Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:34]([NH:36][NH2:37])[CH3:35].CCOC(C)=O>CCN(CC)CC>[F:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[F:24])[CH2:17][C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[N:36]([CH2:34][CH3:35])[N:37]=1
Reactant: O=C(CC(=O)C1CCN(Cc2ccccc2)CC1)Cc1ccc(F)c(F)c1
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCn1nc(Cc2ccc(F)c(F)c2)cc1C1CCN(Cc2ccccc2)CC1
Reaction time: 0.06 h

Procedure:
The title compound was prepared from 1-(1-benzylpiperidin-4-yl)-4-(3,4-difluorophenyl)butane-1,3-dione and ethylhydrazine oxalate using a procedure similar to that described in Example 1, Step B. RF: 0.29 (2:1 EtOAc to hexanes with 1% (v/v) Et3N). It was the fast-eluting isomer on silica gel. 1H NMR (500 MHz, CDCl3): δ7.29˜7.33 (m, 4H), 7.23˜7.28 (m, 1H), 7.05˜7.14 (m, 2H), 6.97˜7.01 (m, 1H), 5.86 (s, 1H), 4.06 (q, 7.2 Hz, 2H), 3.84 (s, 2H), 3.55 (s, 2H), 2.97 (br d, 11.9 Hz, H), 2.64 (tt, 12.1 & 3.7 Hz, 1H), 2.12˜2.16 (m, 2H), 1.83 (br d, 13.1 Hz, 2H), 1.62˜1.71 (m, 2H), 1.35 (t, 7.2 Hz, 3H); ESI-MS 396.2 (M+H), HPLC A: 3.43 min., compared with 3.54 min. for its isomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.C=O.[CH:31](O)=O.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][N:23]([CH3:31])[CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:26])[F:27])[CH:4]=1
Reactant: O=CO
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C)CC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Yield: 61.3 %

Procedure:
The solution of (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) in formaldehyde (37 wt % aqueous solution, 97 mg, 1.16 mmol) and formic acid (54 mg, 1.16 mmol) was heated at 80° C. for 2h. The reaction mixture was diluted with H2O then basified with 1N NaOH to pH 12 and extract with CHCl3. The combined organic solution was dried over MgSO4, concentrated in vacuo, and the residue was chromatographed (silica gel; CHCl3:MeOH 99:1-95:5) to give the title compound as a pale yellow oil (19 mg, 61%). MS (CI, NH3): 403.1 (base, M+H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([CH3:13])[N:7]=[CH:6][N:5]=1>CC(O)=O>[Br:1][CH2:13][C:8]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:4]([Cl:3])[N:5]=[CH:6][N:7]=1
Reactant: BrBr
Reactant: CCCc1c(C)ncnc1Cl
Solvent: CC(=O)O
Product: CCCc1c(Cl)ncnc1CBr
Temperature: 85 °C
Reaction time: 1 h

Procedure:
Br2 (0.153 ml, 3 mmol) is added dropwise to a solution of 4-chloro-6-methyl-5-propyl-pyrimidine (3 mmol) heated at 85° C. in HOAc (10 ml). After the addition, the mixture is stirred at 85° C. for 1 hour. The solvent is removed in vacuo and the residue dissolved in EtOAc (15 ml), washed with Na2S2O3 solution (sat. 5 ml), followed by NaHCO3 (10 ml), and brine (10 ml). The organic phase is dried (Na2SO4) and evaporated. The resulting yellow oil is purified by flash column chromatography, which provides the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:17]([O:19][CH2:20]Cl)=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[I-:23].[Na+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH:4]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:17]([O:19][CH2:20][I:23])=[O:18])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C(c1ccccc1)C1CCCCN1C(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C(c1ccccc1)C1CCCCN1C(=O)OCI
Reaction time: 8 h
Yield: 73.3 %

