Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:16][C:17]3[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=3[C:19]([O:21]C)=[O:20])[CH:13]=2)[CH2:8]1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][NH:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:16][C:17]3[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=3[C:19]([OH:21])=[O:20])[CH:13]=2)[CH2:8]1
Reactant: COC(=O)c1ccccc1Nc1ccc2c(c1)CC(NCc1ccc(Cl)c(Cl)c1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1Nc1ccc2c(c1)CC(NCc1ccc(Cl)c(Cl)c1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.5 %

Procedure:
Methyl 2-[2-(3,4-dichloro-benzylamino)-indan-5-ylamino]-benzoate (0.98 g) was dissolved in 20 mL 1:1 THF/MeOH, and this solution was treated with 9 mL 50% NaOH and stirred at room temperature for 24 hours. When the starting material was no longer observed by mass spec, the mixture was concentrated to remove the MeOH, extracted with diethyl ether, and the precipitate was collected by filtration and dried in vacuo overnight to give 2-[2-(3,4-dichlorobenzylamino)-indane-5-ylamino]-benzoic acid (0.09 g, 10% yield). MS (APCI) m/z 427.1 (M++1). CHN for (C23H20Cl2N2O2.1.85HCl) calc: C, 55.83, H, 4.45, N, 5.66; found: C, 55.45, H, 4.22, N, 5.50.
Reaction SMILES: [CH:1]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH:12]=O>CO.[Pd]>[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][NH:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(C=O)OC
Reactant: NC1CCCCCC1
Agent: [Pd]
Solvent: CO
Product: COC(CNC1CCCCCC1)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of cycloheptanamine (8.62 g) in methanol (20 mL) was added 2,2-dimethoxyacetaldehyde (11.49 mL) and the mixture stirred at room temperature for 5 h. Palladium on carbon 10% (1 g) was added and the mixture hydrogenated at 5 bar for 16 h. It was filtered and concentrated under vacuum to give N-(2,2-dimethoxyethyl)cycloheptanamine as an oil (15.26 g). 1H NMR (300 MHz, CDCl3) δ 4.47 (t, J=5.6 Hz, 1H), 3.39 (s, 6H), 2.73 (d, J=5.6 Hz, 2H), 2.67-2.55 (m, 1H), 1.90-1.25 (m, 12H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]([F:20])([F:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:12]([F:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]2[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=2)[CH:3]=1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: COc1nc(Cl)cc(NCC(F)(F)c2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCC(F)(F)c2ccccc2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Reaction time: 6 h
Yield: 105.7 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-(2,2-difluoro-2-phenyl-ethyl)-amine (0.19 g, 0.62 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [190 mg, 0.94 mmol, see Example 49(b), step 2], and Cs2CO3 (0.51 g, 1.6 mmol) in ethylene glycol dimethyl ether (10 mL) and water (2 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium (0) (36 mg, 0.03 mmol) at room temperature. After 6 h at 85° C., the mixture is diluted with water (15 mL), and extracted with EtOAc (2×20 mL). The extracts are dried (MgSO4), filtered, and concentrated. The residue is chromatographed on SiO2 eluting with 70% EtOAc in heptane to afford 2-{3-[6-(2,2-difluoro-2-phenyl-ethylamino)-2-methoxy-pyrimidin-4-yl]-phenyl}-2-methyl-propionic acid [0.28 g Example 67]. LCMS: RT=2.82 minutes; MS: 428 (M+H); 1H NMR (300 MHz, CDCl3) 9.6 (1H, s), 8 (1H, s), 7.81 (1H, d, J=7.5 Hz), 7.5-7.4 (7H, m), 6.4 (1H, s), 4.2-4 (2H, m), 3.96 (3H, s), 1.65 (6H, s). IC50=38 nM
Reaction SMILES: [CH3:1][C:2]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21])([CH3:17])[CH2:3][C:4]([C:13]([F:16])([F:15])[F:14])([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][C:6]#[CH:7].[N:27]1C=CC=CC=1.S(Cl)(Cl)=O>ClCCl>[CH3:1][C:2]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:27])=[O:21])([CH3:17])[CH2:3][C:4]([C:13]([F:16])([F:15])[F:14])([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][C:6]#[CH:7]
Reactant: c1ccncc1
Reactant: C#CCC(CC(C)(C)c1ccccc1C(=O)O)(O[Si](C)(C)C)C(F)(F)F
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C#CCC(CC(C)(C)c1ccccc1C(N)=O)(O[Si](C)(C)C)C(F)(F)F
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
To a solution of 2-(1,1-dimethyl-3-trifluoromethyl-3-trimethylsilanyloxyhex-5-ynyl)benzoic acid (246 mg, 0.64 mmol) in 5 mL of dichloromethane was added pyridine (77 μL, 0.96 mmol) followed by thionyl chloride (56 μL, 0.76 mmol). The reaction was stirred for 15 minutes then the volatiles were removed in vacuo. The crude acid chloride was treated with 7 M ammonia in 5.0 mL of MeOH. The mixture was stirred for 15 minutes then diluted with 75 mL of EtOAc, washed with two 25 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (12 g SiO2, hexanes to 1:1 hexanes:EtOAc) gave 2-(1,1-dimethyl-3-trifluoromethyl-3-trimethylsilanyloxyhex-5-ynyl)benzamide as a pale yellow solid (108 mg, 44%). MS (ES+) m/z 386 [M+H]+.
