Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=1[OH:18].C1N2CN3CN(C2)CN1C3.Cl.FC(F)(F)C(O)=[O:33]>>[CH:3]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=1[OH:18])=[O:33]
Reactant: CC(C)(C)c1cc(CN)c(O)c(S(C)(=O)=O)c1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CC(C)(C)c1cc(C=O)c(O)c(S(C)(=O)=O)c1

Procedure:
14.65 g (0.05 mol) of 2-aminomethyl-4-(1,1-dimethylethyl)-6-methylsulfonylphenol hydrochloride are dissolved in 100 ml of trifluoroacetic acid, 9 g (0.065 mol) of urotropine (hexamethylenetetraamine) are added, and the mixture is boiled under reflux for 2.5 h. Then 50 ml of 4 N hydrochloric acid are added, the mixture is again boiled under reflux for 10 minutes, and the reaction mixture is poured onto ice-water and filtered with suction. Pale yellow crystals of melting point: 134°-136° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2cccc(F)c2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (20 mg, 0.042 mmol), 3-fluoro benzyl bromide (5.5 μL, 0.045 mmol, 1.1 equiv), and potassium carbonate (11.7 mg, 0.09 mmol) in dimethylformamide (0.6 mL) was stirred at room temperature for 16 h. The solvents were removed in vacuo and the residue purified by column chromatography to afford 15.2 mg (63%). Mass spec.: 580.04 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1.[CH2:17](C1C=CC=C2C=1C=CC=C2O)[CH3:18]>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][CH3:18])[C:8]3=[CH:9][CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1
Reactant: O=c1cc(O)c2ccc3ccccc3c2o1
Reactant: CCc1cccc2c(O)cccc12
Product: CCc1cccc2c1ccc1c(O)cc(=O)oc12
Yield: 25 %

Procedure:
The procedure was identical to that used for the preparation of 10a: 25% yield (starting with 5-ethyl-1-naphthol 9c); 1H NMR (DMSO) δ 1.31 (3H, t, J=7.2 Hz, CH3CH2—), 3.12 (2H, q, J=7.2 Hz, CH3CH2—), 5.69 (1H, s, H-3), 7.61 (2H, m, H-8, 9), 7.85 (1H, d, J=8.7 Hz, H-5), 7.99 (1H, d, J=8.7 Hz, H-6), 8.25 (1H, d, J=7.8 Hz, H-10).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][CH:3]=1.C([Li])CCC.[Cl:20][C:21]1[CH:32]=[CH:31][C:24]([C:25](N(OC)C)=[O:26])=[CH:23][N:22]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:20][C:21]1[N:22]=[CH:23][C:24]([C:25]([C:2]2[CH:14]=[CH:13][C:5]([O:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][O:8]3)=[CH:4][CH:3]=2)=[O:26])=[CH:31][CH:32]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: Ic1ccc(OC2CCCCO2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Cl)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
2-(4-Iodophenoxy)tetrahydro-2H-pyran (18.2 g, 59.9 mmol) was dissolved in 100 mL dry tetrahydrofuran and cooled to −78° C. under nitrogen atmosphere, and then n-butyllithium was added dropwise to the solution. After addition, the solution was stirred at −78° C. for 0.5 h, 6-chloro-N-methoxy-N-methylnicotinamide (8.0 g, 39.9 mmol) in 50 mL tetrahydrofuran was added dropwise and keep the temperature under −78° C. for 2 h. Then 100 mL of aqueous saturated ammonium chloride was added. The mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography to give the desired product as a yellow solid (8.4 g, 66.3%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1.S(=O)(=O)(O)O>C1COCC1.ClCCl.[O-2].[O-2].[Mn+4]>[Cl:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(CCCl)cc1
Agent: [Mn+4]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
4-(2-Chloroethyl)benzoic acid (2.00 g, 10.83 mmol) was dissolved in THF (40 ml) under an argon atmosphere, and 1M borane-THF complex (16 ml, 16.00 mmol) was slowly added dropwise under ice-cooling. After stirring at room temperature for 2 hours, 1N sulfuric acid (36 ml) was added, and the mixture was stirred for 1 hour and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was dissolved in dichloromethane (50 ml). Manganese dioxide (10.00 g) was added, and the mixture was stirred overnight at room temperature. After filtration through celite, the filtrate was concentrated under reduced pressure to give the title compound (1.71 g, 91%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][CH:12]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][C:14](Cl)=[O:15]>O>[CH3:11][CH:12]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][C:14]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:15]
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(CC(=O)c1ccccc1)CC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 143.4 grams of aluminum chloride and 351.6 grams of benzene was stirred at room temperature while 100 grams of 3,5,5-trimethylhexanoyl chloride was added to the reaction keeping the reaction temperature at approximately 35° C. over a period of 1.5 hours. The mixture was then stirred for 3hours. The reaction mixture was poured into 500 grams of ice and stirred until all the ice dissolved. Water was added with cooling to give a homogenous mixture followed by extraction with 400 mL of ethyl acetate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate and stripped to dryness to give 3,5,5-Trimethylhexanoylbenzene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>O>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Yield: 85.2 %

