Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[CH:4]=1.[C:11](=[O:13])=[O:12]>C1COCC1>[CH2:9]([C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:11]([OH:13])=[O:12])[CH3:10]
Reactant: O=C=O
Reactant: CCc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1cccc(C(=O)O)c1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Magnesium turnings (829 mg, 34.1 mmol) were placed in an oven-dried 50 mL RBF and heated three times under high vacuum, then filled with nitrogen. The flask was sealed with a rubber septum and a pressure release system. Anhydrous THF (6.0 mL) and 1-bromo-3-ethylbenzene (297 mg, 1.6 mmol) were added. The reaction mixture was heated to 50-60° C. for 5 min. 1-Bromo-3-ethylbenzene (5.812 g, 31.4 mmol) was dissolved in anhydrous THF (12.0 mL) and added drop-wise via syringe maintaining 50-60° C. The reaction mixture was stirred for 2 h cooling to room temperature. The septum was replaced by a balloon with carbon dioxide and stirred for 16 h at room temperature. The reaction was quenched with a few grams of dry ice, acidified with hydrochloric acid (2M, 50 mL) and extracted with diethylether (2×100 mL). The combined organic layers were washed with a solution of sodium hydroxide (1M, 100 mL). The organic layer was disposed. The aqueous layer was acidified with hydrochloric acid (2M, 100 mL) and extracted with diethylether (2×100 mL). The combined organic of this extraction were dried (MgSO4), filtered and concentrated in vacuo. The title compound was obtained as pale pink crystalline solid (2.698 g, 54%).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([OH:22])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:34](Cl)(=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([O:22][C:34](=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C(C)(C)C)c(O)c1
Reactant: CC(C)CC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: CC(C)CC(=O)Oc1cc(C(=O)CNC(C)(C)C)ccc1OC(=O)C(C)(C)C

Procedure:
Following a procedure similar to that described in Example 2A above, when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with isovaleryl chloride there is obtained 3-(isovaleryloxy)-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone, which reacts with hydrochloric acid to yield the hydrochloride salt as a white crystalline solid, m.p. 216°-220° C. (uncorr.).
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([CH3:11])=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C([Li])CCC.[CH3:26][CH:27]([CH3:37])[C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[O:29].O>O1CCCC1>[OH:29][C:28]([C:2]1[C:3]([CH3:20])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([CH3:11])=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9])([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)[CH:27]([CH3:37])[CH3:26]
Reactant: Cc1ccc(C(=O)C(C)C)cc1
Reactant: COc1c(C)c(C)c(NC(=O)OC(C)(C)C)c(C)c1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)c(C)c(NC(=O)OC(C)(C)C)c(C)c1C(O)(c1ccc(C)cc1)C(C)C
Reaction time: 0.33 h
Yield: 75.4 %

Procedure:
To a solution of tert-butyl 3-bromo-4-methoxy-2,5,6-trimethylphenylcarbamate (27.8 g, 80.8 mmol) in tetrahydrofuran (150 ml) was added at -78° C. n-butyllithium (1.6 M, 110 ml, 176 mmol) and the reaction mixture was stirred at the same temperature for 20 minutes. To the reaction solution was added 2-methyl-1-(4-methylphenyl)propan-1-one (13.1 g, 80.7 mmol) and stirred at room temperature for 1 hour. Water (150 ml) was added to the reaction mixture and the product was extracted three times with ethyl acetate. The combined organic layers were washed with water, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 26.0 g of tert-butyl 3-[1-hydroxy-2-methyl-1-(4-methylphenyl)propyl]-4-methoxy-2,5,6-trimethylphenylcarbamate as a crude product. A mixture of this compound and 47% hydrobromic acid (100 ml) was refluxed with heating for 4 hours under argon atmosphere. The reaction mixture was cooled down to room temperature and neutralized with an 8 N aqueous solution of sodium hydroxide. The product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous, saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to obtain 14.8 g (62% yield) of the title compound. Melting point: 114-115° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[H-].[Na+].[O:11]=[C:12]1[C:24]2[C:19](=[N:20][C:21](C#N)=[C:22]([C:25]#[N:26])[N:23]=2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2.CO>CN(C=O)C>[C:6]([C:5]([C:21]1[N:20]=[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12](=[O:11])[C:24]2=[N:23][C:22]=1[C:25]#[N:26])=[C:4]([O:3][CH2:1][CH3:2])[OH:8])#[N:7]
Reactant: N#Cc1nc2c(nc1C#N)-c1ccccc1C2=O
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCOC(O)=C(C#N)c1nc2c(nc1C#N)C(=O)c1ccccc1-2
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Ethylcyanoacetate (110 mg, 0.970 mmol) was dissolved, under inert atmosphere, in dry DMF (1 ml) and NaH (39 mg, 0.970 mmol) was added in one portion. After 30 min, a solution of 1 (150 mg, 0.646 mmol) in dry DMF (2 ml) was added dropwise. After 15 min MeOH was added and the solution stirred for 10 min. The solvents were evaporated and the crude purified by flash chromatography (EtOAc:MeOH 9:1) affording 22 as a dark red solid (200 mg, 97%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36]1[N:37]=[C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[S:39][CH:40]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[N:37]=[C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[S:39][CH:40]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2csc(-c3ccccc3)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 4-(chloromethyl)-2-phenyl-1,3-thiazole (0.71 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.20 g, 66%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[OH:10].Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[F:8][C:7]1[C:2]2[NH:1][C:13](=[O:14])[CH2:12][O:10][C:3]=2[C:4]([F:9])=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(F)ccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(F)ccc(F)c2N1
Yield: 93.6 %

