Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=[C:6]([S:25][CH3:26])[C:3]=1[C:4]#[N:5].[NH2:27][NH2:28].CCN(C(C)C)C(C)C>C(O)C>[CH3:24][NH:23][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:27][NH:28]3)=[C:6]([S:25][CH3:26])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:13]=1
Reactant: NN
Reactant: CNc1nc(-c2cc(F)c(C#N)c(SC)c2)cc(N2CCOC[C@H]2C)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(-c2cc(SC)c3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C)n1
Temperature: 150 °C
Yield: 67.9 %

Procedure:
A 2-mL microwave vial was charged with 2-fluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-6-(methylthio)benzonitrile (40 mg, 0.107 mmol), hydrazine (0.037 mL, 0.643 mmol), Hunig's base (0.056 mL, 0.321 mmol) and ethanol (1.5 mL). The mixture was heated at 150° C. for 90 minutes in a microwave reactor. The reaction mixture was allowed to cool, and then concentrated. The resulting residue was dissolved in DMSO and purified by RP-HPLC (0-30% CH3CN in H2O, 0.1% TFA). The product fractions were pooled, basified with NaHCO3, then extracted into EtOAc. The organic layer was dried, then concentrated to afford the title compound (28 mg) as an off-white solid. LC-MS (ES) m/z=386 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.19 (d, J=6.8 Hz, 3H), 2.61 (s, 3H), 2.83 (d, J=4.3 Hz, 3H), 3.04-3.22 (m, 1H), 3.40-3.52 (m, 1H), 3.55-3.66 (m, 1H), 3.67-3.79 (m, 1H), 3.85-3.99 (m, 1H), 4.05-4.23 (m, 1H), 4.44-4.59 (m, 1H), 5.10 (s, 2H), 6.38-6.71 (m, 2H), 7.26-7.49 (m, 1H), 7.66-7.88 (m, 1H), 11.62-11.92 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.[F:20][C:21]([F:40])([F:39])[C:22]1[CH:23]=[C:24]([C:32]2[O:36][N:35]=[C:34]([CH2:37]Cl)[N:33]=2)[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1>>[F:40][C:21]([F:20])([F:39])[C:22]1[CH:23]=[C:24]([C:32]2[O:36][N:35]=[C:34]([CH2:37][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:3][CH:2]([CH3:19])[CH3:1])[N:33]=2)[CH:25]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:27]=1
Reactant: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Product: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 using 2-(2-methylpropyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 2H), 8.09 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 6.65 (s, 1H), 5.50 (s, 2H), 2.84 (d, J=7.1 Hz, 2H), 2.14 (m, 1H), 1.08 (d, J=6.6 Hz, 6H); MS (ES) m/z 561 (M+1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([SH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[C:28](=[O:41])[CH:29]=[C:30]([CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[O:31][CH:32]=1>CN(C=O)C.O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([S:13][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]3[C:28](=[O:41])[CH:29]=[C:30]([CH2:33][O:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][O:36]4)[O:31][CH:32]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=c1cc(COC2CCCCO2)occ1OCCCCCCCBr
Reactant: FC(F)(F)c1ccc2c(S)ccnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(COC2CCCCO2)occ1OCCCCCCCSc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Trifluoromethyl-4quinoline-thiol (320 mg, 1.4 mmol) was charged in a 50 mL round-bottomed flask equipped with a magnetic stirrer and under inert atmosphere. Anhydrous DMF (10 mL) and NaH 60% dispersion in oil (55 mg, 1.4 mmol) were successively added at 4° C. After 30 min a solution of 5-(7-bromo-heptyloxy)-2-(tetrahydro-pyran-2-yloxymethyl)-4H-pyran-4-one 4 (520 mg, 1.3 mmol) in DMF (6 mL) was added at room temperature. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was poured in 150 mL of H2O, extracted with EtOAc (3×80 mL). The organic layer was washed with brine (2×20 mL), dried over MgSO4, filtered and evaporated to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=95:5 to 98:2) to give 5-(7-(7-(trifluoromethyl)quinolin-4-ylthio)heptyloxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one EHT 8883 (310 mg, 43% yield) as an oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:35])=[CH2:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2].C1C(=O)N([Br:48])C(=O)C1>ClC1C=CC=CC=1>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([C:33]([CH2:35][Br:48])=[CH2:34])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)c1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Solvent: Clc1ccccc1
Product: C=C(CBr)c1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Temperature: 135 °C
Reaction time: 2 h