Procedure:
The title compound was synthesized by triturating aniline (0.5 g, 5.36 mmol), powdered sodium bicarbonate (0.9 g, 1.07 mmol) and powdered p-toluene sulfonyl chloride (1.02 g, 5.36 mmol) for 5 min at rt. The reaction mixture was stirred with water, filtered, washed with water and dried to give 16 (1.13 g, 84.9%). Product was purified by FCC by using eluent as in 15 to give 16 as white powder (0.9 g), mp-95-97° C. (lit32A 96° C.); IR(CHCl3) 3255, 1599, 1342, 1160, cm−1; 1H NMR (500 MHz, DMSOD6) δ 2.37 (s, 3H, CH3), 6.53 (br, 1H, NH), and 7.04-7.65 (m, 9H, aromatic). HRMS calcd 270.05592 (C13H13NO2S.Na+), found 270.05589.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23][O:24][CH2:25]Cl.O>CN(C)C=O>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2([CH3:12])[C:6](=[O:20])[C:5]3[C:10](=[CH:11][C:2]([O:1][CH2:23][O:24][CH3:25])=[CH:3][CH:4]=3)[O:9][CH2:8]2)=[CH:14][CH:15]=1
Reactant: COCCl
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc2c(c1)OCC(C)(c1ccc(O)cc1)C2=O
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of 7-hydroxyl-3-(4-hydroxyphenyl)-3-methylchroman-4-one (4.65 g, 17.20 mmol) in dry dimethylformamide (120 ml) was added sodium hydride (454 mg, 18.92 mmol) at room tempetarure and stirred for 30 minutes. To the reaction mixture was then added methoxymethyl chloride (1.523 g, 18.92 mmol) at the same temperature and stirred for 2 h. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=8:2 to 7:3) to give 3.55 g (yield: 66%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(Cl)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-chloro-Phenylboronic acid to give [1-(4-chloro-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19].[CH3:21][O-:22].[Na+].CO>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:22][CH3:21])=[N:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19]
Reactant: COC(=O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OC)nc1Nc1ccc(Br)cc1F
Temperature: 62.5 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid methyl ester (2.00 g, 5.56 mmol) and sodium methoxide (0.791 g, 13.9 mmol) was added MeOH (50 mL) to give a slurry that was stirred at 60-65° C. for 16 hours under N2. Additional sodium methoxide (0.791 g, 13.9 mmol) was added and the reaction mixture was allowed to stir another 3 days at 60-65° C. The reaction mixture was cooled to room temperature and glacial acetic acid was added dropwise until the pH was 7. The resulting suspension was filtered and washed with H2O to yield a pink solid that was collected and dried under vacuum to yield 1.74 g (88%) pure desired product.
Reaction SMILES: [CH:1]1([CH:7]([CH2:19][C:20]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=O)[CH2:8][C:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[OH:18])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.C[N:32](C)C=O>>[CH:1]1([C:7]2[CH:19]=[C:20]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)[N:32]=[C:9]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[OH:18])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: O=C(CC(CC(=O)c1cc(F)ccc1O)C1CCCCC1)c1ccco1
Solvent: CC(=O)O
Product: Oc1ccc(F)cc1-c1cc(C2CCCCC2)cc(-c2ccco2)n1
Temperature: 100 °C

