Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:14][CH:11]([CH2:12][CH2:13]1)[C:10]1[CH:9]=[C:8]3[N:3]([CH2:4][CH2:5][NH:6][C:7]3=[O:15])[C:2]2=1.Br[C:17]1[N:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:18]=1[CH:19]=[O:20].C([O-])(=O)C.[K+].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>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>[Cl:25][C:21]1[CH:22]=[CH:23][N:24]=[C:17]([N:6]2[C:7](=[O:15])[C:8]3[N:3]([C:2]4[C@@H:1]5[CH2:14][C@H:11]([C:10]=4[CH:9]=3)[CH2:12][CH2:13]5)[CH2:4][CH2:5]2)[C:18]=1[CH:19]=[O:20]
Reactant: O=Cc1c(Cl)ccnc1Br
Reactant: O=C1NCCn2c1cc1c2C2CCC1C2
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2[C@H]2CC[C@@H]3C2)C1=O
Temperature: 80 °C
Yield: 57.2 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (30 mL), 167f (400 mg, 2.0 mmol), 2-bromo-4-chloronicotinaldehyde (1.30 g, 6.0 mmol), and potassium acetate (390 mg, 4.0 mmol). After bubbling nitrogen through the resulting mixture for 30 minutes, Xantphos (110 mg, 0.20 mmol) and tris(dibenzylideneacetone)dipalladium(0) (180 mg, 0.20 mmol) were added and the reaction mixture was heated at 80° C. for 10 h. It was then cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (50 mL) and water (30 mL). The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine (20 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified with silica-gel column chromatography eluting with 2:1 petroleum ether/ethyl acetate to afford 167g (391 mg, 57%) as yellow solid. MS-ESI: [M+H]+ 342.2
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[CH2:10][CH2:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>[Pd].C1(C)C=CC=CC=1>[CH2:30]([O:29][C:26]1[CH:27]=[CH:28][C:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[CH2:10][CH2:9][C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=3[CH:20]=2)=[CH:24][CH:25]=1)[CH3:31]
Reactant: CCOc1ccc(OB([O-])[O-])cc1
Reactant: CN1CCC(C(=O)OC(C)(C)C)=Cc2cc(Br)ccc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CCN3C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To t-butyl 7-bromo-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylate (4.0 g), 4-ethoxyphenyl borate (2.35 g), 1M potassium carbonate solution (25 ml) and ethanol (25 ml) was added toluene (100 ml), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetraklstriphenylphosphine palladium (0.55 g), and the mixture was refluxed under argon atmosphere overnight. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give t-butyl 7-(4-ethoxyphenyl)-1-methyl-2,3-dihydro-1-benzazepine-4-carboxylate (4.0 g) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[CH2:11]([O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([C:7]2[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:10])[CH:6]=2)[CH:22]=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Product: Nc1c(F)cc(-c2cccc(OCc3ccccc3)c2)cc1F
Yield: 32.8 %