Procedure:
A mixture of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(prop-1-en-2-yl)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (intermediate AZ) (236 mg, 0.412 mmol) and NBS (110 mg, 0.618 mmol) in chlorobenzene (5 mL) was stirred at 135° C. for 2 h. The solids were filtered and washed with AcOEt. The organic portion was washed 1× with H2O and 1× with brine prior to drying over Na2SO4. Concentration and purification of the resulting residue by preparative TLC gave intermediate AZ (144 mg).
Reaction SMILES: [O:1]([CH:8]([C:11]1[S:15][C:14]([NH2:16])=[N:13][N:12]=1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(Cl)=[O:18]>C(OC(=O)C)C>[O:1]([CH:8]([C:11]1[S:15][C:14]([N:16]=[C:17]=[O:18])=[N:13][N:12]=1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCC(Oc1ccccc1)c1nnc(N)s1
Solvent: CCOC(C)=O
Product: CCC(Oc1ccccc1)c1nnc(N=C=O)s1

Procedure:
The procedure of Example Ib was followed using 8 g. of the 5-(1-phenoxypropyl)-2-amino-1,3,4-thiadiazole (prepared above) and 100 ml. of ethylacetate saturated with phosgene. Topping and removing of the phosgene resulted in a glassy, orange residue of 5-(1-phenoxypropyl)-1,3,4-thiadiazol-2-yl isocyanate dimer (10.9 grams).
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9]OC(=O)CC(=O)C)[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].[SH:27][C:28]1[N:32]([CH3:33])[N:31]=[N:30][N:29]=1>O>[NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:27][C:28]3[N:32]([CH3:33])[N:31]=[N:30][N:29]=3)[CH2:7][S:8][C@H:3]12
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cn1nnnc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 60 °C
Yield: 82.3 %

Procedure:
In water (30 ml) were dissolved 7β-amino-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (3.14 g), sodium hydrogen carbonate (1.84 g) and 5-mercapto-1-methyl-1H-tetrazole (1.4 g) and the solution was adjusted its pH to 5.5, followed by stirring and heating at 60° C. for one hour. After cooling, the reaction solution was washed with dichloromethane (20 ml) and the aqueous layer was adjusted to pH 3.3, followed by stirring for one hour under ice-cooling. The resultant precipitates were collected by filtration and washed with water, methanol and acetone in this order, followed by drying to give 7β-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (2.7 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.O=[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CCO>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][C:13]1[CH:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:16][CH2:17][C:18]2=1
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1CCCc2c1[nH]c1ccc(OC)cc21
Temperature: 85 °C
Yield: 53.6 %

Procedure:
A mixture of 4-methoxyphenylhydrazine hydrochloride (50.0 mmol, 8.73 g) and ethyl 2-oxocyclohexaneacetate (50.0 mmol, 9.21 g) in absolute EtOH (25 ml) was heated at 85° C. for 1 h. After cooling to room temperature the mixture was filtered and the solvent was evaporated. Column chromatography (5% EtOAc in toluene) gave crystalline ethyl 6-methoxy-1,2,3,4-tetrahydrocarbazol-1-ylacetate (7.7 g, 53%).
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH3:20][S:21]SC>C(OCC)C.O>[C:1]([C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH2:14][S:21][CH3:20])[CH:11]=[CH:10][N:9]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSSC
Reactant: Cc1ccnc(NC(=O)C(C)(C)C)c1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CSCc1ccnc(NC(=O)C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of 2-tert-butylcarbonylamino-4-picoline (Step A, 250 mg) in anhydrous ethyl ether (5 mL) was cooled to -78° C. and treated with tert-butyllithium (1.7 mL, 1.7 M), and stirred at -78° C. for 3 hrs. To this was added dimethyl disulfide (0. 177 mL) and the reaction was allowed to warm to room temperature. The mixture was diluted with water and ethyl ether. The aqueous layer was extracted with ether. The combined organic layers were washed with saturated sodium chloride, dried over sodium sulfate, and concentrated in vacuo. The resulting oil was purified by medium pressure liquid chromatography on a 21×300 mm silica column eluted with 40% ethyl acetate/methylene chloride to afford the title compound (260 mg, lower Rf spot) and 2-tert-butylcarbonylamino-4-methylthiomethylpyridine (40 mg, higher Rf spot).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][Cl:39]>CN(C)C=O>[Cl:39][CH2:38][CH2:37][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:14][C:15]3[C:16]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=4)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: ClCCBr
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 453) (30 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (107 mg) and 1-bromo-2-chloroethane (0.03 ml) were added to the suspension, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (36 mg, yield 100%).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:45])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])=[CH:9][C:8]=1[F:44].[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:45])=[O:4])=[C:8]([F:44])[CH:9]=2)=[C:14]([CH3:43])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([OH:39])([C:35]([F:36])([F:37])[F:38])[C:31]([F:33])([F:34])[F:32])=[C:24]([CH3:40])[CH:23]=1)[CH2:41][CH3:42])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(F)c2)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.5 %