Procedure:
A mixture of 37 (0.28 g, 0.86 mmol) and sodium iodide (0.387 g, 2.58 mmol) in acetone (6 mL) was stirred overnight. The acetone was evaporated. The residue was dissolved in ethyl acetate (80 mL) and washed with saturated sodium bisulfate (30 mL) and brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried in vacuum to give 38 as a syrup (0.263 g) (yield, 73%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:5]1[S:1][C:2]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[C:3]=2[CH:4]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C1CCCc2sccc21
Agent: O=S(=O)(O)O
Product: O=C1CCCc2sc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
6,7-Dihydrobenzo[b]thiophen-4(5H)-one (5 g, 32.9 mmol) was dissolved in concentrated sulphuric acid (30 mL) and cooled to 0° C. in an ice/salt bath. Concentrated nitric acid (3.5 mL) in concentrated sulphuric acid (20 mL) was added drop-wise keeping the temperature of the reaction below 0° C. The reaction mixture was stirred at 0-5° C. for 1 hr. The solution was poured onto ice and the resulting solid filtered, washed with water and dried in a vacuum oven, affording the title compound (5.68 g, 88%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:13][CH:14]=2)=[O:19])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(NS(=O)(=O)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
Benzenesulfonyl chloride (0.26 mL, 2.03 mmol) was slowly added to an ice-cooled solution of (4-amino-phenyl)-(4-methoxy-phenyl)-methanone (178) (0.42 g, 1.85 mmol) and pyridine (0.16 mL, 2.03 mmol) in dry dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 20 h then partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated to give a solid. The solid was recrystallized from hot dichloromethane and methanol to give 0.451 g (66%) of the title compound 182. 1H NMR (400 MHz, DMSO-d6): δ 3.82 (s, 3 H), 7.03 (d, J=8.8 Hz, 2 H), 7.22 (d, J=8.6 Hz, 2 H), 7.57-7.65 (m, 7 H), 7.84 (d, J=7.3 Hz, 2 H), 10.87 (s, 1 H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([OH:38])=O)[C:31]2=[O:39])=[CH:26][CH:25]=1.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1.C(N(CC)CC)C>CN(C=O)C>[C:44]1([CH3:47])[CH:45]=[CH:46][C:41]([NH:40][C:36]([C:32]2[C:31](=[O:39])[N:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[CH:35]=[CH:34][CH:33]=2)=[O:38])=[CH:42][CH:43]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 273.6 %

Procedure:
TBTU (276 mg, 0.851 mmol) was added to the mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (147 mg, 0.567 mmol), p-toluidine (73.7 mg, 0.681 mmol), and triethylamine (120 μl, 0.851 mmol) in DMF (3 ml) at rt. The combined mixture was stirred at rt for 16 h. After that time, the solvent was removed to give a black solid (500 mg). It was purified by chromatography on silica gel (15 g) eluting with 40% (100 ml), 50% (100 ml), 60% (100 ml) and 70% (100 ml) EtOAc/hexane to give the title compound as a light-brown solid. 1H NMR (400 MHz, CDCl3): δ=2.31 (s, 3H), 6.58 (dd, J=6.8 & 7.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.23-7.29 (m, 2H), 7.38-7.42 (m, 2H), 7.56-7.63 (m, 3H), 8.74 (dd, J=2.0 & 6.8 Hz, 1H), 11.69 (brs, 1H). MS (ES+): m/z 323.09 [MH+]. HPLC: tR=3.69 min (polar—5 min, ZQ3).
Reaction SMILES: [N:1]1([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:25]O>>[N:1]1([C:11]2[CH:19]=[CH:18][C:14]([C:15]([O:17][CH3:25])=[O:16])=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)c1ccc(N2CCNc3ccccc32)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N2CCNc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.8 g of 4-(3,4-dihydroquinoxalin-1(2H)-yl)benzoic acid and 70 ml of methanol are introduced into a 250 ml round-bottomed flask equipped with a magnetic stirrer. 4.4 ml of 97% sulfuric acid are added dropwise and the reaction medium is stirred at ambient temperature for 18 h. The methanol is partially evaporated. The remaining solution is poured onto a water-plus-ice mixture, neutralized by slow addition of sodium hydrogencarbonate and extracted 3 times with ethyl acetate. The organic phases are combined, washed with water and with a saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel eluted with a gradient of ethyl acetate from 10% to 20% in heptane. 2.8 g of methyl 4-(3,4-dihydroquinoxalin-1(2H)-yl)benzoate are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]2[CH3:26])=[C:4]([F:28])[CH:3]=1.[CH3:29][C:30]1[C:34]([CH2:35][C:36](O)=[O:37])=[C:33]([CH3:39])[O:32][N:31]=1>>[CH3:29][C:30]1[C:34]([CH2:35][C:36]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][N:10]3[C:14](=[O:15])[C:13]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]3[CH3:26])=[C:4]([F:28])[CH:3]=2)=[O:37])=[C:33]([CH3:39])[O:32][N:31]=1
Reactant: Cc1noc(C)c1CC(=O)O
Reactant: CCCC1(c2ccc(F)cc2)N=C(C)N(CC(=O)c2ccc(N)cc2F)C1=O
Product: CCCC1(c2ccc(F)cc2)N=C(C)N(CC(=O)c2ccc(NC(=O)Cc3c(C)noc3C)cc2F)C1=O