Procedure:
2-Amino-3,6-difluorophenol (0.44 g, 3.0 mmol), 2-chloroacetyl chloride (0.38 g, 3.3 mmol) and K2CO3 (0.88 g, 6.4 mmol) were mixed according to GP1. Purified by extraction gave the title compound (0.52 g, 93%). Rf=0.57 (heptanes/EtOAc 1:1); 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.78-6.69 (m, 2H), 4.72 (s, 2H); 13C NMR (CDCl3) δ 163.7, 148.0 (dd, J=242.4 Hz, J=2.1 Hz), 145.9 (d, J=237.9 Hz), 132.9 (dd, J=16.7 Hz, J=4.4 Hz), 117.2 (dd, J=16.9 Hz, J=3.8 Hz), 110.2 (dd, J=20.5 Hz, J=8.6 Hz), 108.6 (dd, J=20.0 Hz, J=7.7 Hz), 67.4.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:20]=2)[NH:15][CH:14]=1)[CH3:12].Br[C:32]1[C:33]([C:38]([F:41])([F:40])[F:39])=[N:34][N:35]([CH3:37])[CH:36]=1.C([O-])([O-])=O.[K+].[K+].O>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.O1CCOCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[C@H:11]([C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:32]3[C:33]([C:38]([F:41])([F:40])[F:39])=[N:34][N:35]([CH3:37])[CH:36]=3)[CH:20]=2)[NH:15][CH:14]=1)[CH3:12]
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Cn1cc(Br)c(C(F)(F)F)n1
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: O
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cn(C)nc3C(F)(F)F)cc12

Procedure:
A mixture of 3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (9.00 mg, 0.0209 mmol), 4-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazole (9.57 mg, 0.0418 mmol), Pd(PPh3)4 (1.21 mg, 0.00104 mmol), K2CO3 (0.00866 g, 0.0627 mmol) and 4:1 dioxane:H2O (0.8 mL, 8 mmol) was heated in a microwave reactor at 95° C. for 20 min. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.78 (d, J=7.1 Hz, 3H), 3.62 (br. s., 3H), 3.96 (s, 3H), 5.08 (q, J=6.9 Hz, 1H), 6.86 (dd, J=9.1, 4.3 Hz, 1H), 7.01-7.09 (m, 1H), 7.35 (d, J=1.3 Hz, 1H), 7.52 (s, 1H), 7.78 (s, 1H), 8.10 (d, J=2.0 Hz, 1H). MS (ES+): m/z=453.11/455.11 (100/50) [MH+]. HPLC: tR=1.36 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.[Cl:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=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>[Cl:21][C:22]1[CH:27]=[C:26]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:3]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3cccnc32)cc1
Reactant: OB(O)c1ccnc(Cl)c1
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: CCOC(C)=O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccnc(Cl)c3)c3cccnc32)cc1
Yield: 68 %

Procedure:
A mixture of azaindole 3 (80 mg, 0.23 mmol), 2-chloropyridine-4-boronic acid (41 mg, 0.27 mmol), Pd(Ph3P)4 (20 mg, 0.11 mmol) and 2 M sodium carbonate (0.34 mL, 0.68 mmol) in 2 mL of DME was microwaved on high at 160° C. for under nitrogen for 15 minutes. Diluted with ethyl acetate and the organic phase washed with water and brine then dried (Na2SO4) and concentrated in vacuo. The residue was subjected to flash chromatography (40% EtOAc/60% hexanes) to give 60 mg (68%) of the desired product 14. 1H NMR CDCl3 8.6 (d, 2H), 8.1 (m, 4H), 7.25 (m, 5H), 2.5 (s, 3H). The 2-chloropyridine could be displaced, for example, with benzylamine in a microwave reaction at 250° C. for 30 min followed by deprotection to give compound 15.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14](Br)=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+]>CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:9][NH:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(N)cc1
Reactant: CNc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(Nc2ccc(C)cc2)c2c1C(=O)c1ccccc1C2=O
Reaction time: 6 h
Yield: 82 %

