Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C@H:16]([C:20]([OH:22])=O)[CH:17]([CH3:19])[CH3:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4].[OH:23][N:24]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([CH:17]([CH3:19])[CH3:18])[C:20]([NH:24][OH:23])=[O:22])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4]
Reactant: On1nnc2ccccc21
Reactant: C=C=CCOc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=C=CCOc1ccc(S(=O)(=O)NC(C(=O)NO)C(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
To a solution of product from Example 12 (210 mg, 0.65 mmol) in dimethylformamide (6 ml) was added 1-hydroxybenzotriazol (105 mg, 0.78 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (173 mg, 0.90 mmol), and N-methylmorpholine (0.106 mmol, 0.97 mmol) and the resulting mixture was stirred for 1 hour at room temperature. A 50% aqueous solution of hydroxylamine (0.119 ml, 1.94 mmol) was added and the mixture was stirred for 15 hours at room temperature. The reaction mixture was concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, water, saturated sodium bicarbonate, saturated sodium chloride and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave 100 mg (45%) of the product.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1OC)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:7].C1(OC)C(=CC=CC=1)OC.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)C1C=CC=CC=1>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[C:6]([C:5]1[CH:18]=[CH:19][CH:20]=[CH:3][CH:4]=1)=[O:7]
Reactant: COc1ccc(C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=C(Cl)c1ccccc1
Solvent: COc1ccccc1OC
Product: COc1ccc(C(=O)c2ccccc2)cc1OC

Procedure:
3,4-Dimethoxybenzophenone was prepared analogously to 3,4,3′,4′-tetramethoxybenzophenone using veratrole (2 mL, 15 mmol), aluminum chloride (2.2 g, 16.5 mmol) and benzoyl chloride (1.8 mL, 15.5 mmol). The crude mixture was purified by flash column chromatography (silica gel, 3% ethyl acetate/methylene chloride) to yield 3.44 g (93%) of the product as a white solid: mp 99-100° C.; 1H NMR (CDCl3) δ 7.82-7.30 (m, 7 H), 6.95-6.85 (m, 1 H), 3.96 (s, 3 H), 3.94 (s, 3 H); 13C NMR (CDCl3) δ 195.5, 153.0, 149.0, 138.2, 131.8, 130.2, 129.6, 128.1, 125.4, 112.1, 109.7, 56.0, 56.0; Anal. Calcd for C15H14O3. Theoretical: C, 74.36; H, 5.82. Found: C, 74.21; H, 6.01.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18]C.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18]
Reactant: COc1ccc2c(-c3ccccc3F)csc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc2c(-c3ccccc3F)csc2c1Cl
Temperature: 190 °C
Yield: 98.4 %

Procedure:
A mixture of 9.5 g of 7-chloro-3-(2-fluorophenyl)-6-methoxybenzo[b]thiophene and 80 g of pyridine hydrochloride is heated at 190° C. for 7 hours, with stirring. Water (500 ml) is added to the cooled reaction mixture and the resulting suspension is extracted with ether (3 times). The combined etheral extracts are cooled with dilute hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated to afford 8.9 g of 7-chloro-6-hydroxy-3-(2-fluorophenyl)benzo[b]thiophene.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([C:15]2[C:16](F)=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:23]>>[NH2:23][C:16]1[C:15]([C:13]([C:11]2[N:10]=[CH:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:12]=2)=[O:14])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(c1cn(Cc2ccccc2)cn1)c1cccnc1F
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ncccc1C(=O)c1cn(Cc2ccccc2)cn1
Temperature: 160 °C
Yield: 30 %

Procedure:
A microwave vial was charged with (1-benzyl-1H-imidazol-4-yl)(2-fluoropyridin-3-yl)methanone (50 mg, 0.18 mmol) and a saturated aqueous solution of ammonium hydroxide (1 ml). The reaction mixture was heated under microwave irradiation at 160° C. for 25 minutes. The mixture was evaporated to dryness. The residue was and purified on silica gel by flash column chromatography to give the title compound as a solid (15 mg, 30% yield).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([N:13]2[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=[C:14]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[C:32]([C:33]#[N:34])=[C:31](Cl)[N:30]=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:26][C:27]1[C:32]([C:33]#[N:34])=[C:31]([NH:25][C@H:23]([C:14]2[N:13]([C@H:11]3[CH2:12][C@@H:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:10]3)[C:17]3[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=3[N:15]=2)[CH3:24])[N:30]=[CH:29][N:28]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 90 °C
Yield: 72.9 %