Procedure:
The title compound (0.143 g) was prepared from 2,6-difluoro-4-bromo aniline (0.3 g, 1.4 mmol) and 3-(benzyloxy)phenylboronic acid (0.426 g, 1.8 mmol) as a colourless liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.49-7.44 (m, 2H), 7.39 (t, J 7.2, 2H), 7.35-7.26 (m, 4H), 7.24 (s, 1H), 7.18 (d, J 7.8, 1H), 6.91 (dd, J 1.9, 8.0, 1H), 5.33 (s, 2H), 5.16 (s, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)[C:5]([N:7]([CH3:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[OH-].[Na+].O>C1(C)C=CC=CC=1.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH3:14][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([CH:4]1[C:15]2[N:16]([CH:17]=[CH:18][CH:19]=2)[CH2:2][CH2:3]1)=[O:6]
Reactant: CN(C(=O)C(CCCl)c1ccc[nH]1)c1ccccc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C(=O)C1CCn2cccc21)c1ccccc1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A crude solution of 4-chloro-N-methyl-N-phenyl-2-(2-pyrrolyl)butanamide in toluene from the preceding step was added dropwise at 85° C. over 40 minutes to 1 hour to a stirred suspension of ALIQUAT® 336 (2.01 g, 2 mol % with respect to pyrrolylbutanamide) and granular sodium hydroxide (29.9 g, 750 mmol, 3 equivalents) in toluene (50 mL). After the addition was complete, the suspension was stirred under a nitrogen atmosphere at a temperature of 85° C. for 30 minutes, then cooled to 35° C. Cooled water (200 mL) was rapidly added to the mixture and stirred for 15 minutes at 25° C. The solution was rinsed with water and the layers were separated. The organic layer was washed with water (2×100 mL), then distilled under atmospheric pressure to recover the toluene and water. The resultant solution was cooled to 50° C. and allowed to crystallize after the addition of hexane (2×50 mL) and a seed crystal. The suspension was cooled to 5° C. and stirred for 15 minutes. The resultant precipitate was filtered, washed with 100 mL of hexane, and dried under vacuum at 25° C. to yield approximately 38 g (63%) N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide as a beige solid. This solid was recrystallized from toluene (2-2.5 mL/g) to yield large colorless crystals of N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide, mp 112° C. to 112.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([CH2:21][OH:22])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7].[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)[CH3:28].Cl.O1CCOCC1>C1COCC1.CN(C1C=CN=CC=1)C.CO>[ClH:1].[CH2:27]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:37])[O:22][CH2:21][C:8]2([C:6](=[O:7])[NH:5][CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[Cl:1])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:31][CH:30]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(C(=O)NCc2ccccc2Cl)CC1
Reactant: CCc1ccc(N=C=O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)OCC2(C(=O)NCc3ccccc3Cl)CCNCC2)cc1
Reaction time: 1 h
Yield: 151.9 %

Procedure:
To a solution of tert-butyl 4-(2-chlorobenzylcarbamoyl)-4-(hydroxymethyl)piperidine-1-carboxylate (1.8 g, 4.8 mmol) in THF were added DMAP (118 mg, 0.9 mmol, 0.1 equiv.) and 4-ethylphenylisocyanate (1.1 mL, 7.3 mmol, 1.5 equiv.) at r. t. The reaction mixture was stirred for 1 h. The reaction mixture was concentrated to dryness. To a solution of the above product in CH3OH was added 4M HCl in dioxane (3.6 mL, 3 equiv.), which was stirred overnight. The white solid was filtered and dried to give (4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-ethylphenylcarbamate hydrochloride (1.7 g, 81%). LRMS (M-Boc+H+) m/z 430.1.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[N:11]=[C:12]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>ClCCl>[Cl:9][C:10]1[N:11]=[C:12]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:23][CH:22]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(Nc2nc(Cl)cc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1ccc(Nc2nc(Cl)cc3ccccc23)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A mixture of ethyl 2-bromopropionate (1.33 g), 4-[N-(3-chloroisoquinolin-1-yl)amino]phenol (1.80 g), anhydrous potassium carbonate (1.01 g) and dimethyl formamide was heated, with stirring, at a temperature of 100° C. for a period of 1 hour. The mixture was cooled and poured into dichloromethane and the resulting mixture was repeatedly washed with water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(3-chloroisoquinolin-1-yl)amino]phenoxy}propionate (1.74 g) as a yellow oil. The assigned structure was confirmed by proton magnetic resonance spectroscopy and mass spectrometry. Proton magnetic resonance spectrum (CDCl3 ; δ ppm); 1.20 (3H, t); 1.50 (3H, d); 4.12 (2H, q); 4.60 (1H, q); 6.60-8.20 (10H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].S(Cl)(Cl)=O.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH:29][C:7](=[O:9])[C:6]2[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:23][CH2:22]1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: NCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(NCCN1CCOCC1)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 75 °C

