Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[CH:8][C:9]=1I)=[O:4].C([Mg]Cl)(C)C.CC1OCCC1.Br[C:24]1[CH:52]=[CH:51][C:27]([C:28]([N:30]([C:44]2[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[CH:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]2)=[O:29])=[CH:26][CH:25]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[CH:8][C:9]=1[C:24]1[CH:52]=[CH:51][C:27]([C:28]([N:30]([C:44]2[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[C@@H:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:32]2)=[O:29])=[CH:26][CH:25]=1)=[O:4]
Reactant: COC(=O)c1c(I)cnn1C
Reactant: Cc1cccnc1N(C(=O)c1ccc(Br)cc1)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: COC(=O)c1c(-c2ccc(C(=O)N(c3ncccc3C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 4-iodo-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (8.1 g, 30.45 mmol) in THF (anhydrous, 60 mL) was added isopropyl magnesium chloride (16.5 mL, 16.5 mmol) at −45° C. The solution turned from clear to light green-yellowish. Stirred at this temperature for 30 min, GC-MS (sample in CD3OD) indicated all halogen-metal exchange completed. To the mixture was added 1.9 N ZnCl2 in 2-MeTHF (9.62 mL, 18.3 mmol) dropwise and the reaction was warmed to room temperature. The mixture was stirred for 2 h, over which time it turned from clear yellowish to an opaque yellowish mixture. To this reaction was added Preparation 2 tert-butyl 3-[(4-bromobenzoyl)(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate (12.04 g, 25.37 mmol) as a solid in one batch. The reaction temperature was then raised to 50° C., 1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (166 mg, 0.254 mmol) was added. The reaction was then stirred at 60° C. for 2 h then cooled to room temperature. The reaction was quenched with water and extracted 3× EtOAc. The organic layer was dried and concentrated. Purification was performed by Combiflash ISCO column (220 g) 0-75% EtOAc/heptane to isolate the desired title compound (12.8 g, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]3([CH3:23])[CH3:22])[C:7]=1[O:8][CH3:9].CN(C)[CH:28]=[O:29]>C1COCC1>[CH3:21][C:16]1([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]2[CH:11]=[C:10]([C:6]3[C:7]([O:8][CH3:9])=[C:2]([CH:3]=[CH:4][C:5]=3[O:24][CH3:25])[CH:28]=[O:29])[CH:19]=[CH:18][C:17]1=2
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)c(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: C1CCOC1
Product: COc1ccc(C=O)c(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 72.2 %