Procedure:
A mixture of (S)-1-[1-(cis-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamine (50 mg, 0.15 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (23 mg, 0.15 mmol) and DIPEA (0.13 mL, 0.74 mmol) in IPA (3 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the reaction mixture was concentrated in vacuo, dissolved in DCM and loaded onto an Isolute® SCX-2 cartridge which was washed with DCM then MeOH and then 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) to afford the title compound as a colourless glassy solid (50 mg, 75%). LCMS (Method B): RT 3.11 min [M+H]+ 458. 110185004
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:35])[CH2:15][NH:16][C:17](=[O:34])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:7]1.C1CCNCC1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>ClCCl>[C:46]([NH:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:35])[CH2:15][NH:16][C:17](=[O:34])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:8][CH2:7]1)(=[O:48])[CH3:47]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c(N)c2)CC1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(=O)Nc1cc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3NC(=O)OC(C)(C)C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.8 %

Procedure:
To a mixture of 1-(3-amino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (27 mg, 0.049 mmol), (piperidinomethyl)polystyrene (2.7 mmol/g, 60 mg, 0.15 mmol) and dichloromethane (2 mL) was added acetic anhydride (0.12 mmol) in dichloromethane (0.12 mL). The reaction mixture was stirred at room temperature for 3 h. The mixture was loaded onto Varian™ SCX column, and washed with CH3OH. Product was eluted off using 2 N NH3 in CH3OH and concentrated to give 1-(3-acetylamino-4-hydroxybenzyl)-4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (30 mg, quant.): ESI/MS m/e 590.4 (M++H, C29H37F2N5O6).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2>CN(C=O)C.CCN(CC)CC>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1/[C:8](=[CH:16]/[C:17]1[NH:18][CH:19]=[CH:20][C:21]=1[O:22][CH3:23])/[C:9](=[O:15])[NH:10]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCO)c21

Procedure:
Using Method D above, propargyl alcohol (43.9 mg, 0.78 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.31 mmol) (Starting Material 1 supra) using DPPFPdCl2 (12.8 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 42 mg, 46%).
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=[C:5]([C:7]#[N:8])[N:6]=1.C([Mg]Cl)(C)C.C([C:24]([O:26][CH2:27][CH3:28])=[O:25])#N>C1COCC1>[CH2:27]([O:26][C:24]([C:2]1[N:3]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:4]=[C:5]([C:7]#[N:8])[N:6]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)C#N
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C#N)cn1COCC[Si](C)(C)C
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 75.2 %

Procedure:
To a solution of 2-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbonitrile (0.55 g, 1.8 mmol) (as prepared in the previous step) in THF (6 mL) at −40° C. was added dropwise a solution of 2M i-PrMgCl in THF (1 mL). The reaction was allowed to stir for 10 min at −40° C. and then cooled to −78° C., and ethyl cyanoformate (0.3 g, 3.0 mmol) was added. The reaction allowed to attain RT and stirred for 1 h. The reaction was quenched with satd aq NH4Cl, diluted with EtOAc (20 mL) and washed with brine (2×20 mL), and the organic layer was dried over Na2SO4 and then concentrated. The title compound was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.40 g (74%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C13H21N3O3Si, 296.1 (M+H), found 296.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.Cl.[C:34](O)(=[O:36])C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH:34]=[O:36])[C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:20]([CH3:22])[CH3:21])=[CH:6][CH:7]=1
Reactant: CC(C)c1oc2cc(O)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1oc2c(C=O)c(O)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 3-(4-chlorophenyl)-7-hydroxy-2-isopropyl-chromen-4-one (12.48 g, 39.6 mmol) and hexamethylenetetramine (39.46 g, 0.28 mol) in acetic acid (250 ml) is stirred at 100° C. for 20 h. After the mixture has cooled to room temperature, the solvent is removed in vacuo to afford a black oily residue. 5M HCl solution (150 ml) is added, and the mixture is heated under reflux for 30 min. The reaction mixture is poured onto ice/water, and the resulting brown solid is isolated by filtration. The solid is taken up in dichloromethane, the mixture is passed through a bed of Celite, and the solvent is evaporated in vacuo. The solid residue is stirred at room temperature with ethyl acetate, filtered and washed with hexane to afford the desired product as a pale brown solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4][CH:3]1C(OCC)=O.[OH-].[Na+].Cl>O1CCOCC1.O>[O:1]=[C:2]1[CH2:3][CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reaction time: 8 h
Yield: 77.4 %

