Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C@H:11]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:12]1)=[O:10]>C(#N)C.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[OH:12][C@H:11]1[C:9](=[O:10])[NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][C@@H:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccccc1O)[C@@H]1O[C@H]1c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: O=C1Nc2ccccc2O[C@H](c2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
Scandium triflate (730 mg, 1.48 mmol) was added to a stirred suspension of (2R,3S)—N-(2-hydroxyphenyl)-3-phenyloxirane-2-carboxamide (64b) in dry acetonitrile (150 mL) under nitrogen. The mixture was stirred at ambient temperature for 24 hours then heated at reflux for an additional 1 hour. The solvent was evaporated, the residue dissolved in ethyl acetate, and filtered through diatomaceous earth. Evaporation afforded an off-white solid which was purified by flash chromatography on silica gel eluting with 10:1 (v/v) dichloromethane: ethyl acetate to afford the title compound (2.290 g, 60%) as a white solid. TLC Rf=0.20 (10:1 dichloromethane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ3.70 (d, 1H, J=5 Hz), 4.63 (m, 1H), 5.28 (d, 1H, J=10 Hz), 6.89 (m, 1H), 7.02-7.16 (m, 3H), 7.35-7.47 (m, 5H), 7.78 (br, 1H). MS APCI, m/z=256 (M+1). LC/MS: 1.84 min. [α]D 25=+288° (c=5.0, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]Cl)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:19][C:20]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:22]=2[C:23]#[N:24])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[NH:19][C:20]([C:25]([F:28])([F:26])[F:27])=[C:21]([S:9][C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[C:22]=2[C:23]#[N:24])=[CH:16][CH:17]=1
Reactant: ClSc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Sc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3,4-Dichlorophenylsulfenyl chloride (1.6 g, 7.49 mmol) is added to a solution of 2-(p-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile (2.02 g, 7.48 mmol) and triethylamine (1.67 g, 16.5 mmol) in methylene chloride. The reaction mixture is stirred at room temperature for 24 hours and concentrated in vacuo to obtain a residue. The residue is slurried in ethyl acetate and the resultant mixture is filtered to remove solids. The filtrate is diluted with hexanes to precipitate a solid which is collected and dried to give the title product as a cream colored solid (mp 94°-97° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C[C:15]1[N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[CH:17][C:16]=1[CH:26]=O.[C:28](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:26][C:16]3[C:17]([CH3:28])=[N:18][N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:15]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1c(C=O)cnn1-c1ccccc1
Reactant: Clc1nccnc1N1CCNCC1
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccc2)cc1CN1CCN(c2nccnc2Cl)CC1
Yield: 96.5 %

Procedure:
Stir together 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (2.00 g, 10.07 mmol) and 5-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (2.25 g, 12.08 mmol) in dry tetrahydrofuran (10 mL) at room temperature for 10 min., under nitrogen. Add sodium triacetoxyborohydride (3.20 g, 15.10 mmol) and stir reaction for 1 hr. Quench reaction mixture with saturated aq. sodium bicarbonate (30 mL), then extract with DCM (3×20 mL) and pass through an IST Phase Separator Frit®. Concentrate and purify (silica gel chromatography, eluting with 0:100 to 5:95 methanol:DCM). Concentrate and dry in vacuum oven to give the free base as a brown oil (3.585 g, 96.5%). MS (ES): m/z=369 [M+H]+.
Reaction SMILES: C(C1C=CC(C2SC=CC=2CO)=CC=1)C.OC1C=CC(CCC(OCC)=O)=C(F)C=1F.[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([C:40]2[S:41][CH:42]=[CH:43][C:44]=2[CH2:45][O:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][C:55]([O:57]CC)=[O:56])=[C:49]([F:60])[C:48]=2[F:61])=[CH:36][CH:35]=1)[CH3:33]>>[CH2:32]([C:34]1[CH:35]=[CH:36][C:37]([C:40]2[S:41][CH:42]=[CH:43][C:44]=2[CH2:45][O:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][C:55]([OH:57])=[O:56])=[C:49]([F:60])[C:48]=2[F:61])=[CH:38][CH:39]=1)[CH3:33]
Reactant: CCOC(=O)CCc1ccc(OCc2ccsc2-c2ccc(CC)cc2)c(F)c1F
Agent: CCOC(=O)CCc1ccc(O)c(F)c1F
Agent: CCc1ccc(-c2sccc2CO)cc1
Product: CCc1ccc(-c2sccc2COc2ccc(CCC(=O)O)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 208 by coupling of (2-(4-ethylphenyl)thiophen-3-yl)methanol and ethyl 3-(4-hydroxy-2,3-difluoro phenyl)propanoate followed by hydrolysis of ethyl 3-(4-((2-(4-ethylphenyl)thiophen-3-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=7.1 Hz, 2H), 7.25 (m, 4H), 6.82 (t, J=6.5 Hz, 1H), 6.66 (t, J=6.5 Hz, 1H), 5.10 (s, 2H), 2.95 (t, J=7.5 Hz, 2H), 2.65 (t, J=7.0 Hz, 2H), 1.31 (t, J=9.5 Hz, 3H). LCMS (ESI, M/Z) for C22H20F2O3S: 403.1 (MH+).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH3:5].[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[C:7]([C:9](=[C:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:8]
Reactant: CCC(=O)CC
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C(CC)CC
Reaction time: 48 h
Yield: 50.8 %