Procedure:
To a solution of 6-(5-bromo-2,6-dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthlene (0.24 g, 0.55 mmol) in anhydrous THF (6 mL) was added at −78° C. under argon n-BuLi (1.6 M in hexane, 0.7 mL, 1.1 mmol). The solution was stirred for 5 minutes at −78° C. and N,N-dimethylformamide (0.13 mL, 1.65 mmol) was added. The reaction mixture was stirred 2 hours at −78° C. then quenched with aqueous ammonium chloride and brought to room temperature. The solution was diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed and silica gel (eluent: ethyl acetate/hexane, 1:9) to give 0.14 g (72%) of 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxy-benzaldehyde. 1H NMR (500 MHz; CDCl3): δ 1.29 (s, 6 H); 1.32 (s, 6 H); 1.72 (s, 4 H); 3.37 (s, 3 H); 383 (s, 3 H); 6.83 (d, J=9.0 Hz, 1 H); 7.14 (dd, J1=2.0 Hz, J2=8.5 Hz, 1 H); 7.33 (d, J=8.0 Hz, 1 H); 7.36 (s, 1 H); 7.85 (d, J=8.5 Hz, 1 H); 10.29 (s, 1 H).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[O:27]1[CH2:31][CH:28]1[CH2:29][OH:30].CN(C)P(N(C)C)(N(C)C)=O.CCOCC>O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:31][CH:28]([OH:27])[CH2:29][OH:30])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: OCC1CO1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 3.6 g. of 4-(n-hexadecylamino)benzoic acid and 1.0 g. of 2,3-epoxypropan-1-ol in 100 ml. of hexamethylphosphoramide is heated at 90° C. for 8 hours. After addition of ether and water, the ether layer is separated and the ether extraction repeated several times. Following evaporation of the ether extracts, the mixture of starting material and desired 2,3-dihydroxypropyl ester is separated by chromatography on silica gel and recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][C:2]1N=C[O:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:24]=1[NH2:25])=[CH:22][CH:21]=[CH:20][CH:19]=2.[CH3:26][N:27](C)P(N(C)C)(N(C)C)=O>C(#N)C.C(=O)(O)[O-].[Na+]>[NH2:25][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[NH:14][C:7]([C:6]1[O:5][N:27]=[CH:26][C:2]=1[CH3:1])=[O:9]
Reactant: Nc1cnc2ccccc2c1N
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: Cc1ncoc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: Cc1cnoc1C(=O)Nc1cnc2ccccc2c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 300 mg of 4-methyloxazole-5-carboxylic acid in 4 ml of hexamethylphosphoramide and 0.4 ml of acetonitrile is added 268 mg of thionyl chloride at -5°-0° C. under nitrogen. After stirring at the same temperature for 30 minutes, 340 mg of 3,4-diaminoquinoline A1 is added and stirred at 0°-5° C. for 3 hours. The mixture is diluted with ice-water and neutralized with saturated aqueous sodium bicarbonate. The resulting solid is filtered and washed with water to give 425 mg of 4-amino-3-(4-methylisoxazole-5-ylcarbonylamino)quinoline as crude crystals. It is suspended in 12 ml of Dowtherm A (Dow Chemimical Co.) and refluxed for 2.5 hours. The cooled mixture is diluted with 50 ml of n-hexane and the resulting solid is collected by filtration. It is chromatographed on silica gel with dichloromethane-methanol (20:1 v/v) as eluent to yield a crude solid which is recrystallized from ethyl acetate-methanol, giving 297 mg of C99 as pale yellow crystals.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1)=[N+]=[N-].[ClH:16].[H][H]>CO.[Pd].O.C(O)C>[ClH:16].[NH2:1][CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])cc1O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(CN)cc1O
Temperature: 25 °C
Yield: 65 %

Procedure:
Crude methyl 4-(azidomethyl)-2-hydroxybenzoate was dissolved in methanol (750 mL) in a 2 L Parr hydrogenation flask. Palladium on carbon catalyst (10% [w/w], 3.8 g) in water (25 mL) was added, followed by concentrated hydrochloric acid (35 mL). The flask was affixed to a Parr hydrogenator, and the mixture was shaken at room temperature under 40 psi of hydrogen for 16 hours. The reaction mixture was then filtered through a 0.45 mm nylon filter. The retained solid was then washed with methanol (150 mL), water (100 mL), and methanol again (150 mL). The combined filtrates were evaporated to dryness to afford a tan solid. This solid was dissolved in hot denatured ethanol (150 mL) and the solution was allowed to cool to room temperature. White crystals formed quickly. Finally, the mixture was then chilled for 16-18 hours at 4° C. to complete crystallization. The solid was filtered, washed with a little cold ethanol (50 mL) and then diethyl ether (150 mL), and dried in vacuo over potassium hydroxide pellets to afford 51.5 g (65% yield based on methyl 4-bromomethyl-2-hydroxybenzoate) of methyl 4-aminomethyl-2-hydroxybenzoate hydrochloride (m.p. 225-227° C., open capillary, uncorrected).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([OH:9])[N:4]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:4]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Oc1nccc(C(F)(F)F)n1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1nccc(C(F)(F)F)n1)c1ccccc1
Yield: 39.3 %

Procedure:
A solution of 4-(trifluoromethyl)-2-pyrimidol (0.49 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.35 g, 39% yield) as a colourless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.CCN(CC)CC.O>CS(C)=O>[C:21]1([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:6]2[CH:7]=[C:3]([CH:2]=[O:1])[N:4]=[CH:5]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 110 °C