Procedure:
Synthesis in analogy to Example 14 and Example 1 starting from enantiomerically pure 3-[2-(4-amino-2-fluoro-phenyl)-2-oxo-ethyl]-5-(4-fluoro-phenyl)-2-methyl-5-propyl-3,5-dihydro-imidazol-4-one and (3,5-dimethylisoxazol-4-yl)-acetic acid to yield (−)-2-(3,5-dimethyl-isoxazol-4-yl)-N-(3-fluoro-4-{2-[4-(4-fluoro-phenyl)-2-methyl-5-oxo-4-propyl-4,5-dihydro-imidazol-1-yl]-acetyl}-phenyl)-acetamide. LC/MS at 254 nm; [M+H] 523; Rt 3.417 min; optical rotation αD25−1.4°, c=0.5 in methanol.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C=O)C.[C:10]([C:14]1[N:19]=[C:18](O)[CH:17]=[C:16]([C:21]([F:24])([F:23])[F:22])[N:15]=1)([CH3:13])([CH3:12])[CH3:11]>ClCCl>[C:10]([C:14]1[N:19]=[C:18]([Cl:3])[CH:17]=[C:16]([C:21]([F:24])([F:23])[F:22])[N:15]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1nc(O)cc(C(F)(F)F)n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1nc(Cl)cc(C(F)(F)F)n1
Yield: 96 %

Procedure:
Firstly 86.5 ml of thionyl chloride and then 8 ml of DMF were added dropwise to a solution of 60 g (0.27 mol) of 2-t-butyl-4-hydroxy-6-trifluoromethylpyrimidine in 800 ml of dichloromethane, and then the mixture was refluxed. The volatile constituents were removed under reduced pressure, the residue was taken up in 100 ml of dichloromethane, the pH was adjusted to 7 with saturated NaHCO3 solution and, after workup by extraction, 67 g (96%) of a clear oil were obtained.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([OH:24])=[O:23])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](Cl)(=O)C>CO>[O:1]([C:8]1[CH:9]=[C:10]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccccc1Sc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)Cc1ccccc1Sc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Mercaptophenylacetic acid was prepared by a method described in the chemical literature (see D. Papa et al, J. Org. Chem., 1949, 24, 723, R. H. Glauert and F. G. Mann, J. Chem. Soc., 1952, 2127 and references therein). 2-Mercaptophenylacetic acid (1.68 g) was added to a stirred solution of sodium hydroxide (0.8 g) in methanol (10 ml), (compare D. C. Atkinson et al, J. Med. Chem., 1983, 26, 1361). The resulting orange solution was stirred at room temperature for 90 minutes then concentrated under reduced pressure, removing the final residues of methanol by azeotroping with toluene, to leave a yellow solid. Cuprous chloride (0.2 g) and a solution of 3-phenoxybromobenzene (2.49 g, prepared from 3-phenoxyphenol and triphenylphosphine dibromide by the method described by J. P. Schaefer et al, Org. Synth., Coll. Vol.5, 142) in DMF (10 ml) were added successively to a stirred solution of this yellow solid in DMF (20 ml). The resulting mixture was heated at 95° C. for 11/2 hours, at 125° C. for 2 hours, and then at reflux for a further 2 hours. After cooling, the reaction mixture was poured into aqueous sodium hydroxide then washed with ether (×3). The aqueous solution was acidified with concentrated hydrochloric acid and extracted with ether (×3). These extracts were washed with water, dried and concentrated to give a purple oil (2.2 g) consisting mainly of 2-(3-phenoxyphenylthio)phenylacetic acid. A solution of this oil in methanol (20 ml) was added to acidic methanol [prepared by carefully treating methanol (30 ml) with acetyl chloride (3.5 ml)] and the resulting mixture was stirred for 90 minutes at room temperature. The reaction mixture was concentrated and the residue was partitioned between ether and aqueous sodium bicarbonate. The organic layer was separated and washed successively with aqueous sodium hydroxide (×2) and water (×3) then dried and concentrated to give crude methyl 2-(3-phenoxyphenylthio)phenylacetate (2.06 g) as a purple oil.
Reaction SMILES: CON(C)[C:4](=[O:9])[CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][Mg]Cl)=[CH:14][CH:13]=1>>[CH3:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([CH3:16])=[CH:14][CH:13]=1
Reactant: CON(C)C(=O)CC(C)C
Reactant: Cc1ccc(C[Mg]Cl)cc1
Product: Cc1ccc(CC(=O)CC(C)C)cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 36-b) using N-methoxy-N-methyl-3-methylbutanamide and 4-methylbenzyl magnesium chloride to obtain a title compound as a light yellow oily substance.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[CH3:10][C@H:11]1[CH2:16][NH:15][C@H:14]([CH3:17])[CH2:13][N:12]1[C:18](=[O:26])[C@:19]([OH:25])([CH3:24])[C:20]([F:23])([F:22])[F:21].C(N(CC)CC)C>CCOC(C)=O>[CH3:10][C@H:11]1[CH2:16][N:15]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[C@H:14]([CH3:17])[CH2:13][N:12]1[C:18](=[O:26])[C@:19]([OH:25])([CH3:24])[C:20]([F:23])([F:21])[F:22]
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1cccs1
Yield: 30.5 %