Procedure:
A mixture of 473 g (5.5 mol) of 3-pentanone, 565 g (5 mol) of ethyl cyanoacetate, 60 g (1 mol) of acetic acid, 38.5 g (0.5 mol) of ammonium acetate and 500 ml of toluene was stirred and heated under a Dean-Stark trap for 7 hr. and then allowed to stand for 2 days at room temperature. The reaction mixture was washed three times with 1 l of water and concentrated on the rotary evaporator at a low temperature. The residue was distilled in vacuum to give 460 g of ethyl 2-cyano-3,3-diethylacrylate, bp 118°-120°/8 mm.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH2:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]=[C:33]=[O:34])[CH:27]=1)C>>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:33]([NH:32][C:28]4[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=4)[C:25]([OH:35])=[O:24])=[O:34])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(N)ccc32)cc1
Product: CC(C)(C)c1ccc(Cn2ccc3cc(NC(=O)Nc4cccc(C(=O)O)c4)ccc32)cc1

Procedure:
The title compound was prepared from 1-(4-tert-butylbenzyl)-1H-indol-5-amine and 3-isocyanato-benzoic acid ethyl ester following the procedure of Example 5: MS (ESI) m/z 442.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]([Si:14](OS(C(F)(F)F)(=O)=O)([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:14]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Place a 35% oil dispersion of KH (6 g) in a flask under nitrogen, rinse with 50 mL hexanes and dry under vacuum. Cool the solid suspension in 100 mL anhydrous DMF to 0° C. Add dropwise over 10 minutes a solution of 5-bromoindole (10.3 g, 52.5 mmol) in 25 mL DMF. Stir the mixture 1 hour at 0° C. then treat with triisopropylsilyltrifluoromethane sulfonate (32.2 g, 105.1 mmol). Remove the cooling bath and stir the reaction 72 hours before pouring into 500 mL water and extracting with EtOAc. Dilute the combined extracts with hexanes, wash with brine then dry over MgSO4. Concentration under vacuum and chromatograph on silica gel eluting with 1% EtOAc in hexanes to give 5-Bromo-1-triisopropylsilanyl-1H-indole as a colorless oil: 1H NMR (CDCl3) 7.73-7.72 (d, 1H), 7.36-7.34 (d, 1H), 7.24-7.23 (d, 1H), 7.21-7.19 (m, 1H), 6.55-6.54 (m, 1H), 1.72-1.61 (m, 3H), 1.13-1.10 (m, 18H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[O:36][CH3:37].C(#N)C>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][O:26][C:27]4[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=4[O:36][CH3:37])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Reactant: Clc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCN1CCN(c2n[nH]c3cc(Cl)ccc23)CC1
Yield: 23 %