Reaction SMILES: C(=O)(O[CH2:10][C:11]1([Si](C)(C)C)[C:23]2[CH:22]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][C:14]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:15][CH:16]=2)NC1C=CC=CC=1.O.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:24]([C:21]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:15][CH:16]=3)[CH:11]([CH2:10][N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[C:23]=2[CH:22]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)c1ccc2c(c1)C(COC(=O)Nc1ccccc1)([Si](C)(C)C)c1cc(C(C)(C)C)ccc1-2
Reactant: C1CCNCC1
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)C(CN1CCCCC1)c1cc(C(C)(C)C)ccc1-2
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Piperidine Cleavage of 2,7-Di-tert-butyl-9-trimethylsilyl-9-fluorenylmethyl Carbanilate: A solution of 0.4 g of DT-Fmoc-analine in 8.0 mL of piperidine was stirred at room temperature for 22 hours. The mixture was poured into 50 mL of cold water and stirred for 10 minutes. The precipitate was removed by filtration, rinsed with water (2×5 mL), and dried in air to afford 0.30 g (100%) of crude N-(2,7-di-tert-butyl-9-fluorenylmethyl)piperidine as an off-white solid. Recrystallization from CH3OH--CHCl3 (2:1) gave 0.248 g (82.53%) of the pure amine as white crystals, m.p. 159°-160° C., identified by mixture melting point, and IR and NMR spectral comparison with a sample obtained by piperidine cleavage of DT-Fmoc-PCA.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].Br[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1>C(COC)OC.CCOCC>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: Sc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a slurry of sodium hydride (about 60% oil suspension, 397 mg) in dimethoxyethane (4 ml) was added a solution of 2-pyridinethiol (1.05 g) in dimethoxyethane (6 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the mixture was added tert-butyl 4-bromo-1-piperidinecarboxylate (2.74 g), and the mixture was refluxed for 2 hours. After cooling, the resulting suspension was diluted with ether and filtered through a pad of Celite. The filtrate was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; 14% ethyl acetate in n-hexane) to give the title compound (2.2 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.[N:15]#[C:16]Br.CC(C)=O.C(N(CC)CC)C>O>[O:13]=[C:12]1[CH:11]=[CH:10][C:9](=[O:14])[N:8]1[C:4]1[CH:3]=[C:2]([O:1][C:16]#[N:15])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C=CC(=O)N1c1cccc(O)c1
Reactant: N#CBr
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: N#COc1cccc(N2C(=O)C=CC2=O)c1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
A 34.05 gram portion of N-(3-hydroxyphenyl)maleimide (0.18 mole), 20.02 grams of cyanogen bromide (0.189 mole) and 300 milliliters of acetone were added to a reactor and maintained under a nitrogen atmosphere with stirring. The stirred solution was cooled to -10° C. then 18.31 grams of triethylamine (0.1809 mole) was added to the reactor over a fifteen minute (900 s) period and so as to maintain the reaction temperature at -5° to -4° C. After completion of the triethylamine addition, the reactor was maintained at -5° to -3° C. for an additional thirty minutes (1800 s), followed by addition of the reactor contents to 1500 milliliters of deionized water. After five minutes (300 s), the water and product mixture was multiply extracted with three 100 milliliter volumes of methylene chloride. The combined methylene chloride extract was washed with 500 milliliters of 0.05 percent aqueous hydrochloric acid followed by washing with 500 milliliters of deionized water then drying over anhydrous sodium sulfate. The dry methylene chloride extract was filtered and solvent removed by rotary evaporation under vacuum for 60 minutes at 60° C. 3-(2,5-dihydro-2,5-dioxo-1H-pyrrol-1-yl)phenyl cyanate (34.25 grams) was recovered in 88.9 percent yield as a light tan colored powder. Infrared spectrophotometric analysis of a film sample of the product confirmed the product structure (disappearance of phenolic hydroxyl absorbance, appearance of cyanate absorbance at 2232 and 2274 cm-1, maintenance of maleimide carbonyl absorbance at 1714 cm-1).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][CH3:10].[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:23][CH2:24][C:25]([OH:27])=O)=[CH:15][CH:14]=1>>[ClH:12].[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:23][CH2:24][C:25]([N:9]([C@@H:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]2[N:2]([CH3:1])[CH3:11])[CH3:10])=[O:27])=[CH:15][CH:14]=1
Reactant: CN[C@@H]1CCCC[C@H]1N(C)C
Reactant: O=C(O)COc1ccc(Cl)c2ccccc12
Product: CN(C)[C@@H]1CCCC[C@H]1N(C)C(=O)COc1ccc(Cl)c2ccccc12
Product: Cl

