Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[CH:7]=1.[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:11][C:12]([F:23])([F:24])[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[N:9][N:10]=3)[CH:7]=2)=[CH:16][CH:15]=1
Reactant: Brc1ccc2nncn2c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(-c2ccc3nncn3c2)cc1
Temperature: 150 °C
Yield: 43 %

Procedure:
In a 5 mL vial 6-bromo-[1,2,4]triazolo[4,3-a]pyridine (93 mg), 4-trifluoromethoxyphenylboronic acid (115 mg), and potassium carbonate (187 mg) were suspended in DMF (2 mL) that was previously degassed with nitrogen. Tetrakis(triphenylphosphine) palladium (20 mg) was added and the reaction mixture was heated in a microwave reactor at 150° C. for 30 min, filtered, and concentrated. The residue was subjected to gradient chromatography (MeOH/dichloromethane) to produce white powder, 56.4 mg (43% yield).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])[NH2:2].O=[C:12]([CH3:19])[CH2:13][C:14](OCC)=[O:15]>CCO.CC(O)=O>[OH:15][C:14]1[N:1]([C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][N:10]=2)[N:2]=[C:12]([CH3:19])[CH:13]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccnc(NN)c1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(O)n(-c2cc(C#N)ccn2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A mixture of 2-hydrazinylisonicotinonitrile (536 mg, 4 mmol, PREPARATION 2) and ethyl 3-oxobutanoate (780 mg, 6 mmol) in EtOH (10 mL) and AcOH (2 mL) was stirred at 90° C. overnight. The reaction mixture was cooled, concentrated, and purified by flash column chromatography (CH2Cl2) to afford the title compound (500 mg, 67%) as a yellow solid. [M+H] Calc'd for C10H8N4O, 201. Found, 201.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[C:54]([C:56]#[N:57])[CH:53]=[CH:52][C:51]=3[CH3:58])[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[C:54]([C:56]#[N:57])[CH:53]=[CH:52][C:51]=3[CH3:58])[N:48]=[CH:49][C:42]=12)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cc(C#N)ccc1C
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3-c2cc(C#N)ccc2C)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 37.4 %

Procedure:
Trimethylaluminium (2M in toluene) (0.472 mL, 0.94 mmol) was added to a solution of 5-methylpyridin-2-amine (102 mg, 0.94 mmol) in toluene (10 mL) at 0° C. under nitrogen in a microwave vial. The reaction mixture was stirred at 0° C. for 20 mins and then (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(5-cyano-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AM7) (300 mg, 0.47 mmol) was added. The reaction mixture was allowed to warm to room temperature and then heated in the microwave at 120° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and the concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water and DCM (50 mL). The organic layer was separated and the aqueous layer re-extracted with DCM (30 mL). The combined organics were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% Et2O in isohexane to afford the product (125 mg, 37.2%). 1H NMR (400 MHz, CDCl3) 0.99 (9H, s), 2.27 (3H, s), 2.29 (3H, s), 3.69-3.72 (2H, m), 3.81 (2H, t), 4.16-4.24 (2H, m), 6.07-6.09 (1H, m), 7.16-7.41 (6H, m), 7.51 (1H, s), 7.53 (1H, s), 7.63-7.65 (4H, m), 7.68-7.72 (2H, m), 8.08-8.08 (1H, m), 8.14 (1H, d), 8.37 (1H, s), 8.57 (1H, s), 8.67 (1H, s); m/z (ES+) (M+H)+=712.6; HPLC tR=3.65 min.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:47])[CH:6]([CH2:32][C:33]1[CH:34]=[N:35][C:36]([NH:39]C(OC(C)(C)C)=O)=[CH:37][CH:38]=1)[CH2:7][S:8][S:9][CH2:10][CH:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:12][C:13]1[CH:14]=[N:15][C:16]([NH:19]C(OC(C)(C)C)=O)=[CH:17][CH:18]=1)[CH3:3]>C(OC(=O)C)C>[CH2:30]([O:29][C:27](=[O:28])[CH:11]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([NH2:19])=[CH:17][CH:18]=1)[CH2:10][S:9][S:8][CH2:7][CH:6]([C:5]([O:4][CH2:2][CH3:3])=[O:47])[CH2:32][C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[CH:37][CH:38]=1)[CH3:31]
Reactant: CCOC(=O)C(CSSCC(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC)Cc1ccc(NC(=O)OC(C)(C)C)nc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSSCC(Cc1ccc(N)nc1)C(=O)OCC)Cc1ccc(N)nc1
Reaction time: 19 h
Yield: 98.4 %

