Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[F:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][CH:15]=1>C(Cl)(Cl)Cl>[F:9][C:10]1[CH:11]=[C:12]([O:16][CH3:17])[CH:13]=[CH:14][C:15]=1[C:5](=[O:7])[CH3:6]
Reactant: COc1cccc(F)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)=O)c(F)c1
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
Aluminum chloride 30.0 g, 0.6 mol) and chloroform (750 mL) were placed in a 2 L three-necked round bottom flask fitted with a mechanical stirrer and cooled by means of an ice bath. To the stirred solution acetyl chloride (51.0 g, 0.65 mol) was added dropwise, maintaining the temperature between 5-10° C. The mixture was stirred for 10 minutes at 5° C. before the dropwise addition at 5-10° C. of 3-fluoroanisole (63.6 g, 0.5 mol). The mixture was stirred at 0-10° C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL) The combined organic layers were washed with water (2×150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92-94° C.; 1H NMR (DMSO-d6) 7.8 (m, 2H), 7.3 (t, 1H), 3.9 (s, 3H), 2.5 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:19])[C:3]=1[CH:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=1)O>CCOC(C)=O.CC(O)=O.[Pd]>[CH3:19][C:4]1[CH:5]=[C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:20][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=1
Reactant: COCOc1ccc(C(O)c2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1
Reaction time: 5 h
Yield: 34.8 %

Procedure:
A degassed solution of crude (2,6-dimethyl-4-triisopropylsilanyloxyphenyl)-(4-methoxymethoxyphenyl)methanol (12.0 g, 26.84 mmol) and Pd/C (1.2 g) in EtOAc/HOAc (19/1) was stirred under an atmosphere of hydrogen (1 atm) at r.t. After 5 h, the catalyst was filtered through a pad of Celite, rinsed with ethyl acetate and the combined filtrates concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-hexanes; 1:9) to afford 4-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-methoxymethoxybenzene (4.0 g, 41.5% for two steps): 1H NMR (300 MHz, CDCl3): δ 6.93 (s, 4 H), 6.63 (s, 2H), 5.16 (s, 2H), 3.94 (s, 2H), 3.50 (m, 3H), 1.58 (s, 6H), 1.29 (m, 3H), 1.13 (m, 18H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:19); Rf=0.80.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[Br:13]Br>ClCCl>[C:1]([N:6]1[CH2:7][CH2:8][C:9](=[O:12])[CH:10]([Br:13])[CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: BrBr
Reactant: CCOC(=O)N1CCC(=O)CC1
Solvent: ClCCl
Product: CCOC(=O)N1CCC(=O)C(Br)C1

Procedure:
1-carbethoxy-4-piperidone 1 reacts with bromine in an inert solvent such as dichloromethane to give high yields of 1-carbethoxy-3-bromo-4-piperidone 2. The bromo compound 2 reacts with sodium methoxide in methanol to give 1-carbethoxy-3-hydroxy-4,4-dimethoxypiperidine 3, which in turn is alkylated to the corresponding 3-methoxy analog 4 with iodomethane in dimethylformamide in the presence of sodium hydride. The ketal 4 is hydrolyzed to 1-carbethoxy-3-methoxy-4-piperidone 5 by stirring in 1% sulfuric acid at room temperature. The amine 6 of cis-configuration is then readily obtained by reductive alkylation of 5 with benzylamine in the presence of hydrogen gas and 10% Pd/C with a small amount of thiophene. Further hydrogenolysis of the benzyl moiety with Pd/C and no thiophene gives the primary amine 7. Compound 7 in turn reacts with the commercially available 4-amino-5-chloro-2-methoxybenzoic acid in the presence of DCC and dimethyaminopyridine in dichloromethane to give the benzamide 8. Compound 8 is then hydrolyzed to the intermediate 9 with potassium hydroxide in ethanol/water.
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[N+:19](CCC(C1C=CC=CC=1)=O)([O-:21])=[O:20].[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Reactant: O=C(CC[N+](=O)[O-])c1ccccc1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc([N+](=O)[O-])c1
Yield: 98 %