Procedure:
A mixture of 6-chloro-[3-(1-piperazinyl)]-1H-indazole (2.1 g, 8.9 mmol, K2CO3 (1.5 g, 10.7 mmol), KI (100 mg), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (2.2 g, 9.8 mml) and acetonitrile (70 ml) was stirred at reflux for 48 hours under N2. The cooled reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The organic extract was washed with water, dried with MgSO4 and concentrated to yield 6.0 of a light yellow oil. The oil was purified by preparative HPLC (Waters Associates prep LC/System 500, employing 2 silica gel columns and 5.5% methanol/methylene chloride as eluent). Concentration of later fractions provided 1.6 g, of an off-white solid. This was combined with an additional sample (3.4 g total) and two consecutive recrystallizations from ethanol yielded 2.1 g (23%) of 1-[4-[2-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]ethoxy]-3-methoxy-phenyl]ethanone as an off-white solid, m.p.=154-156° C.
Reaction SMILES: Cl[C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[CH3:18][N:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1.[CH2:25]([O:32][CH2:33][CH2:34][OH:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[CH3:18][N:19]1[CH2:23][CH2:22][CH:21]([O:24][C:3](=[O:4])[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[O:35][CH2:34][CH2:33][O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20]1
Reactant: O=C(Cl)C(Cl)(c1ccccc1)c1ccccc1
Reactant: OCCOCc1ccccc1
Reactant: CN1CCC(O)C1
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)C(OCCOCc2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h
Yield: 53.8 %

Procedure:
A mixture of chlorodiphenylacetyl chloride (20 g), 1-methyl-3-pyrrolidinol (7.6 g), and pyridine (35 g) is kept at room temperature for two hours. After adding 45 g of 2-benzyloxyethanol, the mixture is refluxed gently for 18 hours. Excess pyridine and benzyloxyethanol are distilled off under reduced pressure, the residue is dissolved in ether and washed twice with water. The organic phase is dried over magnesium sulfate (MgSO4), filtered and the filtrate evaporated to dryness. Chromatography of the residue on the silica gel with ethyl acetate-hexane-triethylamine (50:50:1) as eluent affords 18 g of 1-methyl-3-[2,2-diphenyl-2-(2-benzyloxyethoxy)acetoxy]pyrrolidine as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[CH:11]=1.[C:18](=[O:21])([O-])[O-].[K+].[K+]>CN(C)P(=O)(N(C)C)N(C)C>[ClH:9].[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:14]1[CH:13]=[C:12]([Cl:17])[CH:11]=[C:10]([O:21][C:18]2[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=2)[CH:15]=1
Reactant: Clc1cc(Cl)cc(Cl)c1
Reactant: O=C([O-])[O-]
Reactant: Nc1cccc(O)c1
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cl
Product: Nc1cccc(Oc2cc(Cl)cc(Oc3cccc(N)c3)c2)c1
Yield: 94.7 %

Procedure:
32.7 g (0.3 mol) of 3-aminophenol, 18.2 g (0.1 mol) of 1,3,5-trichlorobenzene, 28 g (0.2 mol) of anhydrous potassium carbonate and 150 ml of hexamethylphosphoric triamide were charged in a flask equipped with a stirrer. The mixture was maintained at 180° to 190° C. for 24 hours under stirring while passing gaseous nitrogen through it to accomplish the condensation. Then the reaction mixture was treated according to the same procedure as described in Example 1 to obtain 34.4 g of 1,3-bis(3-aminophenoxy)-5-chlorobenzene hydrochloride (yield: 85.8%).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH:15]([OH:18])CO)[CH:11]=[C:10]([C:19]([NH:21][CH2:22][C:23]4[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=4[CH3:29])=[O:20])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1.O>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH:15]=[O:18])[CH:11]=[C:10]([C:19]([NH:21][CH2:22][C:23]4[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=4[CH3:29])=[O:20])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C(O)CO)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c(CNC(=O)c2cc(C=O)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a stirred solution of 1-cyclopentyl-6-(1,2-dihydroxyethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.6 g, 1.4 mmol) in 50% THF/Water (16 mL), was added NaIO4 (0.9 g, 4.2 mmol) at 0° C. and stirred at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure and water was added to it. Extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-formyl-1H-indazole-4-carboxamide (0.4 g, 72.1%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:19](O)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[OH:46][CH:47]1[CH2:50][NH:49][CH2:48]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:46][CH:47]1[CH2:50][N:49]([C:19]([C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:9]=2)=[O:20])[CH2:48]1
Reactant: OC1CNC1
Reactant: CCOC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(C(=O)N2CC(O)C2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 5-(ethoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (2.0 g, 7.0 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.7 g, 14 mmol), 1-hydroxybenzotriazole hydrate (1.1 g, 7.0 mmol), and CH2Cl2 (50 mL) were added 3-hydroxyazetidine hydrochloride (1.2 g, 10 mmol) and N,N-diisopropylethylamine (3.7 mL, 21 mmol). The mixture was stirred at room temperature for 5 h, and then washed with brine and aq. Na2CO3 solution, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column (0-10% MeOH/CH2Cl2) to afford a syrup. LC-MS: 340.4 [M+1]+; 1H NMR (400 MHz, CDCl3): 8.34 (t, 1H, J=1.6 Hz), 8.19 (t, 1H, J=1.6 Hz), 8.04 (t, 1H, J=1.6 Hz), 7.52 (d, 2H, J=8.4 Hz), 7.28 (d, 2H, J=8.4 Hz), 4.75 (bs, 1H), 4.50 (m, 2H), 4.41 (q, 2H, J=7.2 Hz), 4.25 (bs, 1H), 4.10 (bs, 1H), 2.82 (bs, 1H), 2.41 (s, 3H), 1.42 (t, 3H, J=7.2 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]#[N:21])=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26]Br.O>CCCCCC>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2([C:20]#[N:21])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrCCCCBr
Reactant: N#CCc1cn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: N#CC1(c2cn(Cc3ccccc3)c3ccccc23)CCCC1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (60%, 2.26 g, 56 mmol) was added a solution of 1-benzyl-1H-indol-3-ylacetonitrile (5.7 g, 22 mmol) and 1,4-dibrombutane (2.6 ml) in DMSO-ether (10 ml: 80 mL) dropwise and the mixture was stirred for 5 hours at 20° C. Water and hexane were added. Solid was collected by filtration and washed with water and hexane to give 1-(1-benzyl-1H-indol-3-yl)cyclopentanecarbonitrile (5.3 g). MS (ES): 301 (MH+).
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[CH:17]=2)[NH:12][N:11]=1
Reactant: Cc1ccncc1-c1cnc2c(c1)c(-c1nc3ccncc3[nH]1)nn2C1CCCCO1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccncc1-c1cnc2[nH]nc(-c3nc4ccncc4[nH]3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.3 %