Procedure:
Starting with trans-2-dimethylamino-N-methylcyclohexanamine and [(4-chloro-1-naphthalenyl)oxy]acetic acid, the title compound, m.p. 135°-138° C., was prepared employing the method of Example 5.
Reaction SMILES: COC1C(OC)=CC2SC(/C=C/C#N)=CC=2C=1.[ClH:18].[OH:19][NH:20][C:21](=[NH:37])/[CH:22]=[CH:23]/[C:24]1[S:28][C:27]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:26]=2[CH:25]=1>>[ClH:18].[OH:19][NH:20][C:21](=[NH:37])[CH:22]=[CH:23][C:24]1[S:28][C:27]2[CH:29]=[C:30]([O:35][CH3:36])[C:31]([O:33][CH3:34])=[CH:32][C:26]=2[CH:25]=1
Reactant: COc1cc2cc(/C=C/C(=N)NO)sc2cc1OC
Agent: COc1cc2cc(/C=C/C#N)sc2cc1OC
Agent: Cl
Product: COc1cc2cc(C=CC(=N)NO)sc2cc1OC

Procedure:
Using the procedure described in Example 2 (E)-3-(5,6-dimethoxy-benzo[b]thiophene-2-yl)-2-propenenitrile was converted into (E)-N-hydroxy-3-(5,6-dimethoxy-benzo[b]thiophene-2-yl)-prop-2-eneimidamide hydrochloride, m.p. 188°-198° C. (decomp.).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][SH:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:24][C:2]2[N:3]=[N:4][CH:5]=[C:6]3[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=23)=[CH:19][CH:18]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: C=CCn1c(C)c(C)c2cnnc(SCc3ccc(Cl)cc3)c21
Yield: 70.6 %

Procedure:
The title compound was prepared as a yellow solid in 70.6% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 4-chlorophenylmethanethiol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH:8]=1)[OH:7].C(O)(=O)[CH:11]([CH2:13][C:14](O)=O)[OH:12].OS(O)(=O)=O>O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]2[C:8]=1[CH:14]=[CH:13][C:11](=[O:12])[O:7]2
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=C(O)CC(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(O)cc2oc(=O)ccc12
Temperature: 0 °C
Yield: 43.9 %