Procedure:
Compound 9g was synthesized by a procedure similar to that described for 9a using commercially available 3-nitropropiophenone (8g, 5.0 g, 0.028 mol), TBDMSOTf (7.1 mL, 30.7 mmol), and Et3N (6.2 mL) in CH2Cl2 (50 mL). After purification on alumina, 8.0 g (98%) of 9g was isolated as colorless oil: 1H NMR (CDCl3) δ 8.34-8.30 (m, 1H), 8.12-8.06 (m, 1H), 7.80-7.75 (m, 1H), 7.52-7.42 (m, 1H), 5.40 (q, 1H, J=6.9 Hz), 1.78 (d, 3H, J=6.9 Hz), 1.02 (s, 9H), −0.02 (s, 6H); 13C NMR (CDCl3) δ 148.8, 141.6, 131.3, 129.0, 122.1, 120.5, 108.6, 106.8, 25.9, 18.4, 12.0, −3.8. C15H23NO3Si.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1.O.[NH3:16].C1COCC1>[Na+].[Cl-]>[NH2:16][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1
Reactant: N
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc2c([N+](=O)[O-])cccc2n1

Procedure:
450 mg (2.2 mmol) of 2-chloro-5-nitroquinoline, 10 ml of 25% ammonia water and 10 ml of THF are stirred in a pressure vessel for 8 hours at 120° C. The batch is diluted with NaCl solution and extracted with ethyl acetate. The combined organic phases are dried (Na2SO4) and concentrated by evaporation: 370 mg of product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].Br[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Br
Reactant: FC(F)(F)c1cc(Br)c2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc2c(Br)cc(C(F)(F)F)cc21
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of 4-bromo-6-(trifluoromethyl)-1H-indole (1 g, 3.79 mmol) in DMF (6 mL) was added 60% sodium hydride (0.182 g, 4.54 mmol), and the mixture was stirred for 30 min 2-bromopropane (0.533 mL, 5.68 mmol) was added and the mixture was stirred overnight. The reaction was then quenched with 10% NaHCO3 and extracted with EtOAc (3×). The extract was dried over Na2SO4 and concentrated. The residue was purified using column chromatography (Silica gel, 0 to 100% EtOAc/hexanes) to give the title compound (460 mg, 40%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.56-1.61 (m, 6H), 4.66-4.79 (m, 1H), 6.65 (d, J=3.03 Hz, 1H), 7.27-7.31 (m, 1H), 7.45 (d, J=3.03 Hz, 1H), 7.54 (s, 1H), 7.63 (s, 1H). MS: (M+H)+=306.2.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.Cl[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:28]([CH:31]=1)[C:29]#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:29]([C:28]1[CH:31]=[C:24]([CH:25]=[CH:26][C:27]=1[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:23][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)#[N:30]
Reactant: N#Cc1cc(CCl)ccc1C1CCCCC1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(C4CCCCC4)c(C#N)c3)ccc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a solution of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (40 mg, 0.139 mmol) and 5-(chloromethyl)-2-cyclohexylbenzonitrile (35.8 mg, 0.153 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (54.4 mg, 0.167 mmol). The mixture was stirred at 50° C. for 16 h. The mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite®. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to provide the title compound as an off-white foam (57.4 mg). LCMS m/z=485.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.24-1.34 (m, 1H), 1.43-1.53 (m, 4H), 1.50 (s, 9H), 1.80 (dd, J=12.88, 1.26 Hz, 1H), 1.89 (t, J=10.86 Hz, 4H), 2.22-2.34 (m, 1H), 2.50 (dd, J=15.73, 8.40 Hz, 1H), 2.73 (dd, J=15.79, 6.44 Hz, 1H), 2.82-2.92 (m, 1H), 2.99 (t, J=3.09 Hz, 1H), 3.65-3.75 (m, 1H), 3.95-4.04 (m, 1H), 4.07-4.16 (m, 1H), 5.06 (s, 2H), 6.09 (s, 1H), 6.85 (dd, J=8.72, 2.40 Hz, 1H), 7.08 (d, J=2.27 Hz, 1H), 7.14 (d, J=8.72 Hz, 1H), 7.37 (d, J=8.08 Hz, 1H), 7.62 (dd, J=8.15, 1.71 Hz, 1H), 7.71 (d, J=1.52 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH:11]([C:14]1[N:15]=[C:16]([CH3:19])[S:17][CH:18]=1)([CH3:13])[CH3:12].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:19][C:16]2[S:17][CH:18]=[C:14]([CH:11]([CH3:13])[CH3:12])[N:15]=2)[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: Cc1nc(C(C)C)cs1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)c1csc(C=Cc2cccc(C#N)c2)n1
Temperature: 170 °C
Reaction time: 24 h
Yield: 53.7 %