Procedure:
To a solution of 3-(3H-imidazo[4,5-c]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (LIX) (0.110 g, 0.26 mmol) in dry DCM (5 mL) was added triethylsilane (0.104 mL, 0.65 mmol) followed by TFA (2.5 mL) and stirred at room temperature for 3 h under nitrogen. The solvent was evaporated under reduced pressure, the residue was taken up water (10 mL), and basified with concentrated NH4OH. The precipitates were filtered, washed by cold water and dried under vacuum at room temperature. The crude product was suspended in DCM (10 mL), sonicated briefly and then heated to boiling for 5 min. The solution was cooled to room temperature and the solids were filtered, washed with DCM and dried under vacuum at room temperature to produce 3-(3H-imidazo[4,5-c]pyridin-2-yl)-5-(4-methylpyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (29) as a white solid (37 mg, 0.11 mmol, 43% yield). 1H NMR (DMSO-d6) δ ppm 2.33 (s, 3H), 7.45 (d, J=4.78 Hz, 1H), 7.75 (bd, 1H), 8.43 (d, J=5.29 Hz, 1H), 8.54 (bs, 2H), 8.69-8.82 (m, 3H), 14.64 (s, 1H); ESIMS found for C18H13N7 m/z 328.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].[C:12]([NH:15][NH2:16])(=[O:14])[CH3:13]>C1COCC1>[C:12]([NH:15][NH:16][C:10]([NH:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[Cl:1])=[S:11])(=[O:14])[CH3:13]
Reactant: Cc1ccc(Cl)c(N=C=S)c1
Reactant: CC(=O)NN
Solvent: C1CCOC1
Product: CC(=O)NNC(=S)Nc1cc(C)ccc1Cl

Procedure:
One tenth mole, 18.3 g., of 2-chloro-5-methylphenylisothiocyanate and 11.0 g. (0.15 mole) of acetylhydrazine were refluxed for 7 hours in 500 ml. of THF. After cooling, the insoluble product was collected by filtration. The crude product was collected by filtration. The crude product was washed with water, filtered and dried. The yield was 25 g. of 1-acetyl-4-(2-chloro-5-methylphenyl)-3-thiosemicarbazide, m.p. about 145°-157°C.
Reaction SMILES: C[Si](C)(C)O[CH:4]=[CH:5][CH:6]=[CH2:7].[CH3:10][C:11](=[CH2:22])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[OH2:23]>C(C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1)C1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1>[CH3:22][C:11]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7][CH2:6][C:5](=[O:23])[CH2:4][CH2:10]1
Reactant: C=C(C)C(=O)OCc1ccccc1
Reactant: O
Reactant: C=CC=CO[Si](C)(C)C
Agent: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Product: CC1(C(=O)OCc2ccccc2)CCC(=O)CC1
Temperature: 200 °C
Reaction time: 8 h
Yield: 24.89 %