Procedure:
A mixture of 3-nitro-5-(trifluoromethyl)benzoic acid (300 mg, 1.29 mmol, 1.0 equiv) and thionyl chloride (2.0 ml) was heated at 75° C. for 1 h. The solvent was removed in vacuo and the residue taken up in CH2Cl2 (5.0 ml). To the solution was added 2-morpholinoethanamine (185 mg, 1.42 mmol, 1.1 equiv) and triethylamine (0.54 ml, 3.86 mmol, 3.0 equiv). After the reaction was complete, the solution was diluted with CH2Cl2 (ca.10 ml) and washed with water and brine. After drying with Na2SO4 and concentration in vacuo, the resulting N-(2-morpholinoethyl)-3-nitro-5-(trifluoromethyl)benzamide was advanced without further purification. MS m/z: 348 (M+H+); Calculated for C14H16F3N3O4: 347.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[Cl:12][C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc(Cl)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
According to Scheme 3 Step 1, Method A: 2-Chloro-1-fluoro-4-nitrobenzene (1.12 mmol, 0.20 g) was added to a suspension of 3-chlorophenol (1.02 mmol, 0.10 mL), Cs2CO3 (1.25 mmol, 407 mg) in DMF/ACN (40:60, 3.6 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was used without further purification to obtain 2-chloro-1-(3-chlorophenoxy)-4-nitrobenzene (1.02 mmol, 288 mg, 100%) as an orange solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[CH3:26][C:27]1[CH:28]=[C:29]2[CH:35]=[N:34][NH:33][C:30]2=[N:31][CH:32]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:33]3[C:30]4=[N:31][CH:32]=[C:27]([CH3:26])[CH:28]=[C:29]4[CH:35]=[N:34]3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1cnc2[nH]ncc2c1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cnc2c(cnn2-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c1
Temperature: 125 °C

Procedure:
To a stirred solution of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (136 mg, 318 μmol), 5-methyl-1H-pyrazolo[3,4-b]pyridine (42.4 mg, 318 μmol) in dioxane (3.5 mL) was added sodium tert-butoxide (67.3 mg, 700 μmol) and bis(tri-tert-butylphosphine)palladium(0) (16.3 mg, 31.8 μmol). The mixture was degassed then heated in sealed tube at 125° C. for two days. The mixture was cooled, filtered through celite, the cake washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-30% ethyl acetate in hexanes) gave N-tert-butyl-2-(5-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide. 1H NMR (CDCl3) δ: 9.19 (s, 1H), 8.51 (d, J=1.8 Hz, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 8.22 (s, 1H), 7.96 (dd, J=2.0, 1.0 Hz, 1H), 5.72 (s, 2H), 3.52-3.59 (m, 2H), 2.54 (s, 3H), 1.60 (s, 9H), 0.88-0.97 (m, 3H), −0.04 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]#[C:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20]([CH3:27])[N:19]=1>>[CH3:27][C:20]1[N:19]=[C:18]([N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:16][CH2:15]2)[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: Cc1cccc(CC#CC2CCNCC2)n1
Product: Cc1cccc(C#CCC2CCN(c3nc(C)ccc3[N+](=O)[O-])CC2)n1

Procedure:
The title compound was prepared following the procedure described for the Compound of Example 31, using 2-chloro-3-nitro-6-picoline instead of 2-bromo-3-nitropyridine. The crude was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether/EtOAc 7:3, affording the title product as a yellow oil.
Reaction SMILES: Br[C:2]1[C:15](Br)=[CH:14][C:5]2[O:6][C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[O:9][C:4]=2[C:3]=1[N+:17]([O-])=O.C(=O)([O-])[O-].[K+].[K+].[H][H]>CO.[C].[Pd]>[NH2:17][C:3]1[C:4]2[O:9][C:8]([F:10])([F:11])[C:7]([F:13])([F:12])[O:6][C:5]=2[CH:14]=[CH:15][CH:2]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1c(Br)c(Br)cc2c1OC(F)(F)C(F)(F)O2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1cccc2c1OC(F)(F)C(F)(F)O2
Yield: 77.7 %