Procedure:
3-Cyanobenzaldehyde (3.93 g, 30.0 mmol) was mixed with 4-isopropyl-2-methylthiazole (4.19 g, 30.0 mmol), and acetic anhydride (1.53 g, 15.0 mmol) was added. The mixture was heated under stirring at 170° C for 24 hours. After the reaction, acetic acid was distilled out under reduced pressure and the residue was purified by column chromatography (SiO2, n-hexane/ethyl acetate=3/l) to afford the indicated compound (4.10 g) with a yield of 54%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[B:9]([OH:11])[OH:10].O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[B:9]1[O:10][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:11]1
Reactant: Cc1ccc(B(O)O)c(F)c1
Reactant: CC(C)(O)C(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of (2-fluoro-4-methylphenyl)boronic acid (500 mg, 3.24 mmol) in diethyl ether (20 mL) was added pinacol (360 mg, 3.24 mmol) and 4-toluenesulfonic acid monohydrate (30 mg, 162 μmol) and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid, 740 mg, in a 97% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (s, 12H), 2.34 (s, 3H), 6.82 (d, 1H), 6.93 (d, 1H), 7.60 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.[C:37](Cl)(=[O:39])[CH3:38]>C(OCC)(=O)C>[C:24]([O:23][C:21]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]([C:37](=[O:39])[CH3:38])[CH3:20])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CNc1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)N(C)c1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 55 %

Procedure:
To a mixture of the compound (540 mg) obtained in Example 446, potassium carbonate (1.96 g) and acetonitrile (30 ml), acetyl chloride(890 mg) was added and heated under reflux for 24 h. Ethyl acetate was added to the reaction mixture, which was washed with water, dried with magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, methylene chloride:ethyl acetate=5:1) to give 330 mg of the titled compound (yield, 55%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[C:13]([CH3:20])[CH:12]=1>O1CCOCC1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1]2)=[O:19])=[C:13]([CH3:20])[CH:12]=1
Reactant: Cc1cc(Cl)ccc1N=C=O
Reactant: c1ccc2c(c1)CNC2
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1NC(=O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of isoindoline (238 mg, 2.0 mmol) in dry 1,4-dioxane (10 mL) was added 4-chloro-2-methylphenyl isocyanate (335 mg, 2.0 mmol) under argon at room temperature. The reaction mixture was then stirred at RT overnight. The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization from ethanol to give the title compound (540 mg, 94%) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 2.24 (s, 2H), 4.76 (s, 4H), 7.20 (dd, J=2.5, 8.5 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 7.30-7.32 (m, 2H), 7.34-7.37 (m, 2H), 7.42 (d, J=8.5 Hz, 1H), 7.84 (s, 1H); 13C NMR (DMSO-d6): δ 17.7, 51.9, 122.8, 125.6, 126.8, 127.3, 128.1, 129.5, 134.7, 136.8, 154.2; MS (MH+, 287); EA calc'd for C16H15ClN2O: C, 67.02; H, 5.27; N, 9.77. Found C, 66.82; H, 5.41; N, 9.92.
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:11]([F:36])[CH:10]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:11]([F:36])[CH:10]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CC(F)(F)CC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 98.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (79.7 mg, 0.13 mmol) prepared in Example 130a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (60 mg, 99%) as a colorless solid.
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].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18](O)[N:17]=1.C(N(CC)CC)C>ClCCl>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[N:17]=1
Reactant: Oc1cc2ccccc2cn1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1cc2ccccc2cn1)C(F)(F)F
Reaction time: 0.67 h
Yield: 96.4 %

Procedure:
Add trifluoromethanesulfonic anhydride (383 μL, 2.3 mmol) dropwise to a suspension of isoquinolin-3-ol (274 mg, 1.89 mmol) and triethylamine (524 μL, 3.8 mmol) in dichloromethane (12 mL). Stir for 40 min, then load onto a silica column and elute with dichloromethane to give trifluoro-methanesulfonic acid isoquinolin-3-yl ester as a white solid (505 mg, 97%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:37]=[CH:36][C:35](/[C:38](/[CH3:42])=[CH:39]/[CH2:40][OH:41])=[CH:34][CH:33]=1.[CH2:49]([O:51][C@@H:52]([CH2:58][C:59]1[CH:64]=[CH:63][C:62](O)=[CH:61][CH:60]=1)[C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH3:50]>C1COCC1>[C:32]1([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:33]=[CH:34][C:35](/[C:38](/[CH3:42])=[CH:39]/[CH2:40][O:41][C:62]2[CH:61]=[CH:60][C:59]([CH2:58][C@H:52]([O:51][CH2:49][CH3:50])[C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:64][CH:63]=2)=[CH:36][CH:37]=1
Reactant: C/C(=C\CO)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccccc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (0.346 ml, 2.2 mmol) was added at 0° C. to a stirred solution of triphenyl-phosphine (0.656 g, 2.2 mmol) and (E)-3-biphenyl-4-yl-but-2-en-1-ol (0.270 g, 1.2 mmol) in dry THF (20 ml) and the mixture stirred for 5 min. A solution of (S)-ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.238 g, 1.0 mmol) in dry THF (10 ml) was added, the mixture allowed to warm to room temperature, and stirring continued for 48 h. The resulting mixture was evaporated in vacuo and the residue purified by column chromatography on silica gel (20% ethyl acetate in n-heptane) to give (E)-(S)-ethyl 3-[4-(3-biphenyl-4-yl-but-2-enyloxy)-phenyl]-2-ethoxy-propionate as an oil; 0.288 g (65%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[NH:26][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (100 mg, 0.385 mmol) and m-anisidine (43 μl, 0.385 mmol) similar to Example 13 and isolated as a pale yellow solid (38 mg, 29%). 1H NMR (Acetone-d6): 9.61 (d, J=2.4 Hz, 1H), 9.42 (s, 1H), 8.76–8.70 (m, 2H), 7.57–7.53 (m, 2H), 7.39 (s, 1H), 7.36 (s, 1H), 7.15 (s, 1H), 6.79–6.75 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[C:6]([F:15])[CH:5]=1)([O-])=O.C(O)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[C:6]([F:15])[CH:5]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(CCC(=O)O)c(F)c1
Reaction time: 3 h
Yield: 81.2 %