Procedure:
To a solution 1-tert-butyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (429.1, 19.0 g, 66.6 mmol, 1.00 equiv) in 1,4-dioxane (190 mL) was added dropwise sodium hydroxide (4.00 g, 100 mmol, 1.50 equiv) in water (100 mL). The resulting mixture was stiffed at room temperature overnight. The pH was then adjusted to 4-5 with hydrogen chloride (aq. 3 M) and the resulting solution was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 2×10 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography using ethyl acetate/petroleum ether (1:3) as eluent to furnish 11.0 g (77%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18]Br)=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].O.C([O-])(O)=[O:22].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18][OH:22])=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CBr
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CO
Temperature: 50 °C
Reaction time: 72 h
Yield: 100.1 %

Procedure:
To a solution of compound 16A (102 mg, 0.30 mmol) in THF (12 mL) was added water (3 mL) dropwise. The reaction was kept at room temperature for 3 days and then heated to 50° C. for 3 hours. Upon cooling to room temperature, NaHCO3 (70 mg) was added to the reaction mixture. The reaction was concentrated to dryness, redissolved in CH2Cl2 and filtered. The filtrate was concentrated to give compound 16B as a yellow solid (84 mg, 100%). This compound was used in the following steps without further purification.
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[C:10](O)[CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:19].[OH-].[Na+]>>[Cl:19][C:10]1[CH:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[N:7]=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(C(F)(F)F)nc(C2CCCC2)n1
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1cc(Cl)nc(C2CCCC2)n1
Temperature: 75 °C
Yield: 88.5 %

Procedure:
2-Cyclopentyl-6-(trifluoromethyl)pyrimidin-4-ol (2.2 g, 9.47 mmol) was suspended in POCl3 (8.8 ml, 94.7 mmol) and heated to 75° C. for 2 h. After this time, the mixture was added to a chilled sodium hydroxide solution (1 M) and then extracted with ethyl acetate. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (2.1 g, 90%) as a clear oil. MW=250.65. 1H NMR (CDCl3, 500 MHz) δ 7.46 (s, 1H), 3.42 (quin, J=8.2 Hz, 1H), 2.18-2.07 (m, 2H), 1.99-1.80 (m, 4H), 1.76-1.66 (m, 2H); APCI MS m/z 251 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[CH:14]=[C:15]([C:25]([F:28])([F:27])[F:26])[C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:5]([O:4][C:2]([N:22]1[CH2:23][CH2:24][N:19]([C:16]2[C:15]([C:25]([F:28])([F:26])[F:27])=[CH:14][C:13]([Br:12])=[CH:18][N:17]=2)[CH2:20][CH2:21]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: FC(F)(F)c1cc(Br)cnc1N1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(c2ncc(Br)cc2C(F)(F)F)CC1
Temperature: 0 °C

Procedure:
Benzyl chloroformate (806 μL, 5.7 mmol, Aldrich) was added dropwise to a mixture of 1-(5-bromo-3-trifluoromethyl-pyridin-2-yl)-piperazine (1.6 g, 5.2 mmol, Example 112a) and diisopropylethylamine (1.1 mL, 6.24 mmol, Aldrich) in dichloromethane (35 mL) with stirring at 0° C. The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (2%-100% EtOAc/hexane) to give the title compound as an orange oil. MS (ESI, positive ion) m/z: 444 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:26]([CH3:27])=[CH:25][S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1csc2nc(-c3cccnc3)nc(NCc3ccc(Cl)c(Cl)c3)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:9]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+].O.Cl>O1CCOCC1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:8]2[N:9]([CH2:11][C:12]3[CH:16]=[C:15]([C:17]4[S:18][C:19]([Cl:22])=[CH:20][CH:21]=4)[O:14][N:13]=3)[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cn(Cc2cc(-c3ccc(Cl)s3)on2)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cn(Cc2cc(-c3ccc(Cl)s3)on2)c(-c2ccc(Cl)cc2)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
480 mg (1.1 mg) of 2-(4-Chloro-phenyl)-1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-imidazole-4-carboxylic acid ethyl ester was dissolved in 10 ml of dioxan and 10 ml of 2 N aqueous NaOH was added. The solution was stirred at 60° C. for 3 h. The solution was poured into water and the pH was adjusted to 3 by the addition of 2 N aqueous HCl. The precipitated product was filtered off and dried. Yield: 258 mg; MS (LCMS-ES+): m/e=420.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH:24]([CH3:26])[CH3:25])=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
A solution of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in N,N-dimethylformamide (5 mL) was treated with potassium carbonate (698 mg, 5.05 mmol). The reaction was stirred at 25° C. for 15 min and then was treated with 2-iodopropane (0.30 mL, 3.03 mmol). This mixture was heated at 65° C. for 20 h. At this time, the reaction was cooled to 25° C., quenched with water (5 mL), and then partitioned between water (50 mL) and ethyl acetate (50 mL). This mixture was treated with a saturated aqueous sodium chloride solution (1×25 mL), shaken, and separated. The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/1 hexanes/ethyl acetate) afforded 1-(6-chloro-1-isopropyl-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (483 mg, 83%) as a pale pink solid: mp 94-96° C.; EI-HRMS m/e calcd for C13H11ClF3NO (M+) 289.0481, found 289.0482.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.O>[C:26]([Si:23]([O:22][CH2:21][CH2:20][O:12][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:25])[CH3:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 51.8 %