Procedure:
Methanol (1.5 mL) and a 1 N sodium hydroxide aqueous solution (0.200 mL, 0.200 mmol) were added to (4′-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-3-fluoro-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 78-(2); 30.1 mg, 0.050 mmol), and the mixture was stirred at room temperature for five hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, and then the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (chloroform/methanol=10/1) to give the title compound (15.6 mg, 52%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=O)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH2:19][NH2:20].CC(O)=O>CCO>[Cl:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:19][NH2:20])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NN
Reactant: O=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Solvent: CC(=O)O
Solvent: CCO
Product: NN=C(c1c(Cl)cnc2[nH]ccc12)C1CCCCC1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A mixture of (5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)(cyclohexyl)methanone (0.720 g, 2.74 mmol), anhydrous hydrazine (0.430 mL, 13.7 mmol) and AcOH (0.025 mL, 0.44 mmol) in EtOH (40 mL) was heated at reflux for about 20 h. During this time, water was removed from the reaction mixture via the use of a Dean-Stark trap. The reaction mixture was cooled to ambient temperature, the volatiles were removed under reduced pressure and the residue was partitioned between water (29 mL) and EtOAc (30 mL). The organic layer was dried over anhydrous MgSO4, filtered, and the solvent evaporated under reduced pressure. The crude material was purified by silica gel chromatography using a gradient of 10 to 50% EtOAc in heptane as the eluent to provide 5-chloro-4-(cyclohexyl(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine as an off-white solid (0.37 g, 48%); LC/MS (Table 2, Method o) Rt=2.22 min; MS m/z: 277 and 279 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[I:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1.Cl.[NH2:18][OH:19].CCO>O>[OH:19][NH:18][C:15](=[NH:16])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([I:7])[CH:9]=1
Reactant: NO
Reactant: N#CCc1cccc(I)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N=C(Cc1cccc(I)c1)NO
Temperature: 25 °C
Yield: 96.7 %

Procedure:
Add sodium carbonate (2.0 g, 18.5 mmol) to a mixture of 3-iodophenylacetonitrile (4.5 g, 18.5 mmol) and hydroxylamine hydrochloride (1.3 g, 18.5 mmol) in 10:1 EtOH:H2O (11 mL) Heat the reaction mixture to 50° C. for 2 days. Cool to RT, then filter to remove the solids. Concentrate the filtrate to afford the title compound (4.94 g). LC-MS (m/e): 277 (M+1).
Reaction SMILES: [CH:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]=1)=[O:2].[CH3:14][Mg]I>C1COCC1>[OH:2][CH:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]=1)[CH3:14]
Reactant: C[Mg]I
Reactant: O=Cc1cc(-c2ccccn2)no1
Solvent: C1CCOC1
Product: CC(O)c1cc(-c2ccccn2)no1
Reaction time: 1.5 h

Procedure:
To a mixture of 2-(5-formyl-isoxazol-3-yl)-pyridine (3 gm) in THF (30 ml) was added methyl magnesium iodide (19 ml, 1.4 M solution in THF) at 0° C. over a period of 15 minutes. The reaction was stirred for 1.5 h and monitored by TLC. The reaction was quenched by addition of aqueous ammonium chloride solution (20 ml) and extracted with ethyl acetate (100 ml×2). Combined organic layers was washed with water and evaporated under vacuum to provide 1.9 gm crude mass, which was purified by using silica gel column chromatography to provide a title compound in 1.0 gm quantity (42%) as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Yb+3:5].[CH3:6][CH:7]([CH3:9])[O-:8].[CH3:10][CH:11]([CH3:13])[O-:12].[CH3:14][O:15][CH2:16][CH2:17]O>>[CH3:1][CH:2]([CH3:4])[O-:3].[Yb+3:5].[CH3:6][CH:7]([CH3:9])[O-:8].[CH3:10][CH:11]([CH3:13])[O-:12].[CH3:14][O:15][CH:16]([CH3:17])[O-:3].[Yb+3:5].[CH3:14][O:15][CH:16]([CH3:17])[O-:3].[CH3:14][O:15][CH:16]([CH3:17])[O-:3]
Reactant: COCCO
Agent: CC(C)[O-]
Agent: [Yb+3]
Product: COC(C)[O-]