Procedure:
62 g (150 mmol) of 6,7-dibromo-5-nitro-2,2,3,3-tetrafluoro-benzo(1.4)dioxane, 41 g (300 mmol) of potassium carbonate and 5 g of palladium-carbon (10% strength) are stirred at 50° C. and a hydrogen pressure of 90 bar in 500 ml of methanol in an autoclave for 20 hours. The reaction mixture is filtered, the filtrate is mixed with 500 ml of water and extracted thoroughly with ether, and the extract is dried over sodium sulphate and concentrated. Vacuum distillation yields 26 g (78% of theory) of 5-amino-2,2,3,3-tetrafluoro-benzo(1.4)dioxane having a boiling point of 99° to 101° C./16 mm.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:17].[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:17])=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: Nn1nc(-c2cccs2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCCl
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2cccs2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.1 %

Procedure:
The product from Example 10B (60 mg, 0.25 mmol), (3,5-difluorophenyl)acetic acid (51 mg, 0.30 mmol), 1-hydroxybenzotriazole hydrate (HOBT, 76 mg, 0.49 mmol), EDC (95 mg, 0.49 mmol), and DMAP (3.0 mg, 0.025 mmol) were combined in pyridine (3 mL). The mixture was stirred at room temperature for 12 hours. The mixture was concentrated to dryness. The residue was dissolved in EtOAc and washed with NaHCO3, dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative HPLC [Phenomenex Luna C8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A] to afford 19 mg (19%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.79 (s, 1H), 8.42 (ddd, J=7.8, 1.5, 0.6 Hz, 1H), 8.18 (ddd, J=8.1, 1.3, 0.6 Hz, 1H), 8.05 (ddd, J=8.0, 7.3, 1.5 Hz, 1H), 7.99 (ddd, J=7.9, 7.2, 1.3 Hz, 1H), 7.81 (dd, J=5.1, 1.1 Hz, 1H), 7.66 (dd, J=3.6, 1.1 Hz, 1H), 7.29 (dd, J=5.1, 3.6 Hz, 1H), 7.06-7.22 (m, 3H), 3.78 (s, 2H); MS (APCI) M/Z 398 (M+H)+.
Reaction SMILES: COC1C=C2C(=CC=1)C(N)CCC2.FC1C=C(F)C=CC=1S(C)(=O)=O.C(N(C(C)C)CC)(C)C.F[C:36]1[CH:37]=[CH:38][C:39]([S:55]([CH3:58])(=[O:57])=[O:56])=[C:40]([NH:42][CH:43]2[C:52]3[C:47](=[CH:48][C:49]([O:53][CH3:54])=[CH:50][CH:51]=3)[CH2:46][CH2:45][CH2:44]2)[CH:41]=1.[NH:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1>CN(C)C=O.C(#N)C.O>[CH3:54][O:53][C:49]1[CH:48]=[C:47]2[C:52](=[CH:51][CH:50]=1)[CH:43]([NH:42][C:40]1[CH:41]=[C:36]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[CH:37]=[CH:38][C:39]=1[S:55]([CH3:58])(=[O:57])=[O:56])[CH2:44][CH2:45][CH2:46]2
Reactant: COc1ccc2c(c1)CCCC2Nc1cc(F)ccc1S(C)(=O)=O
Reactant: C1CNCCN1
Agent: COc1ccc2c(c1)CCCC2N
Agent: CS(=O)(=O)c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2c(c1)CCCC2Nc1cc(N2CCNCC2)ccc1S(C)(=O)=O
Temperature: 25 °C
Yield: 21 %