Procedure:
Etylacetate saturated with HCl (g) (15 mL) was added to a solution of 3-[3-(6tert-butoxycarbonylamino-pyridin-3-yl)-2-ethoxycarbonyl-propyldisulfanyl]-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-propionic acid ethyl ester (130 mg, 0.191 mmol) in ethylacetate (7 mL) at 0° C. The reaction was allowed to attain room temperature and was stirred for 19 h, then evaporated under reduced pressure. The residue was dissolved in water, saturated aqueous Na2CO3 was added and the aqueous phase was extracted with CH2Cl2. The organic layer was dried and concentrated under reduced pressure to give the title compound (90 mg, 98%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:13]4[S:18][C:17]([CH2:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26]Cl)(=[O:23])=[O:22])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[C:13]4[S:18][C:17]([CH2:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)(=[O:23])=[O:22])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN(Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1cc2nc(-c3cccc4[nH]ccc34)nc(N3CCOCC3)c2s1)S(=O)(=O)CCCN1CCOCC1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
To a solution of 3-chloro-propane-1-sulfonic acid [2-(1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-methyl-amide (18 mg) in acetonitrile (1 mL) at room temperature was added morpholine (15 μL), potassium carbonate (7 mg) and potassium iodide (2 mg). The reaction mixture was stirred at 80° C. for 72 h and allowed to cool to room temperature before quenching with water (30 mL) and extracting into dichloromethane (2×30 mL). The combined organics were washed with brine (30 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give the title compound as an off-white solid (7 mg). NMR: CDCl3: 1.96 (m, 2H), 2.43-2.37 (m, 6H), 2.87 (s, 3H), 3.05 (m, 2H), 3.84 (t, J=4.8, 4H), 4.01 (t, J=4.8, 4H), 4.60 (s, 2H), 7.21-7.27 (m, 2H), 7.39 (s, 1H), 7.42-7.47 (m, 2H), 8.11 (d, J=7.2, 1H), 8.25 (s, 1H). MS: (ESI+): MH+ 571
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[CH:10][C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])=[C:4]2[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.O>C(O)C>[Cl:20][C:14]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:11]1[CH:10]=[N:9][N:5]2[C:6]([NH2:8])=[CH:7][C:2]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[N:3][C:4]=12
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)nc2c(Cc3cccc(Cl)c3Cl)cnn12
Solvent: O
Solvent: CCO
Product: Nc1cc(N2CCOCC2)nc2c(Cc3cccc(Cl)c3Cl)cnn12
Temperature: 150 °C
Reaction time: 3 h

Procedure:
5-chloro-3-[(2,3-dichlorophenyl)methyl]pyrazolo[1,5-a]pyrimidin-7-amine (1.7 g, 4.43 mmol) and morpholine (1.36 g, 15.6 mmol) were mixed in ethanol (10 mL) in a microwave tube. The reaction mixture was irradiated (microwave) and stirred at 150° C. for 3 hours. Reaction mixture was dropped into cold water (100 mL) to precipitate while stirring. Precipitate was collected by filtration. It was washed with water (10 mL) and dried. The titled product was obtained. (1.90 g, 97%); LC/MS: MS (ES+) m/e 378 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 3.43 (br. s., 1H) 3.45 (d, J=5.05 Hz, 3H) 3.63-3.71 (m, 4H) 4.00 (s, 2H) 5.55 (s, 1H) 7.16 (s, 2H) 7.22-7.30 (m, 1H) 7.30-7.40 (m, 1H) 7.46 (dd, J=7.83, 1.77 Hz, 1H) 7.72 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([NH:23][CH3:24])=[O:22].B(Br)(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([NH:23][CH3:24])=[O:22]
Reactant: CNC(=O)c1c(OC)ccc2cc(-c3cccc(OC)c3)ccc12
Agent: BrB(Br)Br
Product: CNC(=O)c1c(O)ccc2cc(-c3cccc(O)c3)ccc12
Yield: 95 %