Procedure:
Ytterbium isopropoxide was synthesized using the method of Brown et al. A flask containing 4.85 g (15 mmole) of ytterbium isopropoxide was reacted with 50 ml of 2-methoxyethanol under an inert atmosphere. After refluxing for approximately 1 hour, two-thirds of the solution (isopropanol and 2-methoxyethanol) was removed by distillation. The flask was allowed to cool, and 20 ml of 2-methoxyethanol was added. The flask was refluxed for 1 hour, and ⅔ of the solution was then removed by distillation. This process of dilution, reflux, and distillation was repeated for a total of three cycles to ensure the complete exchange of the methoxyethoxide ligand for the isopropoxide ligand. It was estimated that this occurs when the boiling point of the solution reaches 124° C. The final concentration of the solution was adjusted to obtain a 0.5 M solution of ytterbium methoxyethoxide in 2-methoxyethanol. Coating solutions were prepared by reacting 1 part of a 1.0 molar solution of water in 2-methoxyethanol with 4 parts of the 0.5 M ytterbium methoxyethoxide solution.
Reaction SMILES: FC1C=C(S)C=CC=1.F[C:10]1[CH:11]=[C:12]([S:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[CH2:24][CH2:23][CH2:22]3)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1>>[C:12]1([S:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=[O:29])[CH2:24][CH2:23][CH2:22]3)(=[O:18])=[O:17])[CH:11]=[CH:10][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: Fc1cccc(S)c1
Product: O=C1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21

Procedure:
Similarly prepared using the above procedure with 3-fluoro-benzenethiol in step 4, was 6-(3-fluoro-benzenesulfonyl)-3,4-dihydro-2H-naphthalen-1-one. MS: 305 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([F:13])=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH3:14][CH:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[C:5]([F:13])=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH2:14][CH:15]([OH:16])[CH3:17])[CH:10]=[CH:9]2
Reactant: CC1CO1
Reactant: Fc1ccc2cc[nH]c2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(O)Cn1ccc2ccc(F)c(Cl)c21
Reaction time: 1 h
Yield: 77.8 %

Procedure:
A suspension of 45 mg of sodium hydride dispersion in 10 ml of tetrahydrofuran was treated with 0.2 g of 7-chloro-6-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.17 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 4 days and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 15 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.21 g (77.8%) of (RS)-1-(7-chloro-6-fluoro-indol-1-yl)-propan-2-ol as white crystals with m.p. 85°-87°.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[N:11][CH:12]=1.[CH3:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1.[Cl-].[NH4+]>C(OCC)C.C1COCC1.CCOC(C)=O>[Si:15]([C:14]#[C:13][C:10]1[N:11]=[CH:12][C:7]([C:26]2([OH:29])[CH2:27][CH2:28][CH:23]([CH3:22])[CH2:24][CH2:25]2)=[CH:8][CH:9]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ccc(Br)cn1
Reactant: CC1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1CCC(O)(c2ccc(C#C[Si](C)(C)C(C)(C)C)nc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
9.5 mL (16.19 mmol) of n-BuLi (1.6 M in THF) was slowly added under argon at −70° C. to a solution of 4.50 g (15.19 mmol) of 5-bromo-2-[(tert-butyldimethylsilanyl)ethynyl]pyridine in 50 mL of diethyl ether and 60 mL of THF and after the addition had ended the mixture was stirred for another 2 minutes. 1.86 mL (15.19 mmol) of 4-methylcyclohexanone was added and the mixture was slowly heated to RT. 150 mL of saturated aqueous ammonium chloride solution were added and the aqueous phase was exhaustively extracted with EtOAc. The combined organic extracts were with washed with semisaturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated down in vacuo. The residue was purified by chromatography (silica gel, PE/EtOAc 4:1). 2 fractions were isolated. Fraction 1: cis-1-{6-[(tert-butyldimethylsilanyl)ethynyl]pyridin-3-yl}-4-methylcyclohexanol; yield: 1.40 g (28% of theoretical); C20H31NOSi (M=329.552); calc.: molpeak (M+H)+: 330; found: molpeak (M+H)+: 330; Rf value: 0.40 (silica gel, PE/EtOAc 4:1). Fraction 2: trans-1-{6-[(tert-butyldimethylsilanyl)ethynyl]pyridin-3-yl}-4-methylcyclohexanol; yield: 1.00 g (20% of theoretical); C20H31NOSi (M=329.552); calc.: molpeak (M+H)+: 330; found: molpeak (M+H)+: 330; Rf value: 0.30 (silica gel, PE/EtOAc 4:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH:11]([CH3:13])[CH3:12])[N:9]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:23][N:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]=[C:25]1S(C)(=O)=O.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH:11]([CH3:13])[CH3:12])[N:9]=[C:8]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:25]4[N:24]([CH3:23])[C:28]5=[N:29][CH:30]=[CH:31][CH:32]=[C:27]5[N:26]=4)=[CH:18][CH:19]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CC(C)n1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1nc(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.2 %

Procedure:
To a stirred solution of 4-[6-fluoro-1-(1-methylethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl]phenol (76 mg) in DMF (4 mL) was added NaH (60% in oil, 11.2 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (59.2 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (60.0 mg).