Procedure:
A mixture of 5-methylresorcin (25.0 g), malic acid (26.0 g) and conc.H2SO4 (55 ml) was gently heated with the gaseous development almost ceased. The reaction mixture was then poured with vigorous stirring into a mixture of water and ice (700 ml), and stirred until the gummy mass initially formed was completely dispersed. The precipitate was collected by filtration, washed with water and crystallized twice (Me2CO) producing 5-methyl-7-hydroxycoumarin (I; 15 g; m.p. 256° C.) ##STR4## free from the isomer 5-hydroxy-7-methylcoumarin (II). ##STR5##
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)#[N:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC1C=CC(/C=C2/C(=O)N(CCNC)C(=O)S/2)=CC=1)C>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[C:7]2/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][CH2:27][C:26]3[CH:29]=[CH:30][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)[C:5](=[O:20])[S:6]/2)=[CH:12][CH:13]=1)[CH3:19]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOc1ccc(/C=C2\SC(=O)N(CCNC)C2=O)cc1
Agent: [Na+]
Product: CCOc1ccc(/C=C2\SC(=O)N(CCNCc3ccc(C#N)cc3)C2=O)cc1

Procedure:
The title compound 23e was prepared from compound 76 (146 mg, 0.50 mmol), 4-cyanobenzaldehyde (37 μL, 0.50 mmol) and sodium triacetoxyborohydride (318 mg, 1.50 mmol) in a manner similar to that described for 23a in 69.0% (140 mg) yield as a light-yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:3])[CH3:2].[N:16](OC(C)(C)C)=O>C(O)(=O)C.O.C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:11]([C:12]([O:14][CH3:15])=[O:13])=[N:16]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)ON=O
Reactant: COC(=O)Cc1ccccc1NC(C)=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)c1nn(C(C)=O)c2ccccc12
Temperature: 90 °C
Yield: 85.2 %

Procedure:
Methyl (2-acetamidophenyl)acetate (24.3 g, 0.12 mol) and acetic anhydride (24.3 ml, 0.26 mmol) were dissolved in acetic acid (60 ml). To the resulting solution, tert-butyl nitrite (90% purity, 18.6 ml, 0.14 mol) was added dropwise over 20 minutes under stirring at 90° C. After completion of the dropwise addition, the reaction mixture was stirred at 90° C. for further 1 hour. The reaction mixture was cooled to room temperature and then, poured in water (500 ml), followed by stirring for 1 hour. The crystals thus precipitated were collected by filtration under reduced pressure and dissolved in chloroform. The chloroform solution was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent, whereby methyl 1-acetylindazole-3-carboxylate (22.3 g, 85%) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].I[CH3:14]>CN(C=O)C>[CH3:14][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[CH:3]1
Reactant: Cc1c[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(C)c2ccccc12
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a stirred solution of 3-methylindole (15.0 g, 114 mmole) in dry DMF (200 mL) was added NaH (60% dispersion in oil, 5.0 g, 125 mmole) in portions. Gas evolution was observed. The mixture was stirred for 30 min, then iodomethane (8 mL, 129 mmole) was added in one portion. The reaction became exothermic and was cooled in an ice bath. After 16 hr at RT, the reaction was concentrated under vacuum and the residue was taken up in ethyl acetate. The solution was washed with H2O then with brine, dried (MgSO4), and concentrated to dryness. Purification by short path distillation under vacuum (bp 88-92° C., 05 mmHg) gave the title compound (16.10 g, 97%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.13 (t, 1H), 7.06 (s, 1H), 7.00 (t, 1H), 3.71 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:13]([Cl:16])(=[O:15])[CH3:14]>CCO>[ClH:16].[CH2:13]([O:15][C:1](=[NH:2])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[CH3:14]
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: CC(=O)Cl
Solvent: CCO
Product: CCOC(=N)c1ccc(C(=O)OC)cc1
Product: Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 84.7 %