Procedure:
The compound is prepared by reaction of 2-methoxy-6-(3-methoxyphenyl)-N-methyl-1-naphthamide (250 mg, 0.78 mmol, 1 eq) with boron tribromide solution (3.89 mmol, 5 eq) according to method G. Purification by column chromatography with dichloromethane/methanol 98/2 as the eluent yielded the desired product in a yield of 95%, 217 mg.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[O:15][CH3:16])=[C:5]([CH3:7])[N:6]=1.C([N:25]=[C:26]=[S:27])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:26]([NH2:25])=[S:27])=[CH:10][C:9]=2[O:15][CH3:16])=[C:5]([CH3:7])[N:6]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc(N)ccc1-c1sc(C)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(N)=S)ccc1-c1sc(C)nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 4-(2,4-dimethyl-thiazol-5-yl)-3-methoxy-phenylamine (100 mg, 0.43 mmol) in tetrahydrofurane (4 mL) was added drop wise under stirring and under an atmosphere benzoyl isothiocyanate (63.6 ul, 0.45 mmol). The reaction was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The residue was dissolved in methanol (6 mL) and a solution of potassium carbonate (177 mg, 1.28 mmol) in water (3 mL) was added. The resulting suspension was stirred at room temperature over night. The precipitate was filtered off, washed with water and diethyl ether to yield the title compound as a pale yellow solid (90 mg, 72%). MS ISP (m/e): 294.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.81 (s, 1H, NH), 7.35 (s, 1H), 7.21 (d, 1H), 7.01 (s, 1H), 3.76 (s, 3H), 2.59 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: N#N.C1(/[CH:9]=[C:10](/[C:12]2[O:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=2)\C)C=CC=CC=1.[OH2:22]>CC(C)=O>[C:10]([C:12]1[O:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1)(=[O:22])[CH3:9]
Reactant: CCOC(=O)c1coc(/C(C)=C/c2ccccc2)n1
Reactant: O
Agent: N#N
Solvent: CC(C)=O
Product: CCOC(=O)c1coc(C(C)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of NalO4 (23 g, 108 mmol) in water (150) mL was slowly added to a vigorously stirred suspension of silica gel (110 g) in acetone (500 mL). The mixture was then concentrated under reduced pressure and the lumpy solid slurried in CH2Cl2 and the solvent was evaporated under reduced pressure. CH2Cl2 (500 mL) was added and the reaction mixture was treated at rt with (E)-ethyl 2-(1-phenylprop-1-en-2-yl)oxazole-4-carboxylate (8.3 g, 32.5 mmol) and RuC1-3 hydrate (550 mg, 1.0 mmol). The reaction mixture was stirred at rt in the dark for 60 min, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:0→1:5 petroleum ether: Et2O) gave the title compound as a yellow solid. TLC:rf (1:1 EA-Hept)=0.52.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[O:31][C:32]=2[CH3:48])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2cccc(F)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3-fluoro-phenoxy)-3-(4-hydroxyphenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyloxazol-4-yl)-ethyl ester according to the method of Example 21.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][CH3:19])[N:4]=1.[C:20]1([CH3:46])[CH:25]=[CH:24][C:23]([C:26]([O:28][C@@H:29]2[C@@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)=[O:37])[O:32][C@H:31](Cl)[CH2:30]2)=[O:27])=[CH:22][CH:21]=1>CC#N.C(Cl)Cl>[Cl:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:31]2[O:32][C@H:33]([CH2:34][O:35][C:36]([C:38]3[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=3)=[O:37])[C@@H:29]([O:28][C:26]([C:23]3[CH:22]=[CH:21][C:20]([CH3:46])=[CH:25][CH:24]=3)=[O:27])[CH2:30]2)=[C:5]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][CH3:19])[N:4]=1
Reactant: CCCc1nccn1-c1nc(Cl)nc2nc[nH]c12
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: [Na]
Solvent: ClCCl
Solvent: CC#N
Product: CCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Yield: 94.7 %