Procedure:
The product from Step 8.a. (2.04 g, 6.00 mmol) was suspended in DMSO (10.0 ml) and Et3N (3.34 ml, 24.0 mmol) and SO3-pyridine complex (2.39 g, 15.0 mmol) were added at room temperature. The mixture was warmed at about 110° C. for about 1 hour and then allowed to cool. The mixture was poured into 150 ml H2O and the product was filtered off. The residue was treated with saturated NaHCO3 solution (50 ml) and extracted 2×100 ml CH2Cl2. The combined CH2Cl2 layers were washed with 5% citric acid solution (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was crystallized from MeOH and H2O. Yield=1.08 g (53%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=1)(=O)=O.[C:21]1([C:27]2[S:31][C:30](B(O)O)=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:17][C:9]1[CH:8]=[C:7]([C:30]2[S:31][C:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:28][CH:29]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)c2ccccc2c1
Reactant: OB(O)c1ccc(-c2ccccc2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1cc(-c2ccc(-c3ccccc3)s2)c2ccccc2c1
Yield: 67 %

Procedure:
A mixture of 3-methoxynaphthalene-1-yl trifluoromethanesulfonate (2.7 g, 8.82 mmol), 5-phenyl-2-thiopheneboronic acid (2.7 g, 13.24 mmol), sodium carbonate (1.4 g, 13.24 mmol) was mixed in de-gassed toluene (50 ml) and ethanol (50 ml), under nitrogen. Pd(PPh3)4 (153 mg, 1 mol %) was added and the mixture heated to reflux for 18 h. The solution was allowed to cool, poured into water (200 ml), extracted with dichloromethane (2×100 ml), dried (Na2SO4), and the solvent removed under reduced pressure. The resulting residue was dissolved in DCM and filtered through a short plug of silica. The solvent was removed under reduced pressure to give a red/brown solid, which was flash chromatographed on silica using EtOAc-hexane (1:9). The fractions were combined and the solvent removed to give the title compound (1.87 g, 67%) as a green solid.
Reaction SMILES: C1(C)C=CC=CC=1.CS(O[CH2:13][C:14]1[S:15][C:16]2[CH2:17][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:20][C:21]=2[N:22]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(OCC)(=O)C>[N:36]1([CH2:13][C:14]2[S:15][C:16]3[CH2:17][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:20][C:21]=3[N:22]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(COS(C)(=O)=O)sc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2nc(CN3CCCCC3)sc2C1
Temperature: 25 °C
Yield: 30 %

Procedure:
To a toluene solution (14 ml) of tert-butyl 2-((methylsulfonyloxy)methyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (2.01 mmol) was added potassium carbonate (10 mmol) and piperidine (1.1 eq.) and the resulting reaction mixture was refluxed for 16 h. It was cooled to room temperature, diluted with ethyl acetate and the organic layer was washed successively with water and brine. After drying over sodium sulfate, the organic layer was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica). Yield: 30%.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:17]([O:20][C:21](Cl)=[O:22])[CH:18]=[CH2:19]>O.O1CCOCC1>[CH2:17]([O:20][C:21]([NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[O:22])[CH:18]=[CH2:19]
Reactant: N#Cc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCOC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Yield: 51.1 %

Procedure:
A suspension of 50 g (0.221 mol) of (S)-2-amino-3-(4-cyanophenyl)propionic acid in 150 ml of water was adjusted to pH=8 with 1N NaOH. 26.6 g (0.221 mol) of allylchloroformate in 225 ml of dioxane were slowly added at 0 to 5° C. (pH kept at 8 by addition of 1N NaOH). After completion of the reaction (thin layer chromatography (TLC) control) the mixture was extracted with DCM and the aqueous layer was acidified to pH=2 with KHSO4. The precipitate was dissolved in DCM, dried (Na2SO4), and evaporated. The residue was recrystallized from ether/petroleum benzene to give 31 g (51%) of the title compound. MS=275.1 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[N:6][CH:5]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:25])(=O)=O.[O:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([NH2:10])[C:7]2[N:6]([N:25]=[C:32]([C:28]3[O:27][CH:31]=[CH:30][CH:29]=3)[N:11]=2)[CH:5]=1)=[O:12]
Reactant: O=Cc1ccco1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: COC(=O)c1cnc(N)c(N)c1
Product: COC(=O)c1cc(N)c2nc(-c3ccco3)nn2c1