Procedure:
4-nitro-2-fluorocinnamic acid (3.32 g, 17 mmol) was dissolved in ethyl acetate (50 mL) and ethanol (10 mL) in the reaction flask of a PAR reactor. Pd/C (100 mg) was added and the reactor charged with 100 psi hydrogen. The reactor was recharged to 100 psi after 3 hours and the reaction stirred overnight. The reaction mixture was filtered through a bed of celite and the product isolated in vacuo, 2.53 g 3-(4-amino-2-fluorophenyl)propionic acid (81.2%).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[CH3:34][CH:35]1[CH2:40][NH:39][C:38](=[O:41])[CH2:37][NH:36]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[CH3:34][CH:35]1[CH2:40][NH:39][C:38](=[O:41])[CH2:37][N:36]1[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:29])([F:31])[F:30])=[CH:23][CH:22]=1
Reactant: CC1CNC(=O)CN1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1CNC(=O)CN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 120 °C
Yield: 7.7 %

Procedure:
((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (350 mg, 0.662 mmol, Intermediate B) was combined with 5-methylpiperazin-2-one (79 mg, 0.695 mmol, Anichem, North Brunswick, N.J.), potassium carbonate (275 mg, 1.99 mmol, Sigma-Aldrich, St. Louis, Mo.) in acetonitrile (4.41 mL) was heated at 120° C. for 30 min. After the reaction was allowed to cool to room temperature, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). The filtrate was concentrated and purified by reverse-phase HPLC (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient). The collected fractions were partitioned between CH2Cl2 and saturated aqueous NaHCO3, the organic layer was dried (Na2SO4), filtered and concentrated. The residue was taken up in MeOH and was passed through an AccuBond SPE SCX cartridge eluting with 2M ammonia/MeOH, to give the title compound (28 mg) as a mixture of four diastereomers.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C>C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1
Reactant: BrCCBr
Reactant: c1ccc2c(c1)CCN2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: BrCCN1CCc2ccccc21
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To 1,2-dibromoethane (58.0 ml) were added indoline (5.0 g) and triethylamine (28.7 ml), and the mixture was stirred at 90° C. for 2 hr. Ethyl acetate (200 ml) was added to the reaction mixture, and the mixture was washed with saturated brine (400 ml) and dried over Na2SO4. Ethyl acetate was evaporated under reduced pressure. The obtained residue was purified by column chromatography to give the title compound (4.09 g).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:24])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:17]([NH:24][C:8](=[O:9])[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCCCCCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 90° C. and MS: m/e=309 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and heptylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[ClH:29].O1CCOCC1>CO>[ClH:29].[NH:20]1[CH2:21][CH:18]([O:17][C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([Br:1])[CH:3]=3)=[N:16][CH:15]=2)[CH2:19]1
Reactant: Cn1cc(Br)cc(Nc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1cc(Br)cc(Nc2ccc(OC3CNC3)cn2)c1=O
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of 206d (1.46 g, 3.2 mmol) and HCl/1,4-dioxane (3.2 mL, 4M, 12.8 mmol) in methanol (20 mL) was heated at 80° C. for 1 h. The mixture was then concentrated under reduced pressure to afford 206e (1.24 g, 99%). MS-ESI: [M+H]+ 351.