Procedure:
2-(Trimethylsilyloxybutadiene (6.46 g, 45.4 mmol), phenylmethyl 2-methyl-2-propenoate (8.00 g, 45.4 mmol), and 4,4′-methanediylbis[2,6-bis(1,1-dimethylethyl)phenol] (0.019 g, 0.045 mmol) were combined together in a 20.0 mL microwave vessel and heated to 200° C. for 300 mins. Sample recovered and removed from vessel using THF (˜3×10 mL). The solvent was removed under reduced pressure and the residual oil taken up in 10% 2N HCl/THF (100 mL) and stirred overnight. After this time a clear solution formed, which was diluted with water (50 mL), partitioned into DCM (2×100 mL) and the organic layers separated, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by FC over Silica (150 g: 5-10% EtOAc/iso-hex) to afford a clear oil. Confirmed by NMR to be phenylmethyl 1-methyl-4-oxocyclohexanecarboxylate (3.48 g, 11.30 mmol, 24.89% yield).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[NH2:18][C:19]1[CH:38]=[CH:37][C:22]([O:23][C:24]2[C:29]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[N:31]=3)=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=1.Cl[C:40]1[S:41][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[N:43][N:44]=1>>[C:45]1([C:42]2[S:41][C:40]([NH:18][C:19]3[CH:38]=[CH:37][C:22]([O:23][C:24]4[C:29]([C:30]5[CH:35]=[CH:34][N:33]=[C:32]([NH2:36])[N:31]=5)=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:21][CH:20]=3)=[N:44][N:43]=2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Reactant: Clc1nnc(-c2ccccc2)s1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: Nc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccccc4)s3)cc2)n1

Procedure:
A slurry of pyridinium p-toluenesulfonate (0.18 g, 0.72 mmol), 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine (0.100 g, 0.36 mmol), and 2-chloro-5-phenyl-1,3,4-thiadiazole (0.077 g, 0.39 mmol; prepared by method described in J. Med. Chem., 31:902 (1988)) was heated in 2 mL 2-BuOH in a sealed tube to 110° C. The reaction became dark brown and homogeneous. After 2 h the reaction was quenched with 1N NaOH and DCM. The aqueous layer was extracted 2×DCM, and the emulsified aqueous layer was filtered and rinsed with dichloromethane. The resulting solid was adsorbed onto silica gel from MeOH/DCM, dried, and purified by silica gel chromatography, 0-100% 90/10 DCM/MeOH in DCM to give 4-(2-(4-(5-phenyl-1,3,4-thiadiazol-2-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-amine as a white solid. MS m/z=440 [M+H]+. Calc'd for C23H17N7OS: 439.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10]#[N:11].O1CCO[CH:14]1[C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:10]#[N:11])=[CH:14][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][N:19]=2)[N:24]=1
Reactant: N#CCC(=O)c1ccccc1F
Reactant: Nc1cccnc1C1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cc2ncccc2nc1-c1ccccc1F
Temperature: 120 °C

Procedure:
3-(2-Fluorophenyl)-3-oxopropanenitrile (1.5 g, 9.2 mmol) and 2-(1,3-dioxolan-2-yl)-3-pyridinamine (1.68 g, 10.12 mmol) were dissolved in toluene (100 mL). To the mixture was added catalytic amount of p-TSA (300 mg) and the reaction flask equipped with Dean-Stark assembly was heated for 4 h at 120° C. After completion of reaction, the reaction mixture was treated with water and ethyl acetate. The organic layer was separated and the aqueous layer was back extracted with ethyl acetate. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a thick oily mass. The oily mass was then purified by silica gel column chromatography using 20% of ethyl acetate and hexane as eluent to give 2-(2-fluorophenyl)-1,5-naphthyridine-3-carbonitrile: 1H-NMR (CDCl3) δ: 7.2-7.0 (m, 3H), 7.8-7.4 (m, 3H), 8.4 (d, 1H), 9.1 (s, 1H).