Procedure:
The title compound, MS m/e (%): 259.1 (M+, 100), was prepared in accordance with the general method of example 1 from 5,6-diamino-nicotinic acid methyl ester, O-mesitylene-sulfonylhydroxylamine, and furan-2-carboxaldehyde. The purification was performed by flash column chromatography on silica eluting with a mixture of ethyl acetate and n-hexane.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:28][C@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@H](O)C2)c(Br)c1
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCC[C@H](O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using (S)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 124.1) and (6-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.16 min, m/z=473.1 [M+H]+, m/z=471.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.39 (m, 2H) 1.53-1.62 (m, 1H) 1.78-1.86 (m, 1H) 2.55 (s, 3H) 2.55-2.62 (m, 1H) 2.69-2.78 (m, 1H) 3.42-3.51 (m, 2H) 3.55-3.63 (m, 1H) 4.37-5.01 (m, 1H) 7.36 (d, J=8.56 Hz, 2H) 7.42 (d, J=8.07 Hz, 1H) 7.83-7.89 (m, 2H) 7.93-8.00 (m, 1H) 8.07 (d, J=2.20 Hz, 1H) 8.71 (d, J=1.22 Hz, 1H) 8.75 (d, J=2.20 Hz, 1H) 10.29 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:20][Cl:21].C([O-])([O-])=O.[K+].[K+]>>[ClH:21].[ClH:21].[CH3:28][O:27][C:23]1[CH:22]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[C:24]=1[O:25][CH3:26])[CH2:20][N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(N2CCN(Cc3cc(OC)c(OC)c(OC)c3)CC2)cc1
Product: Cl
Yield: 101.1 %

Procedure:
3.85 g of N-(4-methoxyphenyl)-piperazine, 4.33 g of 3,4,5-trimethoxybenzyl chloride and 3.5 g of K2CO3 are reacted and processed according to example 2. 4.5 g of N-(3,4,5-trimethoxy-benzyl)-N'-(4-methoxyphenyl)-piperazine dihydrochloride is obtained.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]2[S:13][N:12]=[C:11](SC)[N:10]=2)[CH2:4]1)[CH3:2].Cl[C:17]1C=C(C=CC=1)C(OO)=O.[S:27]([O-:30])(O)=[O:28].[Na+]>C(Cl)(Cl)Cl>[CH3:17][S:27]([C:11]1[N:10]=[C:9]([CH:5]2[CH2:6][CH2:7][CH2:8][CH:3]([CH2:1][CH3:2])[CH2:4]2)[S:13][N:12]=1)(=[O:30])=[O:28]
Reactant: O=S([O-])O
Reactant: CCC1CCCC(c2nc(SC)ns2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC1CCCC(c2nc(S(C)(=O)=O)ns2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
320 mg of 5-(3-ethylcyclohexyl)-3-methylthio-1,2,4-thiadiazole was dissolved in 2.5 ml of chloroform, 738 mg of 3-chloroperoxybenzoic acid (content>65%) was added thereto taking for 20 minutes, and the reaction mixture was stirred for 20 minutes at room temperature. Then, the reaction mixture was added to saturated sodium hydrogensulfite aqueous solution, and separated. The organic layer was washed with sodium hydrogencarbonate aqueous solution, dried over anhydrous sodium sulfate, concentrated to give 380 mg of 3-methylsulfonyl-5-(3-ethylcyclohexyl)-1,2,4-thiadiazole.
Reaction SMILES: Br[CH:2]([CH3:15])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[C:16]([O-:19])(=[O:18])[CH3:17].[Na+].CN(C)C=[O:24]>>[C:5]1([CH:3]([O:4][C:16](=[O:18])[CH3:17])[C:2](=[O:24])[CH3:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH3:15][CH:2]([O:19][C:16](=[O:18])[CH3:17])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(Br)C(=O)c1cccc2ccccc12
Reactant: CC(=O)[O-]
Reactant: CN(C)C=O
Agent: [Na+]
Product: CC(=O)OC(C(C)=O)c1cccc2ccccc12
Product: CC(=O)OC(C)C(=O)c1cccc2ccccc12
Temperature: 80 °C
Yield: 49 %