Procedure:
A mixture of 3-cyclohexyl-1-(2-hydroxy-5-fluorophenyl)-5-(furan-2-yl)-1,5-pentanedione on Wang resin (3.2 g, 1.9 mmol), NH4OAc (1.8 g), and AcOH (1.8 mL) in dimethylformamide (45 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-(4-cyclohexyl-6-furan-2-yl-pyridin-2-yl)-4-fluoro-phenol; 1H NMR (DMSO-d6) d 1.35 (m, 4H), 1.61 (m, 2H), 1.76 (m, 4H), 2.68 (m, 1H), 6.74 (dd, J=3.4, 1.8 Hz, 1H), 6.94 (dd, J=9.0, 5.1 Hz, 1H), 7.18 (m, 1H), 7.26 (d, J=3.4 Hz, 1H), 7.72 (s, 1H), 7.94 (s, 1H), 8.04 (m, 2H), 14.22 (s, 1H); IR (KBr) 1617 cm−1; MS [M+H]+ m/z=338. Anal. calcd for C21H20FNO2.0.2MCF3CO2H: C, 71.29; H, 5.61; N, 3.89; Found: C, 71.24; H, 5.74; N, 3.76.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][CH:12]=[C:11]([CH2:14]O)[CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:11]1[CH:10]=[C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[S:13][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cc(CO)cs2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2cc(CCl)cs2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-3-yl]-methanol (280 mg, 1.40 mmol) in dry CH2Cl2 (2.58 mL) was treated at 0° C. with Et3N (0.25 mL, 1.82 mmol) followed by DMAP (17 mg, 0.14 mmol) and Ms-Cl (0.13 mL, 1.68 mmol). The reaction mixture was stirred at rt for 2 h before being quenched with water (5 mL), extracted with CH2Cl2 (20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 2-(4-chloromethyl-thiophen-2-yl)-2-methyl-[1,3]dioxolane as a yellow oil. A solution of the crude material in acetone (3.5 mL) was treated, under inert atmosphere (N2) with K2CO3 (588 mg, 4.25 mmol) followed by 4-nitro-1H-pyrazole (181 mg, 1.42 mmol) and TBA bromide (91 mg, 0.28 mmol). The resulting mixture was stirred overnight at rt and then the solvent was removed under reduced pressure. Water (10 mL) and EA (20 mL) were added. The aq. layer was extracted with EA (80 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow solid. TLC: rf (50:50 hept-EA)=0.45. LC-MS-conditions 02: tR=0.96 min; [M+H]+=296.04.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:33])[C:16]([C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)([CH3:18])[CH3:17].CI.[C:36](OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]([CH3:36])[C:15](=[O:33])[C:16]([C:19]1[CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=1)([CH3:18])[CH3:17]
Reactant: CC(C)(C(=O)Nc1ccccc1-c1ccccc1N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1-c1ccccc1N
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 151 mg (0.32 mmol) N-(2′-amino-biphenyl-2-yl)-2-(3,5bis-trifluoromethyl-phenyl)-isobutyramide in 1 ml N,N-dimethylformamide under argon 130 mg (0.65 mmol) potassium hexamethyldisilazide were added at 0°. Stirring was continued for 1 h at room temperature and the reaction mixture was cooled to 0° again. At this temperature, 115 mg (0.81 mmol) methyl iodide were added. After stirring for 3 hrs at room temperature, ethyl acetate was added and the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/CH2Cl21:1) to give 56 mg (36%) N-(2′-amino-biphenyl-2-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide as colorless oil, MS(ISP): 481.1(M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10](=[O:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13](O)[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>CN1CCOCC1.O>[CH2:13]([O:12][C:10]1[NH:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1)[CH3:14]
Reactant: CCO
Reactant: O=C1CC(c2ccccc2)=NN1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN1CCOCC1
Product: CCOc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 3-phenyl-1H-pyrazol-5(4H)-one (1.0 g, 6.24 mmol), ethanol (0.288 g, 6.24 mmol) and triphenylphosphine (1.638 g, 6.24 mmol) in N-methylmorpholine (7 mL) was added diethylazo dicarboxylate (0.988 mL, 6.24 mmol) dropwise at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was poured into H2O and extracted with ethyl acetate. The extract was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.89 g). LCMS m/z=189.19 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (t, J=4.2 Hz, 3H), 4.32 (q, J=4.2 Hz, 2H), 6.45 (s, 1H), 7.41-7.94 (m, 5H), 11.3 (s, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]1)(C(C)(C)C)(C)C.Br[C:18]1[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=[C:22]([Br:24])[N:23]=1>CC(O)C>[Br:24][C:22]1[N:23]=[C:18]([NH:16][C:14]2[CH:13]=[N:12][N:11]([CH2:10][CH2:9][OH:8])[CH:15]=2)[C:19](=[O:26])[N:20]([CH3:25])[CH:21]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(N)cn1
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2cnn(CCO)c2)c1=O
Temperature: 90 °C
Yield: 115.1 %

