.39 (3H, s), 2.26 (3H, s), 2.24 (3H, s), 1.71 (2H, d, J=11.27 Hz), 1.52 (2H, br. s.), 1.45 (9H, s), 0.86 (3H, t, J=6.93 Hz).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[I:7][C:8]1[N:9]=[C:10]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:11][C:12]=1I>C(O)C.O.C(OCC)(=O)C>[I:7][C:8]1[NH:9][C:10]([C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(I)c(I)[nH]1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(I)[nH]1
Temperature: 90 °C
Yield: 72.9 %

Procedure:
Sodium sulfite (10.31 g, 82 mmol) was added to a solution of (S)-tert-butyl 2-(4,5-diiodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (4.0 g, 8.2 mmol) in ethanol (75 mL) and water (75 mL). The suspension was heated with an oil bath at 100° C. for 4 hours and at 90° C. for 16 h. The reaction was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted several times with ethyl acetate. The combined organic phases were dried (brine, Na2SO4), filtered and concentrated in vacuo. The residue was purified by a flash chromatography (sample was dry loaded on silica gel and eluted with, 0 to 40% ethyl acetate/CH2Cl2) to afford (S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (2.17 g, 73.1%) as a white solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=O.C=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CCCC)CCCC)CCC>C(OCC)(=O)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=Cc1ccccc1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCC(=O)OCC
Solvent: CCCCN(CCCC)CCCC
Product: C(=Cc1ccc2ccccc2c1)c1ccccc1
Yield: 44.5 %

Procedure:
The procedure described in Example 1 is followed, except that 19.1 g (0.1 mol) of 2-naphthoyl chloride, 13.1 g (0.125 mol) of styrene, 23.2 g (0.125 mol) of tri-n-butylamine and 0.225 g (0.001 mol) of palladium acetate are used. After a reaction time of 2 hours at 130° C., in 100 ml of ethyl butyrate, 10.2 g (0.0445 mol) of 2-styrylnaphthalene, corresponding to a yield of 44.5% of theory, are obtained; melting point 143°-145° C.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].[OH2:11].[C:12]1(C)C=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1.[OH-].[Na+]>O1CCCC1.O1C=CCCC1>[OH:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][O:10][CH:16]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[O:3][CH:4]=1
Reactant: O=c1cc(CO)occ1O
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C1=COCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=c1cc(COC2CCCCO2)occ1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 29265.2 %