Procedure:
A solution of 2-thiophene sulphonyl chloride (129 mg, 0.707 mmol) in EtOAc (10 ml) was added to a stirred mixture of (R)-[(2S,5R)-2-methyl-5-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (J. Med. Chem., 1999, 42, 2741-2746) (150 mg, 0.59 mmol) and triethylamine (0.125 ml, 0.886 mmol) in EtOAc (15 ml). The resultant mixture was stirred at ambient temperature for 4 hours, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbon solution and brine, dried and evaporated. The residue was recrystallized from EtOAc/hexane to give the title compound as a solid (71 mg, 0.18 mmol). Mp: 116-117° C.; NMR: 0.95 (d, 3H), 1.25 (dd, 3H), 1.65 (s, 3H), 3.2 (s, 3H), 3.3 (s, 1H), 3.5 (dd, 1H), 4.05 (s, 1H), 4.15 (s, 1H), 4.3 (s, 1H), 4.75 (s, 1H), 7.0 (dd, 1H), 7.5 (dd, 2H); m/z 399.
Reaction SMILES: [O:1]=[C:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)[CH:3]=[CH2:4].[Cl:18][C:19]1[CH:24]=[C:23]([SH:25])[CH:22]=[C:21]([Cl:26])[C:20]=1[OH:27].C(N(CC)CC)C>CO>[Cl:18][C:19]1[CH:24]=[C:23]([S:25][CH2:4][CH2:3][C:2]([N:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][CH2:10]2)=[O:1])[CH:22]=[C:21]([Cl:26])[C:20]=1[OH:27]
Reactant: Oc1c(Cl)cc(S)cc1Cl
Reactant: C=CC(=O)N1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CCSc1cc(Cl)c(O)c(Cl)c1)N1CCN(Cc2ccccc2)CC1
Reaction time: 12 h

Procedure:
1-(1-Oxo-2-propenyl)-4-(phenylmethyl)piperazine (2.53 g, 0.011 mole) and 2,6-dichloro-4-mercaptophenol (2.15 g, 0.011 mole) were dissolved in methanol (75 ml). Triethylamine (1 ml) was added and the reaction stirred for 12 hours. The solvent was removed, and the product purified by chromatography on silica, eluting with ethyl acetate/hexane.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[CH2:21][C:22]([OH:24])=O.[Si:25]([O:32][CH2:33][C@H:34]1[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:44][CH2:45][C:46]([CH3:49])([OH:48])[CH3:47])[C@H:36]([CH3:50])[NH:35]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>O1CCCC1>[Si:25]([O:32][CH2:33][C@H:34]1[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[CH2:44][CH2:45][C:46]([OH:48])([CH3:49])[CH3:47])[C@H:36]([CH3:50])[N:35]1[C:22](=[O:24])[CH2:21][C:15]1[C:16]([Cl:20])=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: O=C(O)Cc1c(Cl)cccc1Cl
Reactant: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(CCC(C)(C)O)cccc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@H]1c2cccc(CCC(C)(C)O)c2C[C@H](CO[Si](C)(C)C(C)(C)C)N1C(=O)Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.6 %