Procedure:
This reaction was repeated on a larger scale with the sodium salt of 2-chloro-6-(2-propylimidazol-1-yl)purine (1.54 g, 5.87 mmol) in dried CH3CN (100 mL) treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (3.74 g, 9.62 mmol) in CH2Cl2 (100 mL) by general method 2 for 5 h (reaction complete, TLC). Sampling at different reaction times showed no α-nucleoside by 1H NMR (500 MHz). Volatiles were evaporated, and the residue was dissolved in CH2Cl2. The solution was washed (H2O) and dried (Na2SO4), and volatiles were evaporated in vacuo. The residue was chromatographed (EtOAc/hexanes, 1:1→7:3) to give 2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(2-propylimidazol-1-yl)purine (3.42 g, 95%). Recrystallization from EtOAc gave the β-anomer (2.75 g, 76%).
Reaction SMILES: [F:1][C:2]([F:19])([C:15]([F:18])([F:17])[F:16])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2.[Br:20]Br>C(OCC)(=O)C>[Br:20][CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([O:4][CH2:3][C:2]([F:19])([F:1])[C:15]([F:16])([F:17])[F:18])[CH:6]=2)[C:10]1=[O:14]
Reactant: BrBr
Reactant: O=C1CCc2cc(OCC(F)(F)C(F)(F)F)ccc21
Solvent: CCOC(C)=O
Product: O=C1c2ccc(OCC(F)(F)C(F)(F)F)cc2CC1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.9 g of 5-(2,2,3,3,3-pentafluoropropoxy)-1-indanone are dissolved in 100 ml of ethyl acetate, and a solution of 3.9 g of bromine in 15 ml of ethyl acetate is added dropwise. The solution is briefly heated to reflux before the remainder of the bromine solution is added dropwise. It is then stirred at room temperature for 2 h. The reaction solution is concentrated in vacuo and affords 2-bromo-5-(2,2,3,3,3-pentafluoropropoxy)-1-indanone as an oil which is employed without further purification in the next stage.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:16](=[O:21])[C:17]([O:19]C)=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[Li+].[OH-]>O.CO.O1CCCC1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([C:16](=[O:21])[C:17]([OH:19])=[O:18])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: COC(=O)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(C(=O)C(=O)O)cc(C(C)(C)C)c1O

Procedure:
3,5-Bis(1,1-dimethylethyl)-4-hydroxy-α-oxo-benzeneacetic acid, methyl ester (20.0 g, 68.4 mmol) and LiOH (3.2 g, 439.1 mmol) are combined in 125 mL of a water-methanol-tetrahydrofuran mixture (1:1:1). The reaction warms to ca 50° C. and is maintained at this temperature using a heating bath for 5 hours under nitrogen atmosphere. The reaction is poured onto ice water and extracted with diethyl ether (3×). The cold aqueous layer is acidified with aqueous 12N HCl and extracted with diethyl ether (3×). The combined ethereal layers from the second extraction are washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo to give an oil. Crystallizing from diethyl ether/pentane gives 14.0 g of a first crop (mp 125°-126° C.) and 2.7 g as a second crop (mp 124°-125.5° C.). The total yield is 16.7 g (19.0 g theor., 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12]1([CH:17]=O)[CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=CC1CCCC1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/C1CCCC1

Procedure:
In a manner similar to the method described in example 1a, 6-chlorooxindole (1.16 g, 6.59 mmol) was reacted with cyclopentanecarbaldehyde (0.77 g, 7.85 mmol) (Wiley) and piperidine (0.67 g, 7.85 mmol) in methanol to give a mixture of E- and Z-6-Chloro-3-cyclopentylmethylene-1,3-dihydro-indol-2-one as a brown oil (Yield 0.8 g, 49%).
Reaction SMILES: FC1C=C(C2CC(=O)C3C(=CC=C(O)C=3)O2)C=CC=1.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[C:28](=[O:30])[CH3:29].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH:34]=O>>[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH:34]1[CH2:29][C:28](=[O:30])[C:22]2[C:21](=[CH:26][CH:25]=[C:24]([OH:27])[CH:23]=2)[O:20]1
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: O=Cc1ccc(F)cc1F
Agent: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Product: O=C1CC(c2ccc(F)cc2F)Oc2ccc(O)cc21