Procedure:
Step B To a solution of 3-methoxy-4-nitrophenol (1 g, 5.9 mmol) in anhydrous DMF (25 mL) were added K2CO3 (2.45 g, 17.7 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.7 g, 7.1 mmol) sequentially. The reaction mixture was heated at 70° C. for 20 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (0-20% EtOAc in hexanes) to give tert-butyl-[2-(3-methoxy-4-nitro-phenoxy)-ethoxy]-dimethyl-silane as a light yellow oil (1.0 g, 52%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])[CH:2]=[CH2:3].C(N(CC)CC)C.[Cl-].[Ca+2].[Cl-].Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1>[CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(Br)ccc1O
Reactant: C[Si](C)(C)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCc1cc(Br)ccc1O[Si](C)(C)C
Temperature: 2.5 °C
Reaction time: 6 h

Procedure:
21.3 g (100 mmol) of 2-allyl-4-bromophenol, 12.1 g (120 mmol) of triethylamine (hereinafter referred to as “TEA”), and 120 ml of distilled tetra hydrofuran (hereinafter referred to as “THF”) were loaded into a 300-ml four-necked flask equipped with a reflux pipe with a calcium chloride dry pipe, a dropping funnel, a nitrogen gas introducing pipe, and a mechanical stirring device. The mixture was placed under nitrogen, and was stirred at 0 to 5° C. During the stirring, 11.0 g (120 mmol) of chlorotrimethylsilane were slowly added to the mixture from the dropping funnel. After the completion of the dropping, the resultant was subjected to a reaction at the temperature for 1 hour and then at room temperature for 6 hours. After that, the solvent, excessive trimethylamine, and excessive chlorotrimethylsilane were removed by condensation under reduced pressure, and the residue was washed with water and dried. Thus, 2-allyl-4-bromo-1-trimethylsiloxybenzene was quantitatively obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:52][CH3:53])=[N:15][CH:16]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3S(C3C=CC=CC=3)(=O)=O)=[C:21]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:48][CH2:47][N:46]([CH:49]([CH3:51])[CH3:50])[CH2:45][CH2:44]4)=[CH:40][N:41]=3)[CH:20]=2)[CH:18]=1)(=[O:11])=[O:10].[OH-].[Na+]>C(O)(C)C.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:52][CH3:53])=[N:15][CH:16]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[C:21]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:44][CH2:45][N:46]([CH:49]([CH3:50])[CH3:51])[CH2:47][CH2:48]4)=[CH:40][N:41]=3)[CH:20]=2)[CH:18]=1)(=[O:10])=[O:11]
Reactant: COc1ncc(-c2cc(-c3ncc(CN4CCN(C(C)C)CC4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Product: COc1ncc(-c2cc(-c3ncc(CN4CCN(C(C)C)CC4)o3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
2,4-Difluoro-N-[5-[4-(5-{[4-(1-methylethyl)-1-piperazinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]benzenesulfonamide (81 mg, 0.106 mmol) was suspended in isopropanol (2 ml) and 2M sodium hydroxide (aq) (0.53 ml, 1.060 mmol) was added. The reaction mixture was stirred at RT for 2 h, the solvent removed and the residue dissolved in water (1 ml) and acidified to pH˜6 by the addition of 2M hydrogen chloride (aq). The resultant suspension was extracted with dichloromethane (3×2 ml), the organic layer separated (hydrophobic frit) and concentrated in vacuo to give a brown solid which dissolved in MeOH:DMSO (1 ml, 1:1, v/v) and purified by MDAP (method H). The appropriate fractions were concentrated in vacuo to give the title compound as a white solid (45 mg).