Procedure:
A solution of 1,2,3,4-tetrahydro-6-methoxynaphthalen-1-amine (1.0 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (1.0 mmol) and diisopropylethylamine (4.0 mmol) in N,N-dimethylformamide (2 mL) was stirred at 110° C. for 16 h. The reaction was cooled to room temperature, poured over water and extracted with diethyl ether. The solvent was concentrated in vacuo and the residue was used without further purification for the following reaction. N-(5-Fluoro-2-(methylsulfonyl)phenyl)-1,2,3,4-tetrahydro-6-methoxynaphthalen-1-amine (0.5 mmol), piperazine (8.0 mmol), N,N-diisopropylethylamine (4.0 mmol) were stirred at 80° C. in dry acetonitrile (3 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 10% methanol in dichloromethane to afford the title compound (21% yield). 1H NMR (400 MHz, CDCl3): δ 7.61 (d, 1H), 7.21 (d, 1H), 6.72 (dd, 1H), 6.64 (d, 1H), 6.28 (dd, 1H), 6.23 (d, 1H), 4.62 (m, 1H), 3.79 (s, 3H), 3.28 (t, 4H), 3.00 (t, 4H), 2.93 (s, 3H), 2.81 (m, 2H), 1.94 (m, 4H); MS (ESI) m/z: 415.55 (M++1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH2:11][C:12](O)=[O:13].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: COc1ccc(F)c(F)c1CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1CCO
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
To a solution of 2-(2,3-difluoro-6-methoxyphenyl)acetic acid (1 g, 4.95 mmol) in THF (20 mL) at 0° C. was added 1M LAH (9.89 mL, 9.89 mmol) in THF and the resulting mixture was heated at 60° C. for 3 h. Mixture was then cooled and quenched with dropwise addition of water (0.5 mL), 1N NaOH (0.5 mL), and then 1 mL H2O. After stirring for 15 min, the mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was dried under high vacuum to afford 2-(2,3-difluoro-6-methoxyphenyl)ethanol (810 mg, 4.30 mmol, 87% yield) as a clear viscous oil. Used as is in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.01 (q, J=9.2 Hz, 1H), 6.62-6.53 (m, 1H), 3.92-3.75 (m, 5H), 3.00 (td, J=6.6, 1.9 Hz, 2H), 1.65 (t, J=5.7 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:21]([NH2:24])[CH:22]=[CH2:23].CC(N(C)C)=O>C(OCC)(=O)C>[CH2:21]([NH:24][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])[CH:22]=[CH2:23]
Reactant: C=CCN
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C=CCNc1cc(C(F)(F)F)ccc1C(N)=O
Temperature: 140 °C
Yield: 98.4 %

Procedure:
A mixture of 2-fluoro-4-trifluoromethylbenzamide (5.60 g, 27.05 mmol.), K2CO3 (11.2 g, 81.16 mmol), allylamine (7.71 g, 135.26 mmol) and dimethylacetamide (50 mL) was heated at 140° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with a solution of aqueous saturated sodium bicarbonate (3×100 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to give the title compound (6.5 g, 98% yield) as a brown solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH2:13][OH:14].CC(C)([O-])C.[K+]>O1CCCC1>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:12]=1[CH2:13][O:14][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1c(F)cccc1F
Reactant: COc1ccnc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccnc(OCc2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
To a solution of 3.5 g (27.53 mmol) of 2-fluoro-4-methoxypyridine (CAS: 175965-83-0) and 3.97 g (27.53 mmol) of 2,6-difluorobenzyl alcohol in 97 ml of dry tetrahydrofuran, cooled beforehand to 0° C., were added dropwise 27.5 ml (27.53 mmol) of a 1M solution of potassium tert-butoxide in tetrahydrofuran. The resulting mixture was stirred at room temperature for 18 hours. The solvent was evaporated off and the residue was partitioned between water and ethyl acetate. The organic phase was removed, washed with water and aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure, which gave 5.77 g (66% yield, 79% purity) of the product.
Reaction SMILES: C=O.[CH2:3]([O:6][CH2:7][CH2:8][CH2:9]C=O)[CH2:4][CH3:5].[CH2:12]([O:15]CCCC=O)C=C>>[CH2:7]([O:6][CH:3]([CH2:4][CH3:5])[CH:12]=[O:15])[CH2:8][CH3:9]
Reactant: C=CCOCCCC=O
Reactant: CCCOCCCC=O
Agent: C=O
Product: CCCOC(C=O)CC

Procedure:
Conversion of formaldehyde was essentially complete. The crude product contained 4-propoxy-n-butyraldehyde and 4-allyloxy-n-butyraldehyde in a mol ratio of about 13:1, respectively.