Procedure:
2-(2,4-Difluorophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 1,6 ml of 2,4-difluorobenzaldehyde. 1H NMR (400 MHz, d6-DMSO) δ: 9.46 (s, 1H), 7.73 (m, 1H), 7.34 (m, 1H), 7.19 (m, 1H), 7.13 (d, 1H, J 2.9 Hz), 7.04 (dd, 1H, J 8.8, 2.9 Hz), 6.95 (d, 1H, J 8.8 Hz), 5.74 (dd, 1H, J 13.5, 2.8 Hz), 3.28 (dd, 1H, J −16.9, 13.5 Hz), 2.74 (dd, 1H, J −16.9, 2.8 Hz).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28][CH2:29][CH2:30]O)([CH3:21])[CH3:20])[C:13]3=[O:32])[C:9]([CH3:33])=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1.[CH2:36]([N:38](CC)CC)C.CS(Cl)(=O)=O.CN>C(Cl)Cl.C(O)C>[CH:1]1([NH:4][C:5](=[O:35])[C:6]2[CH:11]=[C:10]([N:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]([CH3:20])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28][CH2:29][CH2:30][NH:38][CH3:36])[CH3:21])[C:13]3=[O:32])[C:9]([CH3:33])=[C:8]([F:34])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2SCCO)c1=O
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: CCO
Solvent: ClCCl
Product: CNCCSc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)cc(F)c2C)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Cyclopropyl-3-fluoro-5-{3-[(1-{2-[(2-hydroxyethyl)sulfanyl]phenyl}-1-methylethyl)amino]-2-oxopyrazin-1(2H)-yl}-4-methylbenzamide (Example 320g, 0.15 g) was stirred in DCM (20 mL) and cooled to −40° C. before triethylamine (0.046 mL) and methanesulfonyl chloride (0.024 mL) were added. The reaction was warmed to room temperature and methylamine (40% in water) and ethanol (5 mL) were added. The reaction was then stirred for 18 h at 100° C. The reaction was concentrated in vacuo, then purified on SCX resin eluting with methanol (discarded) and flushing with 20% ammonia in methanol. The crude product was purified by preparative HPLC (Phenomenex Gemini column, eluent: 95-5% gradient of aqueous 0.2% aqueous ammonia in acetonitrile). The fractions containing the desired compound were evaporated to dryness to afford the title compound as a solid (3 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3S(C2C=CC=CC=2)(=O)=O)=[N:5][N:4]=1.CO.[C:37](=O)([O-])[O-:38].[K+].[K+]>>[NH:21]1[C:22]2[C:18](=[C:17]([C:15]3[CH:14]=[C:13]4[C:9]([CH:10]=[N:11][NH:12]4)=[C:8]([C:6]4[O:7][C:3]([CH2:2][O:38][CH3:37])=[N:4][N:5]=4)[CH:16]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCc1nnc(-c2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)o1
Temperature: 110 °C
Yield: 17 %

Procedure:
4-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (25 mg, 0.051 mmol) was placed in methanol (1.5 ml, 37.1 mmol) and potassium carbonate (7.05 mg, 0.051 mmol) added. The mixture was heated under microwave irradiation at 110° C. for 20 mins. The solvent was removed and the residue purified by Mass Directed Automated Preparative HPLC to give the title compound as a white solid (3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]#[CH:11])=[CH:4][CH:3]=1.C([Li])CCC.[F:21][C:22]([F:29])([F:28])[C:23](OCC)=[O:24]>O1CCCC1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]#[C:11][C:23](=[O:24])[C:22]([F:29])([F:28])[F:21])=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)CCOc1ccc(Cl)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C#CC(=O)C(F)(F)F)CCOc1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2.5 g (11.2 mmol) of 5-(4-chlorophenoxy)-3,3-dimethyl-1-pentyne in 25 ml of anhydrous tetrahydrofuran cooled to -78° C. under a nitrogen atmosphere is added 4.5 ml of 2.5M n-butyllithium in hexanes. The mixture is stirred at -78° C. for 1 hour and then is transferred by canula to a solution of 3.19 g (22.4 mmol) of ethyl trifluoroacetate in 10 ml of tetrahydrofuran cooled to -78° C. After the addition is complete, the reaction is stirred at -78° C. for 0.5 hour, is allowed to warm to 0° C. and then is quenched with saturated ammonium chloride followed by 0.1N hydrochloric acid. The layers are separated and the organic phase is washed with saturated sodium bicarbonate and brine. The organic extract is dried over magnesium sulfate, filtered and evaporated. The residue is subjected to flash chromatography on silica gel using hexane:ethyl ether (93:7) as eluting solvent. The appropriate fractions are combined and evaporated to give a light tan oil: IR (film) 2200, 1710 cm-1 ; NMR (CDCl3) δ1.42 (6H, s), 2.04 (2H, d, J=6.5 Hz), 4.1 (2H, t, J=6.6 Hz), 6.81 (2H, d, J=9.0 Hz), 7.23 (2H, d, J=9.0 Hz)