Procedure:
A flask equipped with a magnetic stirrer was charged with 1-(2-(tert-butyldimethylsilyloxy)ethyl)-1H-pyrazol-4-amine 116b (1.7 g, 7.1 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.25 g, 4.7 mmol), and IPA (25 mL). The system was evacuated and then refilled with N2. The reaction mixture was heated at 90° C. for 6 h. Then, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate to afford 140a (1.7 g, 78%). LCMS: [M+H]+ 314.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:27])[C:11]([CH3:26])=[C:12]([CH:25]=2)[C:13]([NH:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[CH3:24])=O)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:27])[C:11]([CH3:26])=[C:12]([CH2:13][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=3[CH3:22])[CH:25]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2c(C)ccc(O)c2C)c1C
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(O)c2C)c1C
Temperature: 60 °C
Yield: 31.4 %

Procedure:
To a solution of 5-(3-fluorophenyl)-N-(3-hydroxy-2,6-dimethyl-phenyl)-2,3-dimethyl-benzamide (300 mg, 0.82 mmol, 1.0 eq) in THF (10 mL) under N2 was added a solution of BH3 (1M in THF, 4.1 mL, 4.1 mmol, 5.0 eq) dropwise at 0° C. The reaction mixture was heated at 60° C. overnight. After cooling, the reaction was quenched by addition of water and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 30:1 to 20:1) to give the title compound as a colorless oil (90 mg, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14]Br)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C-:20]#[N:21].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][C:20]#[N:21])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: [C-]#N
Reactant: COc1cc(OC)cc(Sc2ccccc2CBr)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc(OC)cc(Sc2ccccc2CC#N)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 61.3 %

Procedure:
2-(3,5-Dimethoxyphenylthio)benzyl bromide (9.53 g) was dissolved in dimethyl sulfoxide (90 ml), sodium cyanide (2.77 g) was added thereto and the mixture was stirred at 80° C. for 1.5 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by a silica gel column chromatography (developing solvent; hexane:ethyl acetate=3:1) to give 2-(3,5-dimethoxyphenylthio)-benzyl cyanide (4.91 g, yield of 61%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12](=[O:18])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:6]([CH:11]=1)[N:7]([CH3:10])[CH:8]=O.C(N(CC)CC)C>CCCCCC>[F:1][C:2]1[CH:11]=[C:6]2[C:5]([C:12](=[O:18])[C:13]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][N:7]2[CH3:10])=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: Cn1cc(S(C)(=O)=O)c(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide (0.20 g), prepared in a similar manner to that described in Example 11, and triethylamine (20 ml) was stirred at ambient temperature for 2.5 hours. Hexane (30 ml) was added to the mixture. The solid product collected by filtration of the mixture was washed with hexane (2×5 ml) and dried at 50° in vacuo to give 7-fluoro-1-methyl-3-methylsulphonyl-4-quinolone, m.p. 233°-234.5° (0.16 g).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]([N:44]([CH3:52])[C:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=2)=[O:43])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]1[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:44]([C:45]2[CH:46]=[CH:47][C:48]([NH:51]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:8]4[C:7]\3=[CH:12][CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:49][CH:50]=2)[CH3:52])=[O:43])[CH2:39][CH2:40]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((4-benzyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C37H37N5O4
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[NH2:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[N:35]=[CH:34]2>C(O)(C)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[N:35]=[CH:34]2)(=[O:3])[CH3:2]
Reactant: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Cl)c2cc1OC(C)=O
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Solvent: CC(C)O
Product: COc1cc2nc(-c3cccc(-c4ccccc4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Temperature: 95 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A mixture of 4-chloro-2-[(3-phenyl)phenyl]-7-methoxyquinazolin-6-yl acetate (4.00 g, 9.88 mmole), tert-butyl 5-amino-1H-indazole-1-carboxylate (2.42 g, 10.37 mmole) in iso-propanol (130 mL) was stirred at 95° C. for 2 h. The reaction was cooled to RT and the crude product was filtered and then washed with ether, iso-propanol, and hexane and dried under vacuum to give tert-butyl 5-(6-acetoxy-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (4.33 g, 7.20 mmole, 77% over two steps). MS 602 (M+1). HPLC retention time 6.47 mins.