Procedure:
A 2 L, three-necked round bottomed flask equipped with a magnetic stir bar, a temperature probe, addition funnel and nitrogen inlet was charged with methyl 4-cyanobenzoate (100 g, 620 mmol). The methyl 4-cyanobenzoate was dissolved in EtOH (438 mL) and cooled in an ice bath to 0° C. Acetyl chloride (353 mL, 4960 mmol) was added dropwise into the stirring solution over a 2 h period during which time an exotherm from 0° C. to 21° C. was noted. The reaction flask was capped, sealed with Parafilm®, and allowed to stir at 23° C. for 18 h. the resulting white solid was collected by vacuum filtration and washed with EtOH. The filtrate was concentrated until it became turbid and was then cooled in an ice bath. The resulting precipitate was collected by vacuum filtration, rinsed with EtOH, and the filtrate treated as described to give another crop. The solids were dried to give the title compound as a white solid (128 g, 85%): 1H NMR (400 MHz, CDCI3) δ 12.85 (br s, 1H), 12.20 (br s, 1H), 8.49 (m, 2H), 8.23 (m, 2H), 5.00 (q, 2H), 4.00 (s, 3H), 1.72 (t, 3H).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([OH:25])[C:14]=2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29]([O:35][CH3:36])[N:28]=1.Cl>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH3:36][O:35][C:29]1[N:28]=[C:27]([O:25][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:14]=2[C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH:32]=[C:31]([O:33][CH3:34])[N:30]=1
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: O=C(OCc1ccccc1)c1c(O)cccc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(Oc2cccc(-c3ccccc3)c2C(=O)OCc2ccccc2)nc(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
2.41 Grams of 60% sodium hydride in oil was suspended in 100 ml of N,N-dimethylformamide and to the suspension was added gradually 17.44 g of benzyl 6-phenylsalicylate dissolved in 50 ml of N,N-dimethylformamide. Then, the mixture was stirred at room temperature for 30 minutes. To the reaction system was added 10.01 g of 4-chloro-2,6-dimethoxypyrimidine in 50 ml of N,N-dimethylformamide and the reaction mixture was heated at 100°-110° C. with stirring for 3 hours. After cooling on standing, the reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer separated from the aqueous layer was washed with aqua. saturated sodium chloride solution three times and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue obtained was subjected to silica gel column chromatography (hexane/ethyl acetate (10:1-3:1, v/v) to obtain 21.55 g of benzyl 2-(2,6-dimethoxypyrimidine-4-yloxy)-6-phenylbenzoate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[F:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: NCc1ccccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccccc1CNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.5 %

Procedure:
To a magnetically stirred solution of 2,4-dichloro-5-fluoropyrimidine (0.105 g, 0.63 mmol) in anhydrous THF (5 mL) were added 2-fluorobenzylamine (0.085 g, 0.68 mmol) and triethylamine (0.127 g, 1.26 mmol), and the mixture was warmed to reflux and stirred for 5 h. The reaction mixture was cooled to room temperature and partitioned between CH2Cl2 (15 mL) and 1 N HCl (10 mL). The phases were separated and the aqueous phase was extracted with additional CH2Cl2 (15 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and filtered. The solvent was removed under reduced pressure to yield (2-chloro-5-fluoropyrimidin-4-yl)-(2-fluorobenzyl)amine (0.157 g, 97%) as a yellow solid: mp 117-118° C.; 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.45 (t, 1H), 7.35 (m, 1H), 7.15 (m, 2H), 5.60 (br s, 1H), 4.80 (d, 2H); ESIMS m/z 256 ([M+H]+). Alternatively, 2-chloro-5-fluoropyrimidin-4-yl)-(2-fluorobenzyl)amine was prepared using methods known in the literature, such as Boebel, T. et al. U.S. Patent Application Publication 2010/0022538.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=1.C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:36]3[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[N:10]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CC(=O)O)c3)cc12
Yield: 66.8 %

Procedure:
To a mixture of 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (500 mg, 1.04 mmol) and 3-bromophenylacetic acid (268 mg, 1.25 mmol) in a 20 mL microwave reaction flask was added THF (3 mL), acetonitrile (3 mL) and sodium carbonate (3 mL, 1 N aqueous solution, 3 mmol). The mixture was bubbled with N2 for 1 min. dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) (73 mg, 10% mol) was added and the bubbling continued for another minute. The flask was sealed and irradiated with microwave in Emrys Optimizer at 120° C. for 20 min. The reaction mixture was partitioned between aqueous saturated sodium chloride and ethyl acetate (15 mL: 15 mL). The aqueous layer was extracted with ethyl acetate (10 mL×2). Normal work up of the combined organic layers and purification with flash chromatography on silsca gel using a gradient of methanol in dichloromethane yielded {3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid as a yellow solid (340 mg, 67% yield). MS: m/z 490 (M+H+).