Procedure:
A mixture of 2-bromo-1-naphthalen-1-yl-propan-1-one (20 g), sodium acetate (7.8 g) and N,N-dimethylformamide (300 mL) was heated at 80° C. for 18 hours. After cooling to room temperature the N,N-dimethylformamide was removed under reduced pressure and the resulting residue was partitioned between dichloromethane (300 mL) and water (300 mL). The organic phase was washed with water (300 mL), brine (300 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to afford acetic acid 1-naphthalen-1-yl-2-oxo-propyl ester and acetic acid 1-methyl-2-naphthalen-1-yl-2-oxo-ethyl ester (2:1 mixture) (9.0 g, 49%) as a brown oil, 1H NMR (CDCl3): 1.45 (3H, d, J=7.0 Hz), 2.05 (3H, s), 2.15 (3H, s), 2.2 (3H, s), 5.95 (1H, q, J=7.0 Hz), 6.65 (1H, s), 7.45-7.60 (7H, m), 7.85-7.90 (4H, m), 8.0 (1H, d, J=8.1 Hz), 8.1 (1H, d, J=8.3 Hz), 8.35 (1H, d, J=8.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].Br[C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]([O:43][CH3:44])=[O:42])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([C:41]([O:43][CH3:44])=[O:42])[CH:36]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(B4OC(C)(C)C(C)(C)O4)cccc32)c1C
Reactant: COC(=O)c1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)ccn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
To a degassed solution of 4-(2,3-dimethylphenoxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one (0.020 g, 0.045 mmol), methyl 4-bromopicolinate (0.019 g, 0.089 mmol) and potassium carbonate (0.018 g, 0.134 mmol) in dioxane (0.50 mL)/water (0.20 mL) was added tetrakis(triphenylphosphine)palladium (2.57 mg, 2.225 μmol). Upon completion of addition, the vial was purged with argon, sealed, and stirred at 90° C. for 16 h. After cooling to room temperature, the mixture was extracted with EtOAc. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (17.7 mg, 87% yield) as a clear colorless oil. LCMS, [M+H]+=459.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[F:13].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:56]([SH:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.CCN(C(C)C)C(C)C>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:56]([S:63][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[F:13])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: O=c1[nH]cc(F)c2cc(Br)ccc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]cc(F)c2cc(SCc3ccccc3)ccc12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A vial was charged with 6-bromo-4-fluoroisoquinolin-1(2H)-one (3.88 g, 16.03 mmol), Xantphos (0.464 g, 0.802 mmol), and Pd2(dba)3 (0.367 g, 0.401 mmol). The flask was flushed with Ar (g), then dioxane (32.1 ml), benzyl mercaptan (2.086 ml, 17.63 mmol), and n,n-diisopropylethylamine (5.60 ml, 32.1 mmol) were added in sequence. The reaction was heated to 110° C. and stirred for one hour. The reaction was diluted with water and stirred for 30 minutes. The solution was filtered and the solids were washed with water and dried under a nitrogen blanket overnight. The solids were triturated in ethyl acetate, stirred for two hours, and filtered. The solids were washed with ethyl acetate and vacuum dried to afford 6-(benzylthio)-4-fluoroisoquinolin-1(2H)-one as a yellow/green solid. (ESI) 286.2 (M+H)+.