Procedure:
Add 1,1′-carbonyldiimidazole (112.9 g, 682.36 mmol) to a mixture of 2,6-dichlorophenylacetic acid (173.09 g, 818.83 mmol) in tetrahydrofuran (1.63 L) in an appropriate vessel and stir at 25° C. After 1 hour add a solution of 4-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol (217 g, 545.89 mmol) in tetrahydrofuran (1.63 L) to the mixture, heat the mixture to 45° C. and stir. After 24 hours, cool the mixture to 20° C., remove 2 L of tetrahydrofuran by concentrating under reduced pressure and dilute the residues with ethyl acetate (2.5 L). Wash the ethyl acetate solution with saturated aqueous ammonium chloride (1.5 L), 1M aqueous sodium hydroxide (1 L), water (1 L) and brine (1.5 L). Dry the organics over anhydrous sodium sulfate and concentrate under reduced pressure to give the title compound (376 g, 532.70 mmol). MS (m/z): 564.2 (M+1 (35C1)), 566.2 (M+1 (37Cl)).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C([O-])(=O)C.[Na+].C(O)(=O)C.[Br:18]Br>O>[Br:18][C:8]1[C:4]([N+:1]([O-:3])=[O:2])=[N:5][NH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1n[nH]cc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.9 %

Procedure:
A 1 L 3-neck flask equipped with a stir bar was charged with 3-nitro-1H-pyrazole (41.3 g, 365 mmol), sodium acetate (36.0 g, 438 mmol), and acetic acid (260 mL). The flask was fitted with a septum, addition funnel, and a temperature probe. Bromine (23 mL, 450 mmol) was added over 30 minutes via addition funnel to the reaction mixture; the temperature increased to 40° C. over the course of bromine addition. The heterogeneous reaction mixture became homogeneous as the reaction progressed, with the exception of a few chunks of solid. As the temperature of the reaction mixture fell, a precipitate formed. The reaction mixture was poured into 1.2 L of ice and water and stirred vigorously. After 15 minutes, the solids were collected by filtration and washed with several portions of water (500 mL total). The solids were dried under vacuum to afford the product as a tan powder (49.67 g, 71%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1.[CH3:32][N:33]1[CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:32][N:33]1[CH2:34][CH:35]=[C:36]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][N:27]=4)(=[O:24])=[O:23])=[CH:19][CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH2:37][CH2:38]1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Br)nccc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CC=C(c2cc(C(F)(F)F)ccc2-c2nccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)CC1
Temperature: 100 °C
Yield: 95.2 %

Procedure:
A vial was charged with 1-(2-bromo-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (42.16 mg, 0.083 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (27.7 mg, 0.124 mmol) Pd(AmPhos)2Cl2 (2.93 mg, 4.14 μmol), potassium phosphate (52.7 mg, 0.248 mmol), dioxane (414 μl), and water (138 μl). The vial was sealed and heated in a microwave reactor for 30 min at 100° C. The mixture was extracted with EtOAc (three times). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel, eluting with 5 to 10% MeOH/DCM, then with 15% MeOH/EtOAc, and finally with a solution of 20% of 2N ammonia in methanol in DCM. The fractions containing product were collected and concentrated. The residue was dissolved in DCM and filtered through cotton. The filtrate was concentrated to give 1-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (41.4 mg, 0.079 mmol) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.63 (d, J=5.7 Hz, 1H), 8.55 (d, J=1.5 Hz, 1H), 8.35 (s, 1H), 8.08 (d, J=5.8 Hz, 1H), 8.01 (d, J=6.2 Hz, 1H), 7.91 (dd, J=1.8, 8.9 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.76 (s, 1H), 7.63 (dd, J=8.4, 19.4 Hz, 2H), 6.72 (d, J=6.2 Hz, 1H), 5.37 (br. s., 1H), 2.98 (br. s., 2H), 2.52 (br. s., 2H), 2.20 (s, 3H), 2.16-1.96 (m, 2H). m/z (ESI) 526.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([F:30])[CH:17]=1>O1CCCC1>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:3]([C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[CH:17][C:18]=1[F:30])#[N:29]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)c(F)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.8 %

Procedure:
A solution of methyl 3-oxoheptanoate (7 g) in tetrahydrofuran (30 mL) was added to a mixture of sodium hydride (1.2 g) and tetrahydrofuran (80 mL) at room temperature, and the mixture was stirred at room temperature for 30 min. And then, 4′-(bromomethyl)-2′-fluorobiphenyl-2-carbonitrile (5.3 g) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, the residue was extracted with 5% aqueous potassium hydrogensulfate solution and then with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless oil (7.3 g, 90%).