Procedure:
To a suspension of 14.3 g of kojic acid in 57 mL of tetrahydrofuran, 11 mL of 3,4-dihydro-2H-pyran and 77 mg of p-toluenesulfonic acid monohydrate were added, and the mixture was stirred for 6 hours at room temperature. To the mixture, 1 mL of a 0.5 mol/L sodium hydroxide aqueous solution was added, and the solvent was evaporated under reduced pressure to give 26.8 g of 5-hydroxy-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O.O.S([O-])([O-])(=O)=O.[Mg+2].C(O)(=O)C>C(O)C>[CH2:19]([O:18][C:12](=[O:17])[CH:13]=[C:14]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:16])[CH3:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C=C(C)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
3-Trifluoromethylaniline (2.50 g, 15.5 mmol) and ethyl acetoacetate (2.32 g, 17.8 mmol) are dissolved in absolute ethanol in a 500 ml round bottom flask equipped with a stir bar and a reflux condenser. Magnesium sulphate monohydrate (2.58 g, 18.6 mmol) and glacial acetic acid (14 mg, 0.23 mmol) are added. The suspension is stirred rigorously at reflux for 16 hours under an argon atmosphere. The crude reaction mixture is cooled to room temperature, filtered and concentrated in vacuo to give an oil. The oil is chromatographed over silica gel with cyclohexane/ethyl acetate mixtures as eluent to yield a pale yellow oil which is analytically pure.
Reaction SMILES: Br.[NH2:2][CH2:3][C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH:13][C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:5].CN1CCOCC1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]=[C:42]=[O:43].CCOC(C)=O>CN(C=O)C>[NH2:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@@H:7]2[NH:6][C:4](=[O:5])[CH2:3][NH:2][C:42]([NH:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34]([F:33])([F:44])[F:45])=[O:43])=[O:25])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: NCC(=O)N[C@H]1CCCC[C@H]1NC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: NS(=O)(=O)c1ccc(C(=O)N[C@@H]2CCCC[C@@H]2NC(=O)CNC(=O)Nc2ccccc2C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
N-(cis)-{2-[(aminoacetyl)amino]cyclohexyl}-4-(aminosulfonyl)benzamide hydrogen bromide, (61b), (100 mg) was dissolved in DMF (3 mL) prior to the addition of 4-methylmorpholine (0.13 mL) and 2-trifluoromethylphenyl isocyanate (0.05 mL). After stirring overnight, EtOAc was added and the solution was washed with 1N HCl. The EtOAc was dried, filtered, and concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title benzamide (50 mg). MS found: (M+Na)+=564.3.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[H-].[Na+].Cl[C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.CO>CN(C=O)C.O>[CH3:18][N:17]([CH3:19])[S:14]([N:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:3]1[CH2:2][O:1][C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)(=[O:15])=[O:16]
Reactant: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1CO
Reactant: Clc1cnc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)S(=O)(=O)n1cc(-c2ccccc2)nc1COc1cnc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
2-(Hydroxymethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide (0.79 mmol) was dissolved in anhydrous DMF (5 mL) and cooled to 0° C. NaH (60% dispersion in mineral oil, 47 mg, 1.19 mmol) was added and the suspension was stirred for 2 min. 2-Chloroquinoxaline (195 mg, 1.19 mmol) in anhydrous DMF (3 mL) was added dropwise and the resulting suspension was allowed to warm to room temperature. After 2 h, MeOH (10 mL) was added slowly. The crude reaction mixture was poured into H2O (30 mL) and extracted with Et2O (3×30 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give crude N,N-dimethyl-4-phenyl-2-((quinoxalin-2-yloxy)methyl)-1H-imidazole-1-sulfonamide, which was used directly in the next reaction.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([C:23](OC)=[O:24])=[CH:17]2.Cl>C1(C)C=CC=CC=1.C1COCC1>[Br:11][C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([CH2:23][OH:24])=[CH:17]2
Reactant: COC(=O)c1ccc2c(Br)cc(F)cc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1ccc2c(Br)cc(F)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
1.0 M diisobutylaluminium hydride in toluene (11.5 mL) was slowly added to a solution of 30 (1.3 g, 4.6 mmol) in THF (15 mL) at −78° C. After the addition was completed, the mixture was allowed to warm to room temperature and continuously stirred for 18 h. The mixture was poured in to HCl aqueous solution (0.5 N, 50 mL) and extracted in ethyl acetate (2×100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated rotary evaporation, and purified by column chromatography to give (5-bromo-7-fluoronaphthalen-2-yl)methanol (31) (98%). 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.45 (d, J=11.4 Hz, 1H), 4.90 (s, 2H). GC-MS (ES) for C11H8BrFO [M+1]+ 255.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][C:17]([CH3:33])([CH3:32])[C:18]([NH:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27](O)[C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19].N1C=CC=CC=1>C(Cl)Cl>[CH3:16][C:17]([CH3:33])([CH3:32])[C:18]([NH:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19]
Reactant: COC(=O)c1c(O)cccc1NC(=O)C(C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NC(=O)C(C)(C)C)cccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Trifluoromethanesulphonic anhydride (6.2 g) was added dropwise to an ice cooled, stirred solution of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (Intermediate 40, 5.02 g) and pyridine (3.16 g) in DCM (70 mL) and the mixture was stirred for 1 hour. The resulting solution was washed with 2M hydrochloric acid, filtered through a phase separator and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give methyl 2-(2,2-dimethylpropionylamino)-6-trifluoromethanesulfonyloxybenzoate (7.09 g) as a colourless oil.