Procedure:
In a reactor were charged p-toluidine (80 parts) , 1-methylamino-4-bromoanthraquinone (15.8 parts), sodium acetate (7.5 parts) and copper acetate (0.5 part) and the mixture was kept at 115° to 120° C. for 6 hours under a nitrogen atmosphere. Thereafter, the reaction mixture was diluted with methanol (100 parts) and cooled. The precipitate produced was filtrated, washed with methanol (500 parts) and then water (200 parts), and dried at 80° to 90° C. to obtain 1-methylamino-4- (4 '-methylanilino) -anthraquinone (yield 82% ).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3](O)=[O:4].[NH2:28][CH2:29][CH2:30][OH:31].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[C:12]1=[N:13][O:14][C:15]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)=[C:11]1[CH2:10][CH2:9]2)[C:3]([NH:28][CH2:29][CH2:30][OH:31])=[O:4]
Reactant: NCCO
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)O)ccc2-3)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCc1ccc(-c2onc3c2CCc2cc(C(O)C(=O)NCCO)ccc2-3)cc1
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 2-hydroxy-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetic acid (Example 127, 18 mg, 0.050 mmol) in DMF (1 mL) was added 2-aminoethanol (5.45 mg, 0.089 mmol), 4-methylmorpholine (0.033 mL, 0.29 mmol) and BOP (39.4 mg, 0.089 mmol). The reaction mixture was stirred overnight and was then purified by preparative HPLC (Phenomenex Luna 5 u C18 21.2×100 mm, Solvent A: 90% water with 10% MeOH and 0.1% TFA, Solvent B: 90% MeOH with 10% water and 0.1% TFA, Gradient: 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention time=11.9 min) to give 2-hydroxy-N-(2-hydroxyethyl)-2-(3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)acetamide (14.5 mg, 0.033 mmol, 67.4% yield): product HPLC ret. time=8.79 min. (condition G); LC/MS M+1=407.1; 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (1H, d, J=7.92 Hz), 7.72 (2H, d, J=8.36 Hz), 7.44-7.55 (2H, m), 7.37 (2H, d, J=8.36 Hz), 5.07 (1H, s), 3.58-3.69 (2H, m), 3.34-3.43 (2H, m), 3.05 (4H, s), 2.59-2.74 (2H, m), 1.61-1.80 (2H, m), 0.97 (3H, t, J=7.37 Hz).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])(=O)=O.[F:16][C:17]1[N:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[CH2:24]O)=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Si:7]([O:6][CH2:27][C:23]([C:20]1[CH:19]=[CH:18][C:17]([F:16])=[N:22][CH:21]=1)([CH3:24])[CH3:26])([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(CO)c1ccc(F)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
Tert-butyldimethylsilyl trifluoromethanesulfonate (2.180 mL, 9.49 mmol) was added to a solution of 2-(6-fluoropyridin-3-yl)-2-methylpropan-1-ol (1.46 g, 8.63 mmol) and N,N-diisopropylethylamine (3.31 mL, 18.98 mmol) in CH2Cl2 (43.1 mL) at 0° C., and the resulting mixture stirred at 0° C. for 30 min. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0 to 15% EtOAc/hexanes) to provide 5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluoropyridine (2.22 g, 7.83 mmol, 91% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=2.0 Hz, 1H), 7.79 (td, J=8.2, 2.7 Hz, 1H), 6.85 (dd, J=8.6, 2.9 Hz, 1H), 3.51 (s, 2H), 1.31 (s, 6H), 0.83 (s, 9H), −0.06 (s, 6H). 19F NMR (377 MHz, CDCl3) δ −73.08 (d, J=6.0Hz, 1F). m/z (ESI, +ve) 284.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:13]=3)=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH:30]([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:31][CH:30]([N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[N:13]=2)[CH:10]=[N:9]1)[CH3:32]
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1c[nH]nc1-c1ccccc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncc(-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)c1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 3-(3-phenyl-1H-pyrazol-4-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (325 mg, 0.85 mmol), 2-iodopropane (0.130 mL, 1.3 mmol), and K2CO3 (235 mg, 1.7 mmol) in DMF (3 mL) was stirred overnight at 50° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt followed by separation by preparative HPLC to give the title compounds.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10]1([NH2:13])[CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:10]1([NH:13][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:12][CH2:11]1
Reactant: NC1CC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)NC1CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 46.7 %

Procedure:
To a 250 mL of sealed tube was added ethyl 2-bromo-2-methylpropanoate (19.4 g, 0.1 mol, 1.0 equiv), cyclopropanamine (11.4 g, 0.2 mol, 2.0 equiv), K2CO3 (27.6 g, 0.2 mol, 2.0 equiv), KI (1.66 g, 0.01 mol, 0.1 equiv) and 200 mL of MeCN. The mixture was stirred at 100° C. for 12 h then cooled to room temperature and the solids were filtered. The filtrate was concentrated and purified on silica gel column eluting with pet. ether/ethyl acetate=4/1 to give 8.0 g (46%) of ethyl 2-(cyclopropylamino)-2-methylpropanoate.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])=[O:11])=[C:8]([OH:23])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:24]I.Cl>[OH-].[Na+].C(O)C.O>[CH2:1]([O:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])=[O:11])=[C:8]([O:23][CH3:24])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CI
Reactant: CCCCOc1ccc(C(=O)c2cccc(C(=O)O)c2)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCOc1ccc(C(=O)c2cccc(C(=O)O)c2)c(OC)c1
Temperature: 60 °C

Procedure:
A solution of 3-(4-butoxy-2-hydroxybenzoyl)benzoic acid (0.85 g), prepared as described in Example 26, is heated under reflux in a mixture of 2N sodium hydroxide (2.8 ml) and ethanol (10 ml) for 30 minutes. The reaction mixture is then cooled to 60° C. and methyl iodide (10 ml) is added. The resulting mixture was heated at 60° for 72 hours, cooled, acidified with concentrated hydrochloric acid and diluted with water (100 ml). The product is extracted with ether (3×25 ml). The extracts are dried over magnesium sulfate, filtered and evaporated to dryness. 2N Sodium hydroxide (2 ml) is added to the residue and the mixture heated under reflux for 6 hours. The reaction mixture is acidified with concentrated hydrochloric acid, diluted with water (100 ml), and extracted with ether (3×25 ml). The residue is chromatographed on silica (hexane:ether:acetic acid at 90:10:1) to yield 3-(4-butoxy-2-methoxybenzoyl)benzoic acid (0.46 g), m.p. 144°-145° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:3]=1.[Br:26][C:27]1[C:28](B(O)O)=[N:29][CH:30]=[CH:31][CH:32]=1.BrC1C=NC=C(Br)C=1>>[Br:26][C:27]1[CH:32]=[C:31]([C:6]2[CH:5]=[C:4]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=3)[CH:3]=[C:2]([CH3:1])[N:7]=2)[CH:30]=[N:29][CH:28]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(OS(=O)(=O)C(F)(F)F)n1
Reactant: OB(O)c1ncccc1Br
Agent: Brc1cncc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(Br)c2)n1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl ester (example A.32) (2.0 g, 5.2 mmol) and commercially available 3-bromo-pyridine-boronic acid [CAS-No. 452972-09-07] (alternatively prepared from commercially available 3,5-dibromopyridine according to Tetrahedron 2002, 58(17), 3323 or Synthesis 2003, (7), 1035) (1.152 g, 5.7 mmol) according to the general procedure IVb. Obtained as a white solid (1.70 g, 83%). MS (ISP) 393.0 [(M+H)+] and 395.0 [(M+2+H)+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]#[C:12][C:13]2([OH:19])[CH2:18][CH2:17][S:16][CH2:15][CH2:14]2)[CH:8]=[CH:9][CH:10]=1>CCOC(C)=O.CO>[NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][CH2:12][C:13]1([OH:19])[CH2:14][CH2:15][S:16][CH2:17][CH2:18]1
Reactant: NCCOc1cccc(C#CC2(O)CCSCC2)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: NCCOc1cccc(CCC2(O)CCSCC2)c1

Procedure:
Hydrogenation of 4-((3-(2-aminoethoxy)phenyl)ethynyl)tetrahydro-2H-thiopyran-4-ol was conducted following the method used to prepare Example 2 except that EtOAc-MeOH (90%) was used as the reaction solvent. Example 11 was isolated as a colorless oil. Yield (0.179 g, 98%): 1H NMR (400 MHz, DMSO-d6) δ 7.13 (t, J=8 Hz, 1H), 6.34-6.88 (m, 3H), 4.26 (br s, 1H), 3.86 (t, J=6.0 Hz, 2H), 2.57-2.88 (m, 4H), 2.53-2.56 (m, 2H), 2.32-2.37 (m, 2H), 1.73-1.78 (m, 2H), 1.42-1.62 (m, 6H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:28]([C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])=[CH:27][C:24]=1[CH:25]=O.C(OC(N1CCC[C@H](NCC2C=C(C(F)(F)C)C=CC=2OC(F)(F)F)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:25][C:24]2[CH:27]=[C:28]([C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:30][C:23]=2[O:22][CH3:21])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1c1ccccc1
Reactant: COc1ccc(C(F)(F)C(F)(F)F)cc1C=O
Agent: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This Compound was prepared from Compound 12 and Compound 40 in the same manner of Compound 26. This was